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Sedation and analgesia in pediatric intensive care unit Correspondence Address:
Common indications of sedation in the PICU (Pediatric intensive care unit) include mechanical Ventilation and various procedures performed in the PICU and in radiology or endoscopy suites. Sedation potentiates the effect of narcotics, thereby ensuring better comfort and analgesia. Sedation is a mandatory prerequisite prior to and during administration of neuromuscular blockers. This review includes practical pharmacology and uses of commonly used agents in the PICU.
One of the fundamental tenets of providing care to the critically ill children is to relieve suffering and reduce anxiety. Critically ill children who are conscious, experience fear, normally far in excess of what bedside caregivers can appreciate. Agitation is the motor restlessness that accompanies anxiety. Pain is a common accompaniment critically ill children experience due to wounds, incisions or indwelling catheters and pain further amplifies the fear. Finally, the children confined to the pediatric intensive care unit (PICU) bed, are sleep deprived,[1] which occurs from frequent interruption of patient routine and continuous stimulation with light, touch and noise originating from alarm systems of ventilators, pulse oximeters, intravenous (IV) infusion pumps and continuous electrocardiographic and hemodynamic monitoring. All of the above problems can be taken care of by maximizing the quality and length of sleep with minimal or no pain and anxiety. In this chapter we describe the practice of sedation at authors institution, in pediatric patients in the intensive care setting.
Sedation is given to achieve the following goals: i) To attenuate fear and anxiety. ii) To potentiate analgesia. iii) To reduce unnecessary recall (amnesia). In addition, sedatives are used to reduce metabolic demands particularly during circulatory shock; to facilitate tolerance to procedures and as a mandatory adjunct to neuromuscular blockade.
Common indications of sedation in the PICU include mechanical ventilation and various procedures performed in the PICU. In addition, other areas of the hospital that commonly require sedation of pediatric patients include endoscopy and radiology. It should be emphasized that the most important indication of sedation, is any situation requiring anxiolysis and analgesia to comfort the child. Also, sedation potentiates the effect of narcotics, thereby ensuring better comfort and analgesia. Sedation is a mandatory prerequisite prior to and during administration of neuromuscular blockers.[2] The patient should never be subjected to paralysis without sedation. An additional benefit of sedatives like propofol and benzodiazepines is that of amnesia and opiates provide analgesia in addition to sedation.
Most common procedures requiring sedation in PICU is endotracheal intubation and mechanical ventilation. In addition to mechanical ventilation, many other procedures require sedation. [Table - 1] Many of these procedures can only be done in Radiology department: such as CT (computerized tomographic scan), MRI (magnetic resonance imaging) or radiation therapy, therefore, oxygen, suction and resuscitative and monitoring equipment should be available and only trained and experienced personnel should be administering sedation to ensure safety of the pediatric patient. As much as possible, PICU procedures should be planned ahead of time, so adequate preparation can be made in PICU (For example flexible fiber optic bronchoscopy; renal, liver or bone biopsy and high risk endoscopy). Pre procedure Fasting and Risk of Aspiration In order to decrease the possibility of aspiration if airway reflexes are lost, proper nil by mouth (NBM) status must be assured before an elective sedation. Standard accepted American Society of Anesthesiologists (ASA) Recommendations given below, can be tailored to the individual patient age group as applicable[3]: a) Pre term or Newborn-no milk two hours prior to sedation b) 1-5 months-no milk or solids 4 hours prior to sedation c) 6-36 months-no milk or solids 6 hours prior to sedation d) > 36 months: no milk or solids 8 hours prior to sedation 6-8 ounces of clear liquid may be ingested up to two hours before the procedure by patients with normal gastric emptying. Clear liquids include apple juice, pediatric electrolyte containing fluids, water or aerated drinks. Many include breast milk in the category of clear liquids. No pulp containing juices are considered clear liquids.
