Introduction

Why is an understanding of sedation and analgesia important to the pediatric surgeon?

The alleviation of pain and anxiety is an important component of caring for an infant or child regardless of the underlying diagnosis or disorder. Children require sedation and analgesia as adjuncts to procedures and radiographic studies, to facilitate mechanical ventilation and to assist with postoperative care. The goals of sedation are to ensure the patient’s safety, minimize physical discomfort and pain, control anxiety, minimize psychological trauma and control behavior and movement [1]. Adequate sedation and analgesia also have benefits of reducing the stress response and catabolism associated with surgery [2]. The approach to sedation and analgesia management has implications for a child’s overall recovery. Specifically in the critical care setting, days requiring mechanical ventilation, intensive care unit length of stay, risk of nosocomial infections, unplanned extubation and the risk of withdrawal are all morbidities that are increased with prolonged or ineffective sedation regimens [3][4].

What are the challenging aspects of sedation and analgesia?

Data defining best practices for agents used in the treatment of pain and anxiety in the pediatric population are lacking. Hartman et al published a systematic review of pediatric sedation regimens used to facilitate mechanical ventilation in the pediatric intensive care unit (PICU). From the 39 studies that were included in the review, 39 different sedation algorithms and twenty different scoring systems were used to evaluate the level of sedation. Despite the longstanding use of sedative medications across many neonatal and pediatrics ICUs, this study highlighted the lack of consensus regarding the appropriate dosing, protocols for use, and associated safety [5].

The accurate assessment of pain and sedation is also difficult in pediatric patients due to the child’s inability to clearly express where and how much pain he/she is experiencing. Pain and sedation assessment tools help to quantify pain and discomfort and can aid health practitioners to optimize sedation and analgesia for their patients.

Withdrawal and tolerance are significant concerns in the child who has had a long inpatient stay - especially in the setting of mechanical ventilation. Tolerance and dose escalation occur with benzodiazepine and opioid infusions. The use of adjuvant agents can complement the effects of sedatives and analgesics to help reduce overall exposure or help diminish their side effects when tolerance and withdrawal develop [6].

What are the goals in providing sedation and analgesia?

The critical goals in providing sedation and analgesia are to:

• minimize pain
• control anxiety/behavior
• optimize patient safety
• minimize psychological trauma in order to decrease morbidity, hospital length of stay, days of mechanical ventilation, and overall exposure to sedatives and analgesics

The achievement of these goals, especially in the inpatient and long term care setting, is facilitated by the use treatment algorithms for sedation and analgesia. These protocols help to reduce the cumulative dose, duration and morbidity associated with sedative and analgesic use in any health care setting - be it outpatient, emergency department, periprocedural, postoperative, general inpatient or intensive care unit. Concerns regarding the long term effects of analgesic and anesthetic exposure have recently come to the forefront. Indeed, animal studies have demonstrating that opioids cause neuroapoptosis and neurodevelopmental abnormalities, while other reports have suggested that opioids increase apoptosis in human glial cells. As a result, the need to establish comprehensive sedation and analgesia protocols is essential to reduce potential developmental morbidity related to their use [7][8].

Several pediatric studies have demonstrated the profound impact of sedation on a child’s ICU course. For example, the RESTORE trial prospectively evaluated sedation-related adverse events among 22 PICUs. Inadequate pain or sedation management comprised 70% of the reported adverse events in mechanically ventilated patients [9]. In contrast, a randomized control trial by Randolph et al demonstrated that sedative use in the first 24 hours of weaning was associated with extubation failure and longer mean weaning times in infants and children [10]. Using multivariate analysis, Payen et al found that continuous intravenous sedation was an independent risk factor for prolonged mechanical ventilation [11].

