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US Pharm. 2006;8:HS15-HS27.
The pediatric population is a very
dynamic group of patients, since the physiologic processes that determine drug
disposition undergo rapid changes as children grow and mature. Therefore, the
use of pharmacologic agents in pediatric patients warrants special
considerations.1,2 When administering general anesthesia
medications to children, a clear understanding of the physiologic,
pharmacologic, and psychological differences between children and adults is an
essential component of good patient care.3 This article discusses
the principles and risks and complications associated with pediatric general
anesthesia. Significant emphasis is placed on the various pharmacologic agents
used to anesthetize pediatric patients.
Pediatric Pharmacokinetics
In comparison to adults, infants and young children respond differently to
anesthesia medications due to many factors, including body composition,
protein binding, body temperature, distribution of cardiac output, and
functional maturity of the liver and kidneys.3,4
Body components (fat, muscle, and
water) change with age. Total body water is substantially higher in premature
infants than in term infants and higher in term infants than in toddlers.
Additionally, fat and muscle content increase with age. These changes can
significantly impact the pharmacokinetics of certain medications.
Consequently, water-soluble drugs that have large volumes of distribution
(e.g., succinylcholine) require larger initial doses in neonates. Similarly,
drugs that depend on redistribution into fat for termination of action (e.g.,
thiopental) have a longer clinical effect in neonates.
Neonates have decreased hepatic and
renal function and protein binding, compared to older children, who generally
have mature renal and hepatic function and normal adult values for protein. In
addition, more of the cardiac output is diverted to the liver and kidneys in
older children than in infants. Consequently, the metabolism and excretion of
many drugs, such as morphine, are slowed in neonates, leading to a prolonged
elimination half-life.3 Most medications have a prolonged
elimination half-life in premature and term infants, a shortened half-life in
children older than 2 years up to early teen years, and a lengthened half-life
in teenagers approaching adulthood.3
Temperature regulation is important
in pediatric anesthesia. Young children have disproportionately large body
surface areas, and heat loss is exaggerated during anesthesia, especially
during the induction of anesthesia, unless this is actively prevented.4
Hypothermia, particularly in neonates, delays the metabolism and excretion of
anesthetic agents and can also potentiate neuromuscular blockade.5
General Anesthesia
The perioperative period (immediately before, during, and after surgery) is a
particularly critical time for pediatric patients. In general anesthesia,
medications blunt physiologic responses and render patients unaware of what is
being done to or around them. The increased risk for morbidity and mortality
in the perioperative period demands the utmost vigilance. Such risks may be
increased in certain disease states.5 Table 1 lists specific
conditions and their anesthetic complications.5-7
The purpose of general anesthesia is
to suppress the conscious perception of, and physiologic response to, noxious
stimuli and to render the patient unconscious. This is done through analgesia
(decreasing pain), amnesia (blunting consciousness), akinesia (preventing
movement), physiologic support (maintaining cardiovascular function, fluid
management, electrolyte control, and thermoregulation), and vigilance.5
Prior to receiving anesthesia, all
children should have a preanesthetic assessment that includes a brief history,
notation of medical allergies, and a physical examination focusing on the
airway, lungs, and cardiac function. In addition, a family history regarding
reactions to anesthetics, drug allergies, and incidences of sudden death
intraoperatively or hyperthermia postsurgery should be obtained. In children
who have received general anesthesia previously, questions should be asked
concerning complications.5 During this assessment, clinicians
should make every attempt to ensure that the child adhered to the recommended
preoperative fasting guidelines. See Table 2 for a discussion of these
guidelines.5,6
Preanesthetic Phase:
The primary focus of this phase is to ensure that the patient arrives in the
operating room in a calm/relaxed manner, without compromised breathing and/or
impaired cardiovascular status.2,5 Numerous classes of medications
can be given to children (e.g., sedatives, analgesics, anticholinergics,
histamine blockers) during the preanesthetic phase.2
Induction Phase:
General anesthesia can be induced with either inhalation or intravenous (IV)
medications. In most instances, the volatile anesthetic agents are preferred
in children over IV medications because they do not require IV access. IV
medications are used to induce anesthesia in children only in rare
circumstances (e.g., the patient is at risk for malignant hyperthermia [MH]).
However, once the child is asleep and IV access is established, children
commonly receive IV anesthesia medications.5,7
Inhalation induction begins with the
patient inhaling, through a face mask, a high gas flow (5 to 7 L/min of
oxygen), which is usually mixed with nitrous oxide. Once a state of euphoria
is reached (60 to 90 seconds), a volatile inhalation agent is typically added
into the inhaled gas mixture. This combination, leading to unconsciousness
within 30 to 60 seconds, allows the child to continue breathing spontaneously.