There are two broad categories of routes commonly used for sedating a child. i. Oral/Rectal route ii. Intravenous (IV) / Intramuscular (IM) route Oral/Rectal route is best used for premedication before IV sedation as well as for short painless procedures such as CT scan. For longer noisy procedures such as MRI with contrast, IV sedation is invariably required. IV sedation is delivered by two methods: a) as a continuous IV infusion, or b) as intermittent bolus injection. Continuous IV infusion has the advantage of providing a more stable level of sedation which is more comfortable for the patient and more convenient for the nursing staff. However, over sedation can easily occur if larger amount of drug are cumulatively given. It may also increase the need for prolonged mechanical ventilation.[4] Bolus injection is usually given in response to patient arousal therefore less drug may be given over time. However it potentially exposes the patient to uncomfortable subtherapeutic troughs of the drug as well as toxic peak levels.[4]
The primary pharmacological action of benzodiazepines is sedation. They also provide for anxiolysis,[5],[6] muscle relaxation and anticonvulsant activity and induce anterograde amnesia. Benzodiazepines have no analgesic benefits. Commonly used benzodiazepines are Diazepam and Midazolam.Lorazepam has recently become available in India. Diazepam and Midazolam have greater lipophilicity, enabling them to cross the blood brain barrier quickly. They have a much more rapid onset of action and are the appropriate choices among Benzodiazepines when immediate sedating effect is required. Their long-term use causes dependency and abrupt discontinuation causes a withdrawal syndrome resulting in rebound agitation and even seizures in some patients. i) Midazolam: The most commonly used benzodiazepine is midazolam at our institution. IV diazepam however, remains the most commonly available and used sedative with equally good safety record and efficacy in most institutions, due to lower cost compared to Midazolam. Dose of midazolam is age dependent. Because midazolam is water soluble, peak effects are not reached immediately, it is essential to wait 2-3 minutes to fully evaluate the sedative effect before starting the procedure or administering a repeat dose. The dose needs to be titrated. a) In patients 6 months-five years, of age an initial IV dose of 50-100 mg/kg is recommended, a total dose of up to 600 mg/kg may be required, but usually does not exceed a total of 6 mg. b) In patients 6-12 years of age, an initial IV dose of 25-50 mg/kg is recommended, a total dose of 400 mg/kg may be required, total dose not exceeding 10 mg. c) Patients aged 12-16 years should be treated as adults. Sedation for Short procedures: Midazolam and other benzodiazepines are useful as sole agents for procedures that do not require analgesia. For sedation prior to short diagnostic or endoscopic procedures, midazolam may be used alone or in combination with ketamine or opiate agonist.[7] For peroral procedures e. g. (upper Gastrointestinal endoscopy, bronchoscopy), use of a topical anesthetic is recommended and for bronchoscopy, use of an opiate analgesic for pre medication is also recommended. When used concomitantly with opiates, midazolam dosage should be decreased by 30% to adjust for sedative effect of opiates as well as to reduce chances of respiratory depression. The dose for short procedures is as described earlier. For maintenance of sedation midazolam may be administered in incremental IV doses of approximately 25% of the initial dose when lightening of sedation is evident. Sedation in Critical Care Settings: Midazolam is administered as continuous IV infusion. For sedation of intubated and mechanically ventilated patients Midazolam is initiated with an IV loading dose of 50-100 mg/kg administered over at least 2-3 minutes. The drug should not be administered as a rapid IV injection. The loading dose should be followed by continuous IV infusion to maintain the clinical effect. Continuous IV infusion of Midazolam should be initiated at the rate of 1-2 mg/kg per minute; i.e. 60-120 mg/kg /hour. The infusion rate may be increased or decreased generally by 25% of the initial or subsequent infusion rate to achieve the desired effect.Over dosage of midazolam produces symptoms that are extensions of the usual pharmacological effects of benzodiazepines such as sedation, somnolence, confusion, impaired coordination, diminished reflexes and hypotension. Flumazenil, a benzodiazepine antagonist can be used to reverse midazolam- induced sedation, if available. ii) Diazepam: Diazepam is the prototypical benzodiazepine. Like midazolam it has a rapid onset of action and is the benzodiazepine of choice when immediate sedating action is required at bedside. Following an IV injection of 0.1 to 1 mg/kg, this drug is rapidly distributed to brain. The concentration in plasma declines rapidly owing to redistribution with an initial half-life of 10 to 15 minutes. However, drowsiness often returns with an increased concentration of diazepam in plasma after 6-8 hours. This effect is due to absorption from the gastrointestinal tract after excretion in the bile. Usage and adverse reactions are similar to midazolam. Rectal diazepam can be used in emergency situations for seizure control. iii) Lorazepam: Lorazepam has an intermediate duration of action. It has no active metabolite, so it is a more steady agent for long term maintenance of sedation. Half-life of redistribution of this drug is more than twice that of diazepam, therefore onset of drowsiness is less rapid. It is useful when anterograde amnesia is particularly desirable. Like midazolam it requires approximately one third to half of the dose necessary for diazepam.