Sedation regimens can also impact unplanned extubations. In this study, the institution of a sedation algorithm significantly reduced the incidence of unplanned extubations. Best practice recommendations for prevention included the establishment of a sedation protocol and a regular assessment of the level of sedation. Unfortunately, a specific algorithm or sedation assessment tool was not identified [12].

opioid stewardship

infographic from the Practicing Surgeons Curriculum (Steven Lee)

Basic Science

Analgesics

Opioids

Opioids are traditionally used for analgesia. The central nervous system (CNS) has four primary opioid receptors: μ, κ, δ, σ. Each receptor is found in varying concentrations in specific tissues within the CNS (spinal cord, brain, etc.), and there actions are both drug- and organ-specific. Each receptor class will produce some analgesic effect, but the degree of analgesia produced is directly proportional to the selectivity of any one agonist or antagonist for a specific receptor. Hence, drug, dose of drug and receptor activated will ultimately dictate function. Despite the fact that they all may be utilized for analgesic effects, they are also found in other tissues in the body, and the induced effects in these organs will mitigate their effectiveness and utility as pain relieving agents. Therefore, μ agonists are the most commonly used in pain management regimens secondary to their effectiveness, predictable actions in the CNS and elsewhere in the body. Opioids used in clinical medicine for the most part exert their effects as a sedative and analgesic via the µ pathway. Side effects include respiratory depression, nausea, vomiting, delayed gastric emptying, delayed intestinal motility, pruritus, constipation, miosis, tolerance and physical dependence. The elimination half life of opiates is prolonged in neonates due to reduced hepatic activity and blood flow. Symptoms of opioid withdrawal include cramping, vomiting, diarrhea, tachycardia, hypertension, diaphoresis, restlessness, insomnia, movement disorders, reversible neurologic abnormalities and seizures [2][13][14].

Nonopioids

Nonopioid medications include acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs). Nonopioid analgesics are beneficial since they complement the effects to opioids and do not cause respiratory depression, sedation, or tolerance. Acetaminophen has a central effect by inhibiting cyclo-oxygenase (COX) 3. It is safe for use in neonates and has significant analgesic properties. The main adverse effect of acetaminophen is hepatotoxicity at high doses [2][13].

NSAIDs are potent analgesics and have additional anti-inflammatory properties. Their clinical effect is achieved by blocking peripheral and central prostaglandin production by inhibiting COX 1, 2 and 3. Adverse effects include hepatotoxicity, platelet dysfunction, hematuria and gastrointestinal bleeding [13].

Sedatives

Benzodiazepines

Benzodiazepines act by augmenting the transmission of GABA (gamma amino butyric acid), an inhibitory neurotransmitter in the brain. Benzodiazepines have anxiolytic and amnestic properties, but do not have analgesic effects. Clinical effects include decreased cerebral metabolism and blood flow, sedation, hypnosis, anxiolysis, anticonvulsant activity, anterograde amnesia, muscle relaxation, and dose-dependent respiratory depression. The use of benzodiazepines without an opioid in the presence of a painful stimulus can cause hyperalgesia and agitation. Withdrawal symptoms include agitation, poor visual tracking, choreoathetoid and dyskinetic movements of the face, tongue, and limbs, as well as depressed consciousness [2][13].

Barbiturates

Barbiturates act by globally depressing the central nervous system with effects that range from sedation to anesthesia. They have no anxiolytic or analgesic properties. They are used as an adjunctive agent if tolerance to benzodiazepines and opioids develop. Barbiturates can produce idiosyncratic reactions in children including agitation, disorientation, and tantrums. Another effect of barbiturates is the depression of cerebral metabolism and blood flow making them useful in the treatment of elevated intracranial pressure secondary to traumatic head injury. Barbiturates can also cause cardiac depression and the continuous blood pressure monitoring is necessary during their administration [13].

α-2 agonists

α-2 agonists have sedative and analgesic properties and are used as adjuncts to traditional opioid and benzodiazepine therapy and in the management of opioid withdrawal. α-2 agonists activate the α-2 adrenergic receptors that mediate sedation, sleep, analgesia, sympatholysis, and vasoconstriction. There is minimal respiratory depressant effects with use [13].

