UDK: 615.212:615.214.24].015.3-053.2
Durnev V1
1University Clinic for Traumatology, Orthopedic Diseases, Anesthesia, Reanimation, Intensive Care and Emergency Centre, Medical Faculty, University “Ss. Cyril and Methodius,” Skopje, Macedonia
Introduction
Almost all interventions and medical procedures cause great distress such as anxiety, fear and pain in children and their families. Achieving the optimal combination of adequate analgesic and sedation is a major challenge in this patients’ population due to the wide spectrum of age, size and developmental stage.[1]
Under dosing increases the risk of physical and psychological stress that can have long-term consequences. Excessive sedation, on the other hand, increases the risk of side effects of analgesic and sedative agents, prolonged respiratory support, prolonged hospital stays or hospital admission. Both, insufficient analgosedation and overdose, put pediatric, especially critically ill patients at high risk of developing complications such as delirium, withdrawal syndrome, neuromuscular atrophy and weakness, post-traumatic stress and poor rehabilitation.
Optimal analgesia and sedation depend on continuous assessment with validated tools to help titrate analgesic agents.[2]
Many procedural procedures, such as endoscopy, computed tomography, bronchoscopy and magnetic resonance imaging are performed for the diagnostics and therapy of diseases. Also, everyday medical care involves blood sampling from venipuncture, nasogastric tube and urinary catheter placement, lumbar puncture, bone marrow aspiration etc.
All these invasive and inevitable investigation methods often represent a severe burden for children and can only be carried under anesthesia or sedation. Therefore, analgosedation is carrying great significance in the diagnostics and treatment in children to avoid psychological trauma and to optimize the results of the examination. [3]
Analgosedation can principally only be carried out by trained personnel who are capable of independently dealing with any complications that might occur. Prerequisites for dealing with complications are a good background knowledge on the pharmacokinetics and pharmacodynamics of the medications applied, the safe performance of basic and advanced cardiac life support in children, and the appropriate equipment. Complications rarely occur during sedation for diagnostic and therapeutic measures when a competent team takes care of the children based on predefined guidelines.
Pharmacodynamics and pharmacokinetics of analgesic and sedative agents
Clearance, metabolism and duration of drug effect, can be affected by dysfunction or insufficiency of the end organ (hepatic, renal, cardiac). The key factors affecting pharmacokinetics (PK) and pharmacodynamics (PD) can be divided into two elements: Patients’ factors and factors resulting of the Pediatric Intensive Care Unit (PICU).[4], [5]
Patients’Factors
These factors include change in the redistribution of body fluids that affects the volume distribution of the drug, altered protein binding that may affect plasma drug concentration, and end-organ dysfunction that may alter drug absorption, metabolism and excretion. Other factors are natural age-related physiology that can affect drug absorption, metabolism, and excretion and inflammatory conditions that alter drug-metabolizing enzymes, as well as affecting drug absorption, efficacy and clearance.[6], [7]
PICU factors
Non-pharmacological interventions such as the use of continuous renal replacement therapy (CRRT), extra-corporeal membrane oxygenation (ECMO) and therapeutic hypothermia are belonging to PICU factors, all of which affect the extent of volume of distribution, metabolism, absorption and clearance.[8]
Analgesia
Effective, titrated treatment of acute, procedural and chronic pain, especially in PICU is essential tool for good patient’s outcome.
The goal of analgesic therapy is to provide comfort, to reduce the physiological response to stress, to reduce adverse events associated with analgesics, such as respiratory depression, risk of dependence, hemodynamic instability and end-organ injury.
In the critically ill pediatric patient, this balance is delicate and, if failed, can predispose children to inappropriate pain management.[9]
Pain Assessment
In order to titrate analgesic therapy for adequate pain management, and monitor for signs of drug toxicity, or adverse effects, gold standard for monitoring the effectiveness of pain medication is patients’ self-assessment scales. The premise of these scales is assigning a numeric value to the perception of pain, such as designating 0 as“nopain” and 10 as “worstpain”.
Self-assessment is a good tool to detect the presence of pain, as well as the perceived intensity of pain. However, pain self-assessment can be challenging in some pediatric patients because of their limited ability to communicate (PICU patients) or comprehend as a result of age or disability.