Commonly used opiates are morphine, fentanyl and pethidine (also known as meperidine). The primary pharmacological action of opiates is to relieve pain or the sensibility to noxious stimuli via opioid receptors. Opiates provide no appreciable amnesia. A very significant secondary action of opiates is sedation and anxiolysis. Other effects include emesis, urinary retention, ileus, respiratory depression and hypotension. Hypotension occurs due to a combination of venodilatation, sympatholysis, vagal mediated bradycardia and histamine release. i) Morphine: Morphine has a half-life of 2-3 hours after IV administration. The active metabolite morphine-6-glucuronide accumulates in renal failure further extending the duration of action. Morphine should be given in smallest effective dose and as infrequently as possible to minimize the development of tolerance and physical dependence. The subcutaneous or IM dose of morphine sulphate in children is 0.1-0.2 mg/kg every 4 hours or as necessary. Single pediatric dose should not exceed 10 mg. IV dose in children is 0.05-0.1 mg/kg. In children with severe chronic pain associated with cancer, morphine sulphate is given IV in dose of 0.025-2.6 mg/kg/hr. For post operative analgesia,maintenance IV infusion dose is 0.01-0.04 mg/kg/hr. ii) Fentanyl: Fentanyl is a synthetic opiate with 100 times the potency of morphine. It has a more rapid onset of action due to greater lipophilicity. Duration of action is approximately 30 to 90 minutes due to shorter half-life. Fentanyl induces less hemodynamic instability because it does not induce histamine release like morphine. Therefore, fentanyl is the preferred choice in patients with circulatory shock. Like morphine it should be given in the smallest effective dose and as infrequently as possible to minimize the development of tolerance and physical dependence. As a word of caution, in neonates and younger infants, fentanyl can induce chest wall rigidity following rapid IV injection leading to severe respiratory depression, compounding the effect of centrally induced depression of the respiratory center. Use of muscle relaxants and immediate endotracheal intubation and ventilation is the treatment of choice for muscle rigidity induced by fentanyl. As an adjunct to general anesthesia, fentanyl may be given in low dose, moderate dose or high dose regimens: In the low dose regimens which is used for minor but painful surgical procedures an IV dose of 2 mg/kg is administered. In the moderate dose regimen, used in more major surgical procedures, an initial IV dose of 2-20 mg/kg is administered, additional doses of 25-100 mg may be given IV or IM as necessary. In the high dose regimen used in complicated procedures where surgery is more prolonged an initial IV dose of 20-50 mg/kg may be given. To provide general anesthesia without additional anesthetic agents, fentanyl doses of 50-100 mg/kg may be administered IV in conjunction with oxygen and skeletal muscle relaxant. iii) Pethidine (meperidine): It produces a pattern of effect similar to that of morphine. The analgesic effect appears about 15 minutes after oral administration, reaches a peak in about 2 hours and subsides gradually over several hours. After parenteral administration peak effect appears in one hour. Equianalgesic dose of IV pethidine is 100 mg to 10 mg of morphine (morphine is 10 times more potent).Other more potent newer narcotics are Buprenorphine, Alfentanyl and Sufentanyl, used mostly by anesthesiologists in the operation theatre. Narcotic Over Dosage: The standard reversal agent in the setting of opiate over dose is Naloxone, a competitive antagonist. Dose of naloxone is 0.01mg/kg IV slowly. Rapid infusion can result in withdrawl seizures in patients receiving morphine on a chronic basis. The half-life of Naloxone is 45 minutes.