5
Maintenance Phase:
This phase is the period between induction and emergence. During this time,
the child should be asleep, unaware of pain, unresponsive either with motion
or hemodynamic responses to painful stimuli, and homeostatically supported.
Anesthesia is usually maintained with nitrous oxide, an inhalational
anesthetic, and a narcotic for intraoperative analgesia. A benzodiazepine can
be added to the regimen either during premedication or intraoperatively to
supplement hypnosis and amnesia. Neuromuscular blockers are used when muscle
paralysis is needed.5
In some circumstances, anesthesia
can be maintained solely with a volatile anesthetic agent. However, this is
safe only when the airway is secure and patent, the stomach is empty, the
child is older than 6 months, and the duration of the procedure is less than
one hour.5
Reversal Phase: The
volatile inhalation agents rapidly leave the lungs during ventilation and thus
do not require other products to reverse their actions. However, certain
neuromuscular blockers commonly need to be reversed with an
acetylcholinesterase inhibitor.5 Generally, the effects of other
agents (e.g., narcotics, benzodiazepines, IV hypnotics) used in general
anesthesia may be prolonged but do not usually need to be reversed.2
Volatile Inhalation Agents
Five volatile inhalation agents are commercially available in the United
States: desflurane, sevoflurane, isoflurane, enflurane, and halothane.
Desflurane, sevoflurane, and isoflurane are the most commonly used in
pediatric clinical practice.1,2 Halothane is the prototypical
pediatric inhalational agent; however, its use has decreased dramatically
since the availability of isoflurane and sevoflurane. Enflurane is rarely used
in children.5
The advantages of the volatile
anesthetics include rapid onset, rapid offset, and convenient route of
delivery. Additionally, the volatile anesthetics provide analgesia and
amnesia. However, all of these products (in varying degrees) are airway
irritants and can cause laryngospasm, breath holding, coughing, and salivation
in children.5,8
All of the volatile inhalation
agents depress ventilation and dilate constricted bronchial musculature.
2,5 They also commonly induce apnea and hypoxia in premature infants and
newborns; thus, these anesthetics are not routinely used in children younger
than 6 months. Finally, the volatile inhalation products can cause unwanted
cardiovascular effects (e.g., depressed cardiac output, decreased oxygen
delivery, peripheral vasodilation, cerebrovasodilation, and decreased ejection
fraction) that can negatively impact anesthesia.5
Halothane has a high solubility in
tissues and is therefore associated with a slow onset and termination of
effect and recovery. Patients receiving halothane have an increased risk of
arrhythmias and hepatotoxicity. Consequently, halothane is rarely used in
pediatrics today.9 Agents that are more pleasant to breathe and
that induce anesthesia more rapidly have replaced halothane in clinical
practice.2
Isoflurane maintains cardiac output
and cerebral perfusion better than halothane. It is also less of a respiratory
depressant than halothane. Emergence from anesthesia with isoflurane is quite
smooth and faster than with halothane. Isoflurane is pungent and a significant
airway irritant with an unacceptably high incidence of laryngospasm;
therefore, it should not be used to induce anesthesia. Because isoflurane is
not a suitable induction agent, induction with sevoflurane, and maintenance
with isoflurane, is a common pediatric anesthesia practice.5
Desflurane has the lowest blood gas
solubility coefficient (0.42) of all of the volatile anesthetics; therefore,
desflurane is associated with a fast onset and termination of effect and
recovery.2 Unfortunately, desflurane (like isoflurane) is a potent
airway irritant and cannot be used to induce anesthesia.5 Because
desflurane has a low fat/blood solubility, it is primarily used to maintain
anesthesia in longer procedures because less of the drug accumulates in the
fat.2
Sevoflurane is much less pungent
than isoflurane and desflurane and has a low blood gas partition coefficient,
like desflurane.2 In addition, sevoflurane appears to have
fewer hemodynamic effects than halothane and the profile of respiratory
effects at 1 minimum alveolar concentration (MAC) appears to be similar. (See
Table 3 for a discussion of MAC.) Emergence from sevoflurane is quite
rapid. The major use of sevoflurane is induction of anesthesia in children.