Physiological indicators as tachycardia, rise in blood pressure, tachypnea, pupil dilation, increased muscle tone, sweating, etc. are unreliable signs because they lack pain sensitivity and specificity. Behavioral signs of a child in pain, either verbal (vocalized description of intensity, quality, location with concomitant moaning or crying) or non-verbal (facial expression, body posture/repositioning, decreased activity) were also shown to be uncertain signs.[10]
In children <3 years, the standard for pain assessment is the use of behavioral observational pain scales using subjective and objective indicators that interpret facial expression and physiological and motor responses, often including the opinions of family members.
Children aged 4 to 8 years are usually able to self-report pain, so their subjective information is complemented by the application of an appropriate pain tool.
Older children (8 years and older) are usually able to self-assess their pain using more validated methods such as the verbal rating scale (VRS), numerical rating scale (NRS), and visual analog scale (VAS), similar to adults (11).[11]
Not all pain scales require self-assessment and interpretation of verbal cues. The Wong-Baker FACES scale and the Bieri Faces Pain Scale Revised (FPS-R) are suitable for children of any age and developmental stage and rely on nonverbal cues.
Each scale has its limitations. The observational scales as Neonatal Pain, Agitation, and Sedation Scale (N-PASS), Nonverbal Pain Scale (NVPS), and Face, Legs, Activity, Cry and Comfort (FLACC) scale cannot measure pain intensity or quality.
Table 1.FLACC Scale
| 0 | 1 | 2 | |
| Face | Relaxed face, no particular
Expression or smile. |
Occasional grimace or scowl, retiring, disinterested. | Frequent to constant scowl, quavering chin,clenching jaw. |
| Legs | Normal position or relaxed. | Uncomfortable, restless, tense.
|
Kicking or legs pulled up. |
| Activity | Lying down quietly, normal
position, moves easily. |
Wriggling,shifting back
And forth,tense. |
Arched, rigid body or jerking. |
| Cry | No cry (awake or asleep). | Moans of whines, occasional compliant. | Crying consistently, screams or sobs, frequent complaints. |
| Consolability
|
Pleased, relaxed, not require consoling.
|
Reassured by occasional touching, clasping, or being talked to, distractible. | Inconsolable, difficult to comfort. |
| Total score 0=Relaxed and comfortable, 1–3=Mild discomfort, 4–6=Moderate pain, 7–10=Severe discomfort or pain or both. Adapted from Merkel SI et al.22 | |||
Table 2. Comparison of Pain Assessment Instruments.
| FLACC | Children, all ages | Acute, surgical | Observational | Behavioral,physiological |
| FPS-R | ≥4years | Acute, surgical | Self | Pictorial |
| N-PASS | Neonates | Acute, surgical | Observational | Behavioral,physiological |
| NVPS | Children,all ages | Acute, surgical | Observational | Behavioral,physiological |
| NRS | ≥6years | Acute, surgical, chronic | Self | Numeric |
| VAS | ≥6years | Acute,surgical,chronic | Self | Numeric |
| Wong-Baker FACES | ≥4years | Acute,surgical | Self | Pictorial |
Pain Treatment
Non-pharmacologicalTreatment
Non-pharmacological interventions include a range of so-called age-appropriate redirection techniques. Redirection techniques for infants include pacifiers, swaddling, rocking and holding.
For older children, diversion techniques may vary but include using familiar toys, video games and television.
Other non-pharmacological interventions may include music or art therapy, a quiet environment with low stimulation and cognitive behavioral therapy.
The use of non-pharmacological therapies should always be considered and intertwined with pharmacological therapy.[12]
Pharmacological Pain Treatment
Pain assessment and identification of its underlying causes must lead to the choice of analgesic drug which must be of adequate power, and targeted to properly pain treatment.
Acute pain is the most frequent form of pain in PICU, but complex patients with prolonged stay in intensive care unit may present with persistent, chronic forms of pain, for which it may be necessary a multidrug combination.
The therapeutically schedule had to be daily reassessed according to the analgesic requirements.
WHO’s pain ladder, a step grading pain therapy still remains a valid method in treating pain by choosing drugs secondary to pain intensity.
Table 3. Analgesic drugs.
| Drug
|
Intravenous bolus | Intravenous infusion | Per os |
| Morphine | Neonates – 25mcg/kg,
Infants-children – 30-100mcg/kg. |
Neonates – 5-10mcg/kg/h,
Infants-children – 10-50mcg/kg/h. |
Neonates – 80mcg/kg 4-6 hourly,
Infants – children – 200-500mcg/kg/ 4 hourly. |
| Fentanyl | Neonates – 0.5-1mcg/kg,
Infants-children – 1-2mcg/kg. |
Neonates – 0.5-3mcg/kg/h.