Ketamine hydrochloride is an Arylcycloalklyamine (a phencyclidine derivative). It induces a state of sedation, immobility, amnesia and marked analgesia. It induces dissociative anesthesia: strong feeling of dissociation from the environment that is experienced by the patient to whom it is administered.[8] Ketamine has been extensively used in pediatric patients in radiology, burns dressings and other painful procedures. Ketamine is ideal sedative in a relatively hypovolemic patient, patient with bronchospasm and shock due to its indirect sympathomimetic action by releasing catecholamines causing hypertension and bronchodilatation. IV dose is 1 to 4.5 mg/kg over a period of about one minute. The sensation of dissociation is noticed within 15 seconds and unconsciousness becomes apparent within 30 seconds. Intense analgesia and amnesia are established rapidly. Following a single dose, unconsciousness lasts 10-15 minutes and analgesia persists for 40 minutes, amnesia may be evident for 1- 2 hours following the initial injection.[8] If anesthesia of longer duration is required repeat dose equal to half of the initial dose may be administered. Muscle tone may be increased, purposeless movements may sometimes occur and violent and irrational responses to stimuli occur. Pharyngeal and Laryngeal reflexes are retained and although cough reflex is depressed, airway obstruction does not normally occur. Airway resistance is decreased and bronchospasm may be abolished. Unlike barbiturates, ketamine does not act on reticular activating system, rather it acts on receptors in the cortex and limbic system. Awakening may be characterized by disagreeable dreams and even hallucinations. Some of these occurrences may occur days or weeks later. Avoiding exposure to bright light or loud noises following use of ketamine can reduce the emergence hallucinations. Concominant use of midazolam to reduce hallucinations is not proven therefore not necessary. Relative contradictions include known hypertension and raised intracranial pressure.
Propofol(2,6-diisopropyl phenol) is an IV anesthetic which is given to critically ill children for titratable sedation and hypnosis. Propofol has a wide array of benefits, including anxiolysis, anticonvulsant activity, antiemesis and the ability to reduce intracranial hypertension.[9],[10] Similar to the benzodiazepines, propofol has no analgesic activity.[11] The most important advantage of propofol is its rapid onset and offset of action. This behavior of a “rapid on, rapid off” feature, not available with the IV opiates or benzodiazepines, accounts for the increasing popularity of propofol. Because the onset of action after a single dose is rapid and its effect brief (10-15 minutes) due to high lipophilicity and central nervous system penetration, propofol is given only by continuous infusion when used for sedation. The emergence from anesthesia is rapid even following prolonged infusion and is characterized by minimal post operative confusion. Given in conjunction with diazepam or midazolam, propofol provides satisfactory anesthesia for a variety of purposes like emergency surgical procedures, change of dressings, radiological procedures and even some cardiac surgical procedures. The most significant adverse effect of propofol is hemodynamic destabilization. Propofol can substantially reduce cardiac output because it is both a negative inotrope and negative chronotrope. Additionally, it is a vasodilator. The combined effects on cardiac output and systemic vascular resistance can cause significant hypotension.[11]Pancreatitis, perhaps related to hypertriglyceridemia, has been described after the use of propofol.[12] It is a potent respiratory depressant, suppressing both the hypercarbic and hypoxemic drives of ventilation. Following induction of anesthesia, respiration is so depressed that apnea may occur for 30 seconds. Tidal volume, minute volume and functional residual capacity, all are subsequently reduced. It does not impair hepatic or renal function. Pain with peripheral injection has been described; therefore, central delivery routes are preferred. It is chemically unrelated to other IV anesthetic agents. The compound is oil at room temperature and supplied as 1% emulsion. An IV injection of 2 mg/kg induces anesthesia rapidly.