Metabolism of sevoflurane yields free fluoride, which may cause renal damage;
therefore, the FDA has restricted the use of sevoflurane to less than two MAC
hours, preferably with fresh gas flow rates in excess of 2 L/min.5
IV Anesthetic Agents
Anesthesia can be both induced and maintained with either boluses or
continuous infusions of IV anesthetic agents. IV anesthetic agents include
barbiturates, opioid narcotics, benzodiazepines, and miscellaneous products
(e.g., ketamine, propofol). IV anesthetic agents induce anesthesia more
rapidly than inhaled products and with fewer complications. On the other hand,
an IV line must be placed and, unless IV access is already obtained,
inhalation induction may remain the preferred route. For children arriving in
the operating room with IV access, IV induction should be routine, because it
rapidly takes the child from awake to anesthetized with less hemodynamic and
cardiorespiratory compromise.5
Barbiturates are commonly
administered to pediatric patients for premedication and induction of
anesthesia.10 It is important to note that the barbiturates do not
provide analgesia.5 Generally, neonates require lower mg/kg doses
of barbiturates than do older children; and older children require larger
mg/kg doses of barbiturates than do adults.10 Thiopental,
pentobarbital, and methohexital are the most frequently used barbiturates in
pediatric anesthesia.3,5,10
Thiopental, the most commonly used
barbiturate in pediatric anesthesia, also depresses respirations, induces
apnea, and can cause hypotension in the hypovolemic patient. Thiopental
generally has little impact on myocardial function and in the euvolemic, well
child is a useful anesthetic induction agent. Induction with 3 to 5 mg/kg of
thiopental usually produces five to 10 minutes of unconsciousness within
seconds.5
Pentobarbital can also be used for
sedation in children. It is a potent respiratory depressant, particularly in
conjunction with narcotics and benzodiazepines. Pentobarbital is not an ideal
drug for sedation for short procedures because of its prolonged duration of
action.5
Methohexital is similar to
thiopental and has a similar spectrum of respiratory depression to thiopental.
5 Problems associated with the IV administration of methohexital are
burning, hiccups, apnea, and extrapyramidal-like movements. Consequently, IV
methohexital is rarely used to induce anesthesia. Methohexital is more
commonly given rectally to induce anesthesia.10
Opioids are widely used in the
practice of pediatric anesthesia and pediatric perioperative med icine; they
provide analgesia for painful procedures and decrease the incidence of
postprocedural pain.5,11 Because opioids suppress the carbon
dioxide response, induce apnea, and are respiratory depressants, their use
must be monitored closely--especially when they are administered with other
respiratory depressing agents (e.g., inhalational anesthetics, barbiturates,
benzodiazepines).5 Morphine and fentanyl are the most commonly used
opioids in pediatric anesthesia.11
Morphine is a long-acting analgesic
medication that provides effective analgesia.11 Because morphine
can cause bronchospasm (secondary to histamine release), it should be used
cautiously in children who suffer from asthma.5 The usual IV dose
of morphine is 0.1 to 0.2 mg/kg.8,11 Equivalent mg/kg doses of
morphine provide much higher blood concentrations in neonates than in older
children, with plasma concentrations approximating three times those in
adults. This is caused by a prolonged elimination half-life (14 hours) in
neonates as compared with adults (two hours).5 By 2 months of age,
clearance values for morphine reach adult values.11 Because of the
prolonged activity and hemodynamic instability induced by morphine, fentanyl
has largely replaced morphine in general anesthesia.5
Fentanyl (which is 80 to 100 times
more potent than morphine) ranks as the most commonly used opioid in pediatric
anesthesia.3,5,11 It has a shorter duration of activity and a more
stable hemodynamic profile than morphine.3,5 Effective analgesia
and anesthesia with fentanyl can be provided using a 2- to 3-mcg/kg bolus
followed by a 1- to 3-mcg/kg/hour continuous infusion.5
Other synthetic opioids--sufentanil,
alfentanil, and remifentanil--are also available. Sufentanil (which is eight to
10 times more potent than fentanyl) is used primarily in pediatric cardiac
cases. Remifentanil (which is similar in potency to fentanyl) is considered an
ultrashort-acting opioid.5,11,12 It is used when anesthesia needs
to be rapidly induced.5 Because the primary narcotic effect of
remifentanil ends so quickly, additional analgesics must be used to provide
postoperative pain relief.12 Alfentanil (which is five to 10 times
less potent than fentanyl but has a faster onset of action) appears to have an
increased incidence of muscle rigidity, convulsions, and prolonged respiratory
depression compared with fentanyl and is therefore rarely used in pediatric
anesthesia.5,11
Benzodiazepines induce hypnosis,
anxiolysis, sedation, and amnesia and have anticonvulsant activity. In larger
doses, they cause respiratory depression and apnea; they are synergistic with
narcotics and barbiturates in their respiratory depressant effects. The most
commonly used benzodiazepine in pediatric anesthesia is midazolam. It is a
potent hypnotic-anxiolytic-anticonvulsant and is approximately four times more
potent than diazepam. In anxiolytic doses, IV midazolam (0.15 mg/kg) has no
impact on respiratory rate, heart rate, or blood pressure and provides
excellent preoperative sedation, frequently accompanied by amnesia.5
Midazolam can be administered orally, nasally, rectally, and intramuscularly.