Infants-children – 1-5mcg/kg/h. |
|
| Remifentanil | Neonates – 0.01-30.1mcg/kg/min,
Infants-children – 0.02-1 mcg/kg/min. |
||
| Paracetamol | Neonates – 7.5-10mg/kg 6-8 hourly max 30mg/kg/day,
Infants (˃ 10kg) 15mg/kg 6-8 hourly max 60mg/kg/day, Children- (˃ 50 kg) 1g 6-8 hourly max 4g/day.
|
Neonates – 10-15mg/kg 8-12 hourly max 30mg/kg/day,
Infants – 15mg/kg 4-6 hourly max 60mg/kg/day, Children – 15mg/kg 4-6hourly max 90mg/kg/day.
|
|
| Ibuprofen
Above 3 months |
5-10mg/kg 6-8 hourly max 40mg/kg/day. |
Recommendations:
- For children assessed as having mild pain paracetamol and non-steroidalanti-inflammatory drugs (NSAIDs) should be considered as the first options.
- For the treatment of severe pain, administration of opiates delivered by continuous intravenous infusions is recommended because of more accurate control of the dose and more steady plasma concentration.[13]
- Enteral route, when gastrointestinal motility and function are recovered, is also highly
- An iv analgesic drug may be administrated during oral route administration of analgesic treatment as adjuvant or rescue therapy.
- Paracetamol and nonsteroidal anti-inflammatory drugs in children above three months of age, and only paracetamol in neonates, are recommended for treating mild pain.
- Adding nonsteroidal anti-inflammatory drugsor paracetamol to opioids is useful to limit the total opioid dose required.
- Fentanyl is indicated in presence of cardiocirculatory instability, and in neonates with persistent pulmonary hypertension.
Loco-regional techniques must always be considered in cases of localized pain, such as procedures, surgery, trauma or burns. Ultrasound guided peripheral nerves block sare strongly recommended also in infants within 6 months of age even if there is scarce evidence that ultrasound technique is more reliable than traditional land marking.[14]
- Epidural analgesia is effective for acute pain after surgery or trauma to the chest and abdomen.
- Use of EMLA in severe premature infants, mostly in repeated applications during the same day, carries the real risk of developing methemo
Sedation
The sedation targets are reduction of distress, fear, agitation, improvement of patient-ventilator synchrony and decrease in self-removing of invasive devices. Sedation cannot be implemented without an adequate analgesic treatment, since persistent not treated pain undermined the sedation strategy. Since standard sedation protocols suitable for all patients do not exist, one should be able to tailor sedative plan for each patient using minimal effective doses.[15]
Sedation is a particular challenge for anesthesiologists, nevertheless the pediatric patient is assigned for procedural sedation, or the patient is on mechanical ventilation in PICU.
The optimal condition for a patient who is breathing independently is that he wakes up easily, or is conscious, feels comfortable and breathes in synchronizing with the ventilator – the Goldilocks zone (not too deep and not too shallow). Balancing sedation to synchronize the patient with the ventilator is matter of mastering.
Balancing the depth of sedation is important because insufficient sedation can lead to dislocation of intravascular access and catheters, unplanned extubation, and potential injury to staff or the patient. Excessive sedation, on the other hand, can lead to unstable hemodynamics, respiratory depression, and possible extubation failure. Also, prolonged intubation poses an increased risk for muscle hypotonia, delirium, cognitive impairment, decreased tolerance and withdrawal syndrome.[16]
Table 4. Levels of sedation.
| Level of sedation
Minimal(“anxiolysis”) |
Stimulus response
Verbal and tactile |
Airway
Unaffected |
Ventilation
Unaffected |
Hemodynamics
Maintained |
| Moderate(“conscioussedation”) | Verbal and tactile | Unaffected | Unaffected | Maintained |
| Deep | Noxious tactile | Affected | Affected | Maintained |
| Generalanesthesia | None | Affected | Affected | Impaired |
Sedation Assessment
- State Behavioral Scale (SBS),
- COMFORT behavior scale,
- COMFORT-B scale,
- Richmond Agitation Sedation Scale (RASS).