Chloral hydrate is used principally as an oral/rectal hypnotic in the treatment of insomnia. It is effective as hypnotic only for short term use. It may also be used as a routine oral sedative agent. The drug is used pre-operatively to allay anxiety and produce sedation. In post operative cases it may be a useful adjunct to opiates and analgesics. It is also used for non-stimulating procedures requiring sedation only e.g. prior to EEG. Dosage is the same for oral and rectal administration and must be individualized for each patient.[13] For children, the hypnotic dosage of chloral hydrate is 50mg/kg or 1.5 g/m2 with a maximum single dose of 1 gm. The sedative dosage for children is 8.3 mg/kg or 250 mg/m2 three times daily with maximum dosage of 500 mg three times a day. As a pre-medication before EEG, children have been given a dose of 20-25 mg/kg. Toxicity can manifest as gastritis, Skin eruptions or parenchymatous renal damage may develop following prolonged administration of chloral hydrate. Prolonged use may also produce tolerance and physical dependence.Chloral hydrate overdosage produces symptoms which are similar to those of barbiturate overdosage like coma, hypotension, hypotheremia, respiratory depression and cardiac arrhythmias. Miosis, vomiting, areflexia, muscle flaccidity, esophageal stricture, gastric necrosis, perforation and gastrointestinal hemorrhage have been reported.[13] Treatment of chloral hydrate intoxication consists of general supportive therapy including maintenance of adequate airway, assisted respiration, oxygen administration and maintaining body temperature and circulation. Gastric lavage may be performed following over dosage if an endotracheal tube with cuff inflated is in place to prevent aspiration of gastric contents.[13]
Two alpha- 2 adrenergic agonists have recently been registered by U.S Food and Drug Administration,namely: clonidine and dexmedetomidine. The alpha-2 adrenergic agonists provide analgesia, anxiolysis sedation and sympatholysis. Epidural clonidine was used as an adjunct for pain management particularly in patients with cancer.[14] Dexmedetomidine was approved for use as a sedative and analgesic in the intensive care setting specifically for use in early post operative period.[15] Dexmedetomidine is the first sedative with analgesic properties that does not significantly depress respiratory drive or produce respiratory depression. So it holds a promise in ICU of being a sedative analgesic without causing respiratory depression. It can be administered during and after extubation from ventilatory support. Patients are calm and easily arousable from sleep. These agents cause bradycardia, by vagomimetic effect and blockade of cardio-accelerator nerve. They also cause hypotension due to inhibiton of sympathetic activity in the central nervous system leading to vasodilation. [TAG:2]Practical approach to sedation in PICU [/TAG:2] Sedation in children is usually performed with one or combination of benzodiazepines, opiates, neuroleptic agents and anesthetic agents such as propofol and ketamine. Each of these groups of medications has its particular benefits: benzodiazepines provide the greatest analgesia and propofol is the most easily titrable and has a more rapid reversal of sedation other than providing amnesia. For short non-stimulating procedures requiring only sedation, chloral hydrate alone may be used. All patients require sedation of some degree during mechanical ventilation. There have been a number of studies published for the sedation of mechanically ventilated patients. The most important goal in the sedation of these patients is to achieve patient comfort and patient-ventilator synchrony to avoid any mishaps during ventilation such as accidental extubation,circuit disconnection or kinking of circuits.[16] The basis for sedating these patients starts with an infusion of an opioid, usually morphine, or fentanyl. Fentanyl has the advantage of avoiding hypotension from histamine release. Once proper analgesia has been established, an infusion of a sedative should be added. The most popular sedatives at our institution are benzodiazepines, specifically midazolam. If no painful procedures are contemplated, midazolam infusion alone is sufficient.Ketamine or narcotic supplementation should be given before painful procedures such as central line, arterial line insertions and chest tube placement or chest physiotherapy. Older children require muscle relaxants in addition to sedation, especially in cases of acute respiratory distress syndrome or other low compliance lung disease. It is important to remember that the most common condition causing agitation in a child on ventilator is hypoxemia due to mechanical issues such as secretions, endotracheal tube misplacement, kink or pneumothorax. This must be addressed with adequate oxygen delivery, clearance of secretions, delivery of adequate tidal volume, ensuring proper placement of endotracheal tube and treating pneumothorax as the case may be, before sedating the child for anxiolysis and comfort.
Recently bispectral index(BIS) has been evaluated for monitoring of sedation level in a muscle relaxed patient. It was found to correlate well with Ramsay score. The instrument consists of a mini EEG monitor in which a strip of leads is placed on the patients forehead (Aspect medical systems, inc USA)and the sedative dose can be titrated.[17]
We follow a practice of judicious use of sedatives in our PICU to try to make stressful and traumatic experience in PICU smoother for the child as well as for the parents. One must not forget to use analgesia where painful procedure is anticipated in a child. Availability of proper resuscitative equipment as well trained personnel is extremely important to ensure safety of the child during all procedures, specially those performed in radiology or endoscopy suites. Routine use of muscle relaxants can be avoided, to be reserved for mechanically ventilated patients with severe acute respiratory syndrome or raised intracranial tension.
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