Neuromuscular blocking agents

Neuromuscular blocking (NMB) agents provide muscle relaxation without sedation or analgesic effects. Adequate sedation and analgesia must be administered prior to the use of any NMB agent. They are divided into depolarizing and nondepolarizing agents.

The depolarizing agent succinylcholine acts by noncompetitive binding of the acetylcholine receptor at the motor end plate causing an interruption of nerve impulse transmission. Side effects include lethal hyperkalemia, severe bradycardia, myalgia and increased intracranial pressure [13].

Nondepolarizing agents competitively bind to postsynaptic nicotinic acetylcholine receptors. They do not cross the blood brain barrier. Over 80% of the receptors need to be occupied before any weakness or paralysis is achieved. There are several nondepolarizing agents available and each differs in their onset of action, duration of action, elimination and side effects. The degree of neuromuscular blockade from nondepolarizing agents is enhanced by hypercarbia, hypothermia, the use of high dose furosemide, magnesium, aminoglycosides, and in those patients with burn injuries[13].

see Medical Treatment for dosing and use

Assessment

Scales

What assessment tools are used to evaluate level of sedation and pain in children?

Wong-Baker FACES pain rating scale [13]

A six point descriptive and visual scale that patient’s use to self report their current level of pain and used for children ages three years and up. The faces depict progressive levels of pain.

• 6 point scale, score 0 to 10
• corresponding faces to number and description of level of pain from no pain – happy face (0) to worst pain- distraught, crying face (10)

Wong Baker faces scale

WAT-1 [15]

The Withdrawal Assessment Tool is an eleven item symptom assessment of opioid and benzodiazepine withdrawal focusing on motor, behavioral state, autonomic disturbances and gastrointestinal symptoms. WAT-1 has been studied and validated in a multicenter prospective trial by Franck and Curley.

• 12 point scale. Score 0 to 12
• Start scoring on first day of weaning, perform twice daily
• Score of 3 or higher had best sensitivity and specificity of clinically significant withdrawal, and should prompt assessment of weaning plan, with consideration of slowing wean if WAT-1 scores are consistently high.

Withdrawal Assessment Tool Version 1 [15]

Information from patient record in previous 12 hours	Score
any loose/watery stools (no = 0, yes = 1)
any vomiting/retching/gagging (no = 0, yes = 1)
temperature greater than 37.8°C
Two minute prestimulus observation
state (SBS ≤ 0 or asleep/awake/calm = 0, SBS ≥ +1 or awake/distressed = 1)
tremor (none/mild = 0, moderate/severe = 1)
any sweating (no = 0, yes = 1)
uncoordinated/repetitive movement (none/mild = 0, moderate/severe = 1)
yawning or sneezing (none or 1 = 0, ≥ 2 = 1)
One minute stimulus observation
startle to touch (none/mild = 0, moderate/severe = 1)
muscle tone (normal = 0, increased =1)
Poststimulus recovery
time to gain calm state with SBS ≤ 0 (< 2 min = 0, 2 to 5 min = 1, >5 min = 2)
Total score (0-12)

SBS[16]

The State Behavioral Scale is a sedation assessment instrument for infants and children on mechanical ventilation which is a description of the sedation-agitation continuum as measured by responses to voice, gentle touch and noxious stimuli.

State Behavioral Scale [16]