State Behavioral Scale (SBS)
SBS monitors 8 parameters in mechanically ventilated children[17]:
- Respiratory drive,
- Response to ventilation,
- Coughing,
- Best response to stimulation,
- Attention to the care provider,
- Care tolerance,
- It can be comforted,
- Ability to move after comfort.
COMFORT Behavior Scale
The COMFORT behavioral scale is an observational scale that measures eight parameters to determine the level of distress of a critically ill child.[18]
Unlike the SBS, the COMFORT scale contains two physiological parameters and six behavioral dimensions:
- Pulse,
- Mean arterial pressure,
- Alertness,
- Calmness,
- Respiratory response,
- Movement,
- Muscle tone,
- Facial expression.
COMFORT BScale
The COMFORT-B scale eliminates both physiological parameters but adds excessive sedation and insufficient sedation. A limitation of this scale, however, is that scores of 10-23 are not predictive of adequate depth of sedation. The COMFORT-B scale is commonly used in conjunction with other observational scales. [19]
Richmond Agitation Sedation Scale (RASS)
The RASS is an agitation and sedation scale that has been validated for both adults and children (intubated and non-intubated) in the critical care setting.
The RASS is a 10-points scale ranging from 5 (unreactive) to +4 (combative) with 0 indicating readiness for increased attention and calmness.
For infants and children with cognitive or developmental limitations and for whom the level of alertness is difficult to assess, the original RASS is adapted to replace eye contact with eye opening when the RASS is -1 to -3.[20]
An important limitation of all these rating scales is their inability to be used for children with neuromuscular blockade.
Table 5.Initial Doses of Opioids and Sedatives in Children.
Intermittent dose Continuous intravenous infusion
| Chloral hydrate | PO: 0.5–5mcg/kg | N/A |
| Clonidine | PO: 0.5–5mcg/kg
|
N/A |
| Dexmedetomidine | IN: 1–4mcg/kg
IV: 0.5–1mcg/kg |
0.2–0.7mcg/kg/hr |
| Etomidate | IV: 0.1–0.3mg/kg | N/A |
| Fentanyl | IN: 1–2mcg/kg
IV: 0.5–3mcg/kg |
0.5–2mcg/kg/hr |
| Hydromorphone | IV: 0.01–0.02mg/kg | 0.003–0.005mg/kg/hr |
| Ketamine | IM: 5–10mg/kg | 0.3–0.6mg/kg/hr |
| IN: 3–5mg/kg | (5–10mcg/kg/min) | |
| IV: 0.5–3mg/kg | ||
| PO: 5–8mg/kg | ||
| Lorazepam | IV: 0.05–0.1mg/kg
PO: 0.05mg/kg |
0.05mg/kg/hr |
| Midazolam | IM: 0.05–0.15mg/kg | 0.03–0.12mg/kg/hr |
| IN: 0.2–0.3mg/kg | ||
| IV: 0.05–0.1mg/kg | ||
| PO: 0.25–0.5mg/kg | ||
| Morphine | IV: 0.03–0.2mg/kg | 0.01–0.04mg/kg/hr |
| Pentobarbital | IM: 2–6mg/kg
IV: 1–2mg/kg PO/PR: 1.5–6mg/kg |
0.5–1mg/kg/hr |
| Propofol | IV: 0.5–2mg/kg | 1.2–4.8mg/kg/hr
(20–80mcg/kg/min) |
Conclusion
Providing safe, effective and appropriate analgesia and sedation in children is challenging, complex and stressful intervention requiring experienced and well-trained personnel. However, the provision of analgesia and adequate level of sedation is frequently necessary to optimize the healing environment. Challenges with analgosedation in children include understanding of the pharmacokinetics and pharmacodynamics in pediatric patients, as well as how obesity and other illnesses contribute to medication pharmacokinetics. Analgesics and sedatives carry a high risk to imbalance the child homeostasis.
Appropriate analgosedation in children is hard to achieve. Over- or under-treatment are both harmful. Frequently, the reasons are lack of knowledge in pharmacological profiles of drugs and an insufficient applications of assessment tools.
Optimal analgesia and sedation are dependent on the implementation of validated tools to guide the titration of analgosedative agents, and screen for withdrawal and delirium. Optimal sedation should minimize physical and chemical restraints, encourage safe liberal activity, promote restorative sleep, and reduce the incidence of PICU-acquired complications (PACs).
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