Anesthetic adjuncts

Atropine

Atropine is a nonspecific muscarinic acetylcholine receptor antagonist that can be administered orally, intravenously (IV), intramuscularly (IM), and rectally. A wide range of doses have been used for all routes. Palmisano and colleagues studied anesthetized infants and children following a rapid intravenous dose ranging from 5 to 40 mcg/kg ( ). For children older than 2 years of age, all doses of atropine increased heart rate. In children younger than 6 months of age, heart rate increased with all doses except the 5 mcg/kg dose. Similar ranges of doses for IM administration have been used. Sullivan and associates noted that 20 mcg/kg IM in children following submental glossal injection had a faster response than injections into the deltoid or vastus lateralis muscle ( ). Onset of action in this study determined as the time from injection to the slope of the heart rate curve becoming positive was 3 to 6.5 minutes. Onset of action of atropine given IV is 1 minute with a duration of 30 to 60 minutes ( ). Halothane anesthesia was commonly associated with bradycardia, and the development of junctional cardiac rhythms was thought to be vagally mediated ( ). In a review of anesthetics administered to infants and children from 1983 to 1992 in which halothane was the predominant anesthetic, Keenan and colleagues noted that bradycardia occurred in 1.27% of children 0 to 1 year of age, 0.98% of children 1 to 2 years of age, 0.65% of children 2 to 3 years of age, and 0.16% of children 3 to 4 years of age ( ). IM premedication with atropine (0.02 mg/kg) decreased the incidence of bradycardia from 30% to 18% ( ). Sevoflurane does not change the heart rate or cardiac index to the degree that halothane does and thus atropine premedication is not used as commonly ( ). There is controversy as to the response to atropine in patients with Down syndrome. Harris and Goodman reported an exaggerated heart rate ( ), whereas Kobel and associates noted no difference in heart rate response to 18 mcg/kg compared with patients without Down syndrome ( ). Succinylcholine administration has also been linked to bradycardia; however, pretreatment with atropine prior to succinylcholine for rapid sequence intubation in children 1 to 12 years of age did not show a difference in bradycardia ( ). The oculocardiac reflex is responsible for bradycardia commonly seen during ophthalmologic surgery. Both glycopyrrolate 5 to 7.5 mcg/kg and atropine 10 to 15 mcg/kg have been shown to reduce the incidence of bradycardia during ophthalmologic surgery, but neither drug was able to eliminate reductions in heart rate for all patients ( ), ( ). Atropine is not effective as an antiemetic following strabismus surgery ( ). Though not commonly thought of as bronchodilators, atropine and glycopyrrolate are effective as bronchodilators when either inhaled or administered intravenously ( ).

Glycopyrrolate

Glycopyrrolate is a quaternary ammonium anticholinergic agent that is used extensively in pediatric anesthesia to inhibit secretions and prevent vagally mediated bradycardia without producing the tachycardia seen with atropine ( ). As opposed to atropine, glycopyrrolate has minimal activity centrally because it does not readily cross the blood-brain barrier (see Table 14.1 ). In a study of IV glycopyrrolate (10 mcg/kg) and atropine (20 mcg/kg), glycopyrrolate was found to have a better antisialagogue effect ( ). A common pediatric problem is an upper respiratory tract infection (URI). Given the antisialagogue effects of glycopyrrolate, it has been studied in this population but has not been shown to decrease the incidence of adverse perioperative events ( ). Neostigmine and glycopyrrolate have similar onset and duration of action, which has led to the preference of this combination for the reversal of neuromuscular blockade ( ). However, one study showed that the combination of atropine and neostigmine produced less nausea and vomiting following tonsillectomy and adenoidectomy in children than did glycopyrrolate and neostigmine ( ). Similar findings have also been shown in an adult study following minor surgery in which patients reversed with glycopyrrolate and neostigmine had a higher incidence of nausea for the first 2 hours in recovery ( ).

Scopolamine

Scopolamine is a nonselective muscarinic antagonist that acts at both peripheral and central receptors. Scopolamine can be administered intravenously, subcutaneously, intramuscularly (0.006 to 0.01 mg/kg), or transdermally (scopolamine patch) ( ). Scopolamine has much greater activity centrally than atropine, producing sedation, amnesia, and antiemetic activity. The half-life of scopolamine is short, and its adverse effects (hallucinations, vertigo, dry mouth, and drowsiness) are dose related. The transdermal patch is effective for treatment of motion sickness as well as PONV. Currently, pediatric use of the patch is off-label, but it has been studied in children after both abdominal and strabismus surgery (see Table 14.1 ) ( ; ). Case reports of delirium have been reported in children following scopolamine patch application ( ).

Ketorolac

Ketorolac tromethamine and indomethacin are the only IV nonsteroidal antiinflammatory drugs (NSAIDs) available in the United States. First approved by the United States Food and Drug Administration (FDA) in 1989, ketorolac is now available in oral, ophthalmic, and intranasal forms. Ketoprofen, diclofenac, and ibuprofen lysine are available in intravenous form outside of the United States. Ketorolac has been administered intravenously, intramuscularly, intranasally, orally, and intraocularly (see Table 14.2 ) ( , ; ).

Ketorolac is an enantiomeric compound, and its S(–) enantiomer is responsible for its analgesic effects. It has more recently been hypothesized that the R enantiomer is important for ketorolac’s apparent anticancer activity ( ; ; ). Kauffman noted that in children, concentrations of the S(–) enantiomer were lower than those of the R(++) enantiomer and had a shorter half-life, greater clearance, and larger volume of distribution ( ). Hamunen found that the differences in enantiomeric kinetics are similar for children, adolescents, and adults ( Fig. 14.1 ) ( ). Ketorolac’s onset of action is within 30 minutes, its peak analgesic effect is within 1 to 2 hours, its duration of action is 4 to 6 hours, and its half-life is 6 hours ( ). Ketorolac is metabolized through hepatic conjugation with glucuronic acid, and it should be used with caution in patients with impaired hepatic function or a history of liver disease. Its metabolites (40%) are inactive and are renally excreted along with unchanged drug (60%) ( ). Its clearance has been found to be greater in neonates, infants, and children than in adults in several studies; however, its elimination half-life is similar to adult values ( ; ; ; ; ; ). The increased clearance rate may necessitate higher maintenance doses on a milligram per kilogram basis than in adults ( ).

Ketorolac provides postoperative analgesia comparable to opioids but without the side effects of respiratory depression, sedation, nausea, and pruritus ( ; ; ). As concerns surrounding opiate addiction and dependence increase, nonopiate analgesics such as ketorolac are increasingly being utilized preoperatively ( ). Ketorolac may also have antiemetic properties ( ). Multiple studies have looked at ketorolac’s potentially beneficial role in improving human breast and ovarian cancer survival ( ; ; ). In addition, Panigrahy and colleagues found that ketorolac, when given preoperatively, worked synergistically with resolvins to eliminate micrometastases in multiple tumor resection models, resulting in long-term survival ( ).

Ketorolac’s mechanism of action, like other NSAIDs, is not completely understood. Ketorolac acts at central and peripheral sites. Its inhibition of COX-1 and COX-2 prevents the production of prostaglandin-2 (PGE-2). PGE-2 is important for nociception, inflammation, smooth muscle contraction and relaxation, gastric acid and mucus secretion, renal vasculature constriction and dilation, and febrile reactions ( ; ). Through its effects on COX-1, ketorolac also inhibits thromboxane ( ). Ketorolac’s effects on PGE-2 and thromboxane are limited to its duration of action ( ).

In children, ketorolac crosses the blood-brain barrier in small amounts ( ). Although its central mechanism of action is not completely understood, ketorolac, like other NSAIDs, may function by activating spinal glutamate and substance P receptors, which then limit the hyperalgesic response ( ). Kumpulainen and colleagues found that ketorolac’s cerebrospinal fluid (CSF) peak concentration correlated with its peak analgesic effect ( ). CSF concentrations of ketorolac vary inversely with age, height, weight, and body surface area, suggesting a greater central role for younger and smaller patients ( ).

Although ketorolac’s safety profile has been established for over 20 years ( ; ; ), adverse events with its use have been reported. Ketorolac has been associated with allergic and hypersensitivity reactions, bleeding, gastrointestinal erosion and ulceration, and changes in renal perfusion and function ( ; ; ; ). Ketorolac has a minimal effect on prothrombin and partial thromboplastin times but causes a modest increase in bleeding time ( ). Several studies have raised concern about the bleeding risk associated with ketorolac for patients undergoing adenotonsillectomy; however, bleeding complications have not been associated with other types of surgeries ( ; ; ; ). Due to its effect on platelet function, ketorolac should be administered after hemostasis has been obtained ( ; ; ). Buck found the incidence of gastrointestinal and renal side effects comparable to a placebo when given in doses of 0.5 to 1 mg/kg (maximum 30 mg) every 4 to 6 hours for 5 or fewer days ( ).

Although some studies have shown ketorolac to be effective and safe in neonates and premature infants, others have shown NSAIDs to have a significant effect on glomerular filtration rate ( ; ; ). Aldrink also found an increased bleeding risk with ketorolac in neonates younger than 21 days of age and younger than 37 weeks’ corrected gestational age ( ). Presently, the routine use of ketorolac in neonates is not recommended.

Although Lynn found no complications from ketorolac use in 37 infants 6 to 18 months of age, ketorolac should be used with caution in patients with renal dysfunction due to possible detrimental effects on renal perfusion and renal function ( ). To minimize the risk for renal side effects in infants 1 month of age up to children 2 years of age, Burd recommends limiting postoperative use to 48 to 72 hours ( ; ; ; ). The FDA limits the use of ketorolac to 5 days. Foster has also reported sudden and profound bradycardia in two children after rapid injection of IV ketorolac ( ).

Concerns about the association of pseudoarthrosis (nonunion) with ketorolac use have limited the drug’s use in orthopedic surgery. Both animal and human studies have reported pseudoarthrosis with high-dose ketorolac use ( ; ; ; ). In these human studies, patients could receive 120 