Score	Description	Definition
-3	unresponsive	no spontaneous respiratory effort no cough or coughs only when suctioning no response to noxious stimuli does not move
-2	responsive to noxious stimuli	spontaneous yet supported breathing coughs with suctioning responds to noxious stimuli occasional movement of limbs or shifting of position
-1	responsive to gentle touch or voice	spontaneous but ineffective nonsupported breaths coughs with suctioning/repositioning responds to touch/voice able to pay attention but drifts off after stimulation distresses with procedures able to calm with comforting touch or voice when stimulus removed
0	awake and able to calm	spontaneous and effective breathing coughs when repositioned/occasional spontaneous cough responds to voice/no external stimulus is required to elicit response spontaneously pays attention to care provider able to calm with comforting touch or voice when stimulus removed occasional movement of limbs or shifting of position
+1	restless and difficult to calm	spontaneous effective breathing/having difficulty breathing with ventilator responds to voice/no external stimulus is required to elicit response intermittently unsafe does not consistently calm despite five minute attempt restless, squirming
+2	agitated	may have difficulty breathing with ventilator coughing spontaneously no external stimulus required to elicit response spontaneously pays attention to care provider unsafe (biting endotracheal tube, pulling at catheters, can not be left alone) unable to console increased movement (restless, squirming, thrashing side to side, kicking legs)

FLACC[17][18]

Face, Legs, Activity, Cry, Consolability is a behavior and pain assessment scale validated for infants greater than 34 weeks. The five categories are evaluated and scaled 0 to 2 for each to give a summative score randing from 0 to 10. The higher the score, the more severe pain the infant is experiencing.

• pain scores 0 to 10
• mild 0 to 3, moderate 4 to 6, severe 7 to 10

FLACC behavioral and pain assessment tool [17]

Category	Description	Score (0 to 2)
face	0 - no particular expression or smile 1 - occasional grimace/frown, withdrawn or disinterested 2 - frequent/constant quivering chin, clenched jaw
legs	0 - Normal position or relaxed 1 – uneasy, restless, tense 2 – kicking or legs drawn up
activity	0 – lying quietly, normal position, moves easily 1 – squirming, shifting back and forth, tense 2 – arched, rigid or jerking
cry	0 – no cry 1 – moans or whimpers 2 – crying steadily, screams or sobs
consolability	0 – content and relaxed 1 – reassured by occasional touching,being talked to, distractible 2 – difficult to console or comfort

COMFORT-B [13][19]

The original COMFORT scale was validated as a measure for distress in ventilated pediatric intensive care unit patients using physiologic parameters in addition to behavioral categories. The COMFORT-B scale has been validated for ventilated and nonventilated patients.

• total score of 6 to 30
• score of 17 or higher correlates with pain and requires intervention.

COMFORT-B scale [19]

Score	Alertness	Agitation/ calmness	Respiratory response	Physical movement	Muscle tone	Facial tension	Heart rate	Mean arterial blood pressure
1	deeply asleep	calm	no cough or spontaneous respiration	no spontaneous movement	totally relaxed, no tone	totally relaxed	any observation low	any low observation
2	lightly asleep	slightly anxious	spontaneous respiration, minimal response to ventilator	occasional slight movement	reduced tone	normal tone, no tension	all 6 observations within baseline	all 6 observations within baseline
3	drowsy	anxious	occasional cough or resistance to ventilator	frequent, slight movement	normal tone	tension in some facial muscles	1 to 3 observations high	1 to 3 observations high
4	fully awake and alert	very anxious	actively breathes against ventilator	vigorous movement of extremities	increased tone with flexion of fingers/toes	tension throughout facial muscles	4 to 5 observations high	4 to 5 observations high
5	hyper-alert	panicky	fights ventilator, coughing or choking	vigorous movement including head/torso	extreme rigidity and flexion of fingers/toes	facial muscles contorted and grimacing	all 6 observations high	All 6 observations high

PIPP[18][20]

Premature Infant Pain Profile. A pain assessment tool validated for premature infants less than 34 weeks. Seven categories are assessed and given score of 0 to 3 for each. Seven categories include gestational age, behavioral state (ranging from active and awake to quietly asleep), maximum heart rate for 30 seconds, maximum oxygen saturation for 30 seconds and facial actions over 30 seconds (none to maximum - brow bulge, eye squeeze and naso-labial furrow). The higher the score, the more pain the infant is likely experiencing.

• Pain score 0 to 21
• None to minimal pain 0 to 6; slight to moderate 7 to 12; severe greater than 12

Medical Treatment

Medical Decision Making

What are the routine approaches used to provide analgesia in the postoperative patient?