The use of oral midazolam at a dose between 0.5 to 1 mg/kg (with a maximum of
20 mg), mixed in sweet-flavored syrup, induces anxiolysis in approximately 90%
of children.5,8
Propofol has a very rapid onset and
is associated with a reduced rate of postoperative nausea and vomiting.
Propofol ranks as the most commonly used IV induction agent in pediatric
anesthesia.2,5,13 As with thiopental, the induction dose of
propofol is higher in younger patients (2.9 mg/kg for children less than 2
years of age) than in older patients (2.2 mg/kg for patients 6 to 12 years of
age). Propofol is associated with pain on IV administration, particularly in
small veins. As little as 0.2 mg/kg of lidocaine (mixed with the propofol) has
been effective in reducing this discomfort.3 After induction of
anesthesia, propofol is considered a useful agent for maintaining hypnosis and
amnesia. It can be used as a sole anesthetic agent for nonpainful procedures.
Combined with narcotics, propofol provides excellent, brief anesthesia for
painful procedures. Propofol should not be used in children younger than 12
years of age for prolonged sedation because of the risk of serious
consequences (e.g., hemodynamic collapse, metabolic acidosis, cardiac failure,
profound shock, and death). Additionally, the use of propofol for prolonged
sedation in the critical care setting is also not advised.5
Ketamine, which has a rapid onset
and a short duration of action, causes central dissociation while providing
analgesia and amnesia.3,5,10 Induction with 2 mg/kg of ketamine
usually produces 15 to 30 minutes of unconsciousness within seconds.5
Ketamine may also be administered rectally at 10 mg/kg, orally at 6 to 10
mg/kg, or intranasally at 3 to 6 mg/kg to induce anesthesia.3,5
Ketamine does not significantly affect blood pressure and/or cardiac output.
Because ketamine increases the production of secretions, anticholinergic
medications (e.g., atropine, glycopyrrolate) are usually needed.2,5
Dreams and hallucinations are the most common side effects associated with
ketamine: 5% to 10% of prepubescent children and 30% to 50% of older children
experience this adverse effect.2,10 Administration of a
benzodiazepine concomitantly with ketamine decreases the incidence of dreams
and hallucinations.2,5 Contraindications to the use of ketamine in
children include the presence of an active upper respiratory tract infection,
increased intracranial pressure, open-globe injury, and the presence of
psychiatric or seizure disorders.5
Neuromuscular Blocking Agents
The neuromuscular blocking agents are used primarily as an adjunct to general
anesthesia to facilitate endotracheal intubation and to maintain muscle
relaxation during surgery.2,5 It is important to note that
neuromuscular blocking agents have no known effect on consciousness or pain
threshold. Neuromuscular blocking agents are classified based on the type of
blockade produced (depolarizing versus nondepolarizing) and on their duration
of action (e.g., ultrashort, short, intermediate, long).2 Table 4
provides information regarding the neuromuscular blocking agents that are
most commonly used in pediatrics.
The actions of the nondepolarizing
neuromuscular blocking agents cease spontaneously as plasma concentrations
decline or by reversal with anticholinesterase inhibitors (e.g., neostigmine).
Unfortunately, the anticholinesterase inhibitors can cause unwanted
cholinergic side effects, including bradycardia, bronchoconstriction, and
salivation. Consequently, anticholinergic agents (e.g., atropine,
glycopyrrolate) are usually given along with the anticholinesterase inhibitors
in order to minimize the cholinergic side effects.2
In December 2005, the Institute for
Safe Medication Practices (ISMP) issued a safety alert entitled "Paralyzed by
Mistakes," which warned about inadvertently giving neuromuscular blocking
agents to patients who are not receiving ventilator support. The alert noted
that some patients have died or incurred permanent injuries as a result of
these errors. To decrease this type of error, ISMP suggests that health care
facilities provide:
• Limited access to the
neuromuscular blockers, allowing floor stock only in the operating room,
emergency department, and critical care units;
• Separate storage, keeping boxes containing these agents separate in
refrigerators and on shelves;
• Mandated warning labels on vials, syringes, infusion bags, and boxes
that state: "Warning: Paralyzing agent--causes respiratory arrest";
• A double-check process prior to administration; and
• Immediate removal of the agents once the patient has been extubated.
14
Complications Associated with
General Anesthesia
Complications associated with general anesthesia can be divided into four
basic categories: postoperative nausea and vomiting (PONV), oral trauma,
thermoregulation issues, and cardiorespiratory complications.5,6
PONV is the most common problem
associated with general anesthesia. An estimated 40% to 50% of children
experience PONV after receiving general anesthesia. PONV can occur in the
immediate postoperative period, one to two hours postoperatively, or several
hours after surgery. The stress and trauma of surgery and the proemetic
effects of the anesthetic agents and narcotic analgesics most likely cause
PONV.5 Numerous products exist that can prevent and/or treat PONV.
The serotonin antagonists (e.g., ondansetron, dolasetron, granisetron) are
considered to be first-line drugs for PONV. They can be used to treat and/or
to prevent PONV. Studies show that adding dexamethasone to a serotonin
antagonist further decreases the incidence of PONV. IV metoclopramide (0.1 to
0.2 mg/kg up to 10 mg) is also an effective and safe antiemetic for both
prevention and treatment of PONV. The use of droperidol, which was once
considered the gold standard in the treatment of PONV, has decreased
significantly in recent years owing to the fact that the product, even at low
doses, can cause QTc (corrected QT) interval prolongation and/or torsades de
pointes.3
Oral trauma is relatively common
after general anesthesia. The insertion or removal of the endotrachael tube
can irritate the throat, causing a sore throat and/or hoarseness. In rare
instances, dental trauma can also occur due to the insertion and/or removal of
the tube.6
MH is an inherited disorder that is
triggered by the volatile anesthetic agents and/or succinylcholine. It usually
occurs within the first two hours of anesthesia but can occur up to 24 hours
later. MH is characterized by the development of a sudden and rapid high fever
(38.5°C to 46°C, rising 1°C every five minutes), muscle rigidity, acidosis,
and cardiac arrhythmias. Because MH can be fatal, aggressive therapy is
warranted. The treatment of MH includes discontinuing all volatile inhalation
agents, correction of the metabolic acidosis, and treatment with IV dantrolene
(2.5 mg/kg up to 10 mg/kg). All pharmacists, especially those working in
intensive care units and operating rooms, should be familiar with
reconstituting and administering IV dantrolene.
According to Donald Davis, MD,
Anesthesiologist at Children's Healthcare of Atlanta, "Patients experiencing
MH frequently require extremely large doses of IV dantrolene within a short
period of time. This can be very challenging in terms of time and manpower
since IV dantrolene can be very cumbersome to reconstitute." Davis notes that
during such crisis situations, pharmacists should immediately start
reconstituting IV dantrolene and continue until they are told otherwise.15
Once a person is diagnosed with MH, their relatives should be tested to
determine if they also have the disorder.2,3,5
Cardiorespiratory complications
(e.g., respiratory depression, hypertension, arrhythmias, heart attacks,
stroke) can also result from general anesthesia. Fortunately, these problems
are extremely rare and are more likely related to surgical complications.
3,5,6
Preventing Oversedation
The American
Academy of Pediatrics Committee on Drugs (COD) notes that children tend to be
particularly susceptible to oversedation with anesthesia. (Table 5
lists recommendations from the COD for preventing oversedation in children.
16) Consequently, provision for safe sedation in children requires skill
and organization of resources to prevent severe negative patient outcomes.
Pulse oximetry is considered the single most helpful monitoring device for
detecting impending life-threatening events. Pulse oximetry, particularly the
type that provides an audible change in tone as the saturation changes, should
be required for every patient sedated for a procedure, because it provides an
early warning of developing oxygen desaturation. In addition, both clinicians
administering anesthesia and those in the postoperative arena should always
have the appropriate reversal agents (e.g., naloxone, flumazenil) at their
disposal.17
Conclusion
Pharmacists should
be encouraged to take a proactive approach in managing the "littlest of
patients" during the perioperative period, especially in monitoring for side
effects and adverse drug reactions. In order to do this more effectively,
pharmacists must have an understanding of the physiologic, pharmacologic, and
psychological differences between children and adults with regard to
anesthesia pharmacology.
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