Routine approaches for the management of postoperative pain depends upon the individual and type of procedure. A discussion occurs preoperatively with the patient, parents, and the anesthesiologist regarding the type of procedure and expected postoperative analgesic needs.

For invasive procedures or those patients in whom high doses of intravenous opioids are not desired, the use of regional anesthesia such as epidural catheters, paravertebral catheters, transversus abdominus plane blocks, and peripheral nerve catheters can be used as an adjunct.

The analgesic regimen should be given in the lowest effective dose to provide pain control. Usually this begins with intermittent dosing in intravenous form until the patient is able to tolerate enteral medications. If postoperative pain is expected to be significant, continuous intravenous opioids are administered via the patient controlled analgesia route with intermittent dosing. Nonopioid adjuncts such as etorolac can assist in postoperative analgesia.

How does one approach the patient with ongoing analgesia needs in terms of escalation of therapy?

Tolerance and dose escalation occur with benzodiazepine and opioid infusions. Providing optimal sedation and analgesia for prolonged durations can be challenging and require the significant escalation of infusions. Several strategies can be employed to counter this issue.

One is the use of adjuvant agents such as α2 agonists. For example, dexmedetomidine has been used to improve sedation and analgesia in critically ill children. This has been used in burn patients, children recovering from cardiac surgery, as well as the critically ill pediatric patient. Lam, et al., published a retrospective series to evaluate the hemodynamic effects and safety of dexmedetomidine in critically ill infants with congenital heart disease. This study demonstrated that dexmedetomidine infusion was safe from a hemodynamic standpoint and may aid in reducing vasopressors in children with catecholamine refractory shock. Although dexmedetomidine may cause a decrease in heart rate and mean arterial and central venous pressures, all of the children in this study remained hemodynamically stable without dose escalation of vasopressors [6].

What are the routine approaches used to provide sedation for the pediatric patient in the intensive care unit?

Management of sedation and analgesia in the intensive care unit (ICU) is patient dependent. However, having an algorithm for initiation, escalation, and de-escalation of treatment is important in providing effective sedation and analgesia as well as in reducing morbidity. Typically, intermittent dosing is first used with escalation to continuous infusions as needed. Frequent assessment for the adequacy of treatment and withdrawal are necessary.

see Complications regarding the use of daily sedation interruptions

How does one approach the difficult to sedate patient in terms of escalation of therapy?

Each individual patient has a variable response to sedation and analgesic medication, making it hard to develop absolute recommendations. The difficult to manage patient may be adequately treated by using an algorithmic approach that includes

1. continuous clinical assessments
2. incremental progression of medication
3. the potential use of adjuvant therapy and long acting agents. Escalation Algorithm

How should patients be weaned after exposure to sedation/analgesia?

For short term exposure, generally defined as less than five days, infusions may be stopped. Withdrawal assessment, such as WAT-1 scoring, should occur to assess and treat withdrawal if it occurs.

Long term sedation and analgesia of more than five days of infusions should be weaned via a systematic approach. Although there are no uniformly agreed upon weaning methods, the important aspects include frequent assessment with scoring systems such as the SBS for level of sedation and WAT-1 for withdrawal. A general approach is to reduce infusions by 25% if the SBS score is less than target and to begin WAT-1 scoring. In the periextubation period, adjuncts such as dexmedetomidine or propofol may bridge the patient through extubation while allowing for continued weaning of long term infusions. Once a patient is extubated, then a systematic wean by 10 to 20% of the total original dose should occur every eight to twelve hours as long as the WAT-1 is less than five. If the WAT-1 score is greater than five or the patient is unable to wean, then rescue doses are administered or consideration is given to adding a clonidine patch and/or transitioning to intermittent methadone and/or lorazepam. For patients with a WAT score of three, there is still a potential for withdrawal and it is prudent that the wean should be prolonged or that alternate medications should be weaned every twelve hours so that any one medication is reduced only 24 h [2][13]. Titration Algorithm

see Assessment for scoring scales

(for projects on decreasing opioid misuse see the Quality Improvemment toolkit on Opioid Stewardship)

Complications

Sedative and analgesic agents can have significant side effects that highlight the importance of monitoring during both the escalation and weaning phases.

Opioids can cause respiratory depression, hypotension and anaphylaxis. Additional side effects include pruritus, nausea, vomiting, constipation, urinary retention, cognitive impairment, tolerance, and dependence. Titrating the dose, stopping the agent, or administering an antidote may be necessary to treat the acute complications. Naloxone can be administered as a reversal agent for acute opioid induced respiratory depression. Importantly, the rapid administration of naloxone in cases of acute opioid intoxication also has side effects including pulmonary edema, seizures and pain. Naloxone may also be used as a low dose continuous infusion to treat opioid-induced side effects (e.g., pruritis) without affecting its analgesic properties [13].

Acute complications of specific agents include red man syndrome, seizures and chest wall rigidity: Morphine can cause vasodilation and red man syndrome from the release of histamine. It is also associated with seizures in newborns and in older patients at high doses. Fentanyl, when given quickly or in high doses, can cause chest wall rigidity that can impair the ability to ventilate. In these situations, treatment with muscle relaxant or naloxone and manual ventilation is required [13].

Benzodiazepines can cause hypotension and hypoventilation since they block the hypoxic and hypercarbic drive to breath in a dose dependant fashion. The effects of benzodiazepines on respiratory depression are also augmented by opioids. Flumazenil can be administered as the antidote for benzodiazepine induced respiratory depression. Dexmedetomidine can cause bradycardia, hypotension, and conduction defects. It is recommended to titrate the drug slowly as a continuous infusion [13].

What are the major complications associated with prolonged sedation?

All of the following morbidities are increased with prolonged or ineffective sedation regimens [3][4][9].

• inadequate sedation and pain management due to tolerance or inadequate administration of medications
• iatrogenic withdrawal
• unplanned extubation
• extubation failure
• ventilator-associated pneumonia
• pressure ulcers
• acquired neuromuscular disorders

How is tolerance manifested in pediatric patients and how is the associated dose escalation managed?

Tolerance represents receptor desensitization that results in decreasing clinical effectiveness after prolonged exposure due to upregulation of the cAMP pathway. The duration of therapy impacts the development of tolerance. Additionally, it is reported that infants exposed to opioids during the period of rapid brain development may develop long term tolerance. Shorter acting opioids can produce greater tolerance. Approaches to address tolerance include dose escalation, use of longer acting opioids such as methadone, or the addition of nonopioid analgesics such as dexmedetomidine or clonidine [3][15].

What is the concept behind daily sedation interruptions and how should they be incorporated into patient care?

Clinical practice guidelines, as developed by a multi-institutional task force within the American College of Critical Care Medicine, exist for the management of pain, agitation, and delirium in adult patients in the intensive care unit. A multidisciplinary approach to establish and use sedation and analgesia protocols is recommended in the intensive care unit (ICU). Specific recommendations include daily sedation interruption or a light target level of sedation for adult mechanically ventilated patients. Multiple randomized controlled trials in adults have shown the benefits of sedation holidays in decreasing ICU and hospital length of stay (LOS). Such guidelines do not exist in the pediatric population [28].

Numerous studies have suggested that sedation protocols and sedation scales are associated with shorter times on the mechanical ventilator, decreased ICU and hospital LOS, as well as decreased delirium and long term cognitive dysfunction [28]. Verlaat et al reported the results of a randomized controlled trial of sedative interruption in the pediatric population in which sedatives were stopped daily and restarted at the previously used infusion rate when the COMFORT-B score was greater than or equal to seventeen. This study resulted in decreased ventilator days, ICU length of stay, and lower use of morphine and midazolam doses in the intervention group [29]. Gupta et al also published a randomized control trial of interrupted versus continuous sedative infusions in ventilated children which examined the duration of mechanical ventilation, ICU LOS, days awake on sedative infusions, the frequency of adverse events, the total dose of sedatives, and effect on costs. The daily interruptions involved discontinuing the sedative infusion every morning until the patient became fully awake or agitated or uncomfortable. At that point, the infusion was restarted at 50% less than the previous dose, and titrated for sedation. The intervention began 48 hours after intubation. The significant findings in the intervention group were decreased days on mechanical ventilation, ICU LOS, and total cost of sedation. The percentage of awake days was also significantly increased. There was no significant difference in adverse events between groups, specifically with respect to unplanned extubations[30].

How much time does it take for a patient to become dependent on sedation/analgesia agents?

Dependence is the physiologic and biochemical adaptation of neurons such that removing a drug precipitates withdrawal. This generally occurs after two to three weeks of continuous use. Dependence and withdrawal can lead to significant morbidity in critically ill patients. Withdrawal is the clinical syndrome that develops after stopping or reversing a drug after prolonged exposure to that drug and generally occurs after five to seven days of use. Symptoms are evident within 24 hours of drug cessation and peak within 72 hours [13].

What is the effect of delirium upon patient care and outcome and how does one manage the patient with delirium?

Delirium is the acute disturbance of consciousness with inattention and a change in cognition or perceptual disturbance [31]. Delirium is common in adult intensive care units and there is extensive literature describing tools and measures to prevent and treat it. Benzodiazepines and opioids alter sleep patterns and shorten REM sleep which may contribute to the development of delirium [32]. The extensive use of sedatives and analgesics can have profound impacts on the overall morbidity of children. PAD (Pain, agitation and delirium) guidelines were created for adults in 2013 [31].

The SCCM currently has an ICU Liberation Collaborative for PAD implementation which includes a six-step approach called the ABCDEF bundle for adults. This includes

• Assessment and management of pain
• spontaneous Breathing and awakening trials
• Choice of sedation and analgesia with the goal of light sedation and use of arousal scales
• Delirium assessment, prevention, and management
• Early mobilization
• Family engagement

In the ABCDEF bundle guidelines, delirium should be treated by minimizing risk factors. Therefore, interventions that provide cognitive stimulation, orient the patient, establish sleep patterns, allow for early mobilization, remove devices as soon as able, limit noise, and establish pain protocols to effectively treat pain can all aid in treating and reducing delirium. The use of dexmedetomidine is advised over benzodiazepines given its limited effect on sleep patterns [31]. While the pediatric literature is not as robust, more attention is being given to delirium in the pediatric population. Daoud and colleagues performed a systematic review of delirium diagnoses in pediatric ICUs and found a prevalence of five to 28%. Delirium can increase morbidity, ICU length of stay, and hospital length of stay [33].

Van Tuijl and colleagues published a review on the management of pediatric delirium, deriving the data from both the adult and pediatric literature. In the pediatric population, delirium was most frequently infectious- and drug-related (especially opioids, steroids, propofol and ketamine). Other risk factors included age less than three years, males, pre-existing cognitive impairment, history of delirium, developmental delay, and family history or pre-existing emotional or behavioral problems. Additional environmental factors that might contribute to delirium were physical restraints, hospitalization, high noise levels, poor light, frequent staff changes, and lack of windows. Given these risk factors, it is important to try to provide an environment and implement management strategies that reduce these risks. Additionally, given the prevalence and potential morbidity, early detection and treatment are important. Van Tuijl and colleagues break down the management of delirium into three tiers:

1. Identifying and treating underlying causes
2. Implementing nonpharmacologic interventions
3. Considering pharmacologic therapies

Nonpharmacologic interventions address the environmental factors previously noted. Pharmacologic treatment is used to reduce agitation, psychosis, and to prevent harm and is mainly used for the treatment of hyperactive delirium. Haldoperidol is the most common medication used to treat agitation associated with delirium. Other atypical antipsychotics, such as risperidone, have limited data on its use in children [34].

What is the data that engenders concern around the use of sedating and anesthetizing agents in newborns, infants and young children?

The use of sedation algorithms and protocols are important to reduce the cumulative dose and duration of the medications used. The literature regarding the long term effects of analgesics and anesthetics in young children are garnering more concern. Other studies have suggested that opioids increase apoptosis in human glial cells. The data on the long term effects of exposure to sedation is conflicting. McCann and the GAS consortium performed an international randomized control trial to evaluate whether general anesthesia had an increased risk of poor neurodevelopmental outcome compared to spinal anesthesia. There was no increase in the risk of adverse outcome in this large study of over 360 infants based on neurodevelopmental assessment two years after exposure; the definitive results should be available after the five year assessment [35]. It is also unclear if it is repeated exposures or the cumulative dosage that is most associated with neurodevelopmental morbidity. There is a definite impetus to identify potential adverse neurological outcomes resulting from sedatives, analgesics, and anesthetic agent exposure. This information will drive the development of effective sedation and anesthetic protocols that should reduce morbidity [7][8].

What is malignant hyperthermia?

Malignant hyperthermia (MH) is a pharmoacogenetic disorder of skeletal muscle that is known to be triggered by flurane-based, volatile anesthetics and succinylcholine. It produces a profound hypermetabolic response with tachycardia, tachypnea, hyperthermia, acidosis, hyperkalemia, increased oxygen consumption and carbon dioxide production and muscle rigidity with rhabdomyolysis. If left untreated, it is fatal. Treatment is supportive and expectant focusing on resucitation, temperature control, dampening the hypermetabolic response and countering the effects of the defect in the ryanodine receptor in skeletal muscle with the administration of dantrolene in repeated doses every 15 minutes until the patient responds biochemically and physiologically. Response is demonstrated by the lessening of muscle rigidity on exam and normalization of hypercalcemia, hyperkalemia, vital signs, oxygen and carbon dioxide utilization.

Several decades ago the mortality rate was 80% but has decreased to less than foive percent as the condition has better studied, defined and early warning signs and triggers noted. The genetic signature has been localized to chromosome 19q13.1 (RYR1 gene), and some 400 variants have been described. It is inherited in an autosomal dominant fashion, so eliciting a family history of issues with anesthesia is a vital component in any child who will undergo surgery. If suspected or a case occurs, the diagnosis is presumptive, but in vitro muscle response to the triggering agents can and should be performed as the confirmatory measure. Furthermore, all family members should also be tested if at risk and genetic counselors should be involved in the care of the entire family. Finally, if a patient with known or suspected MH warrants surgery, a thorough evaluation by the anesthesia team in advance is critical and a discussion of treatment options provided. Generally, a totally intravenous approach to the induction and maintenance of anesthesia is the recommended option [36].

video link Opioid misuse

Patient Care Guidelines

Escalation Algorithm

NICU Sedation and Analgesia Algorithm

Titration Algorithm

Perspectives and Commentary

To submit comments about this topic please contact the editors at think@apsapedsurg.org.

Additional Resources

APSA Handbook of Pediatric Surgical Critical Care

Quality Improvemment toolkit on Opioid Stewardship

Discussion Questions and Cases

To submit interesting cases which display thoughtful patient management please contact the editors at think@apsapedsurg.org.

An otherwise healthy three year old male with no past medical history is in the operating room being induced for an elective, nonincarcerated unilateral inguinal hernia repair. Upon induction with inhalational agents and after intubation, an immediate increase in the patient’s end tidal CO₂ is noted. It is quickly followed by tachycardia, tachypnea and hyperthermia (105°F).

What is the appropriate repsonse?

Beyond supportive measures including discontinuation of the anesthesia, cooling and hyperventilation with resuscitation with crystalloids, dantrolene should be administered 2.5 mg/kg and repeated as needed for the treatment of malignant hyperthermia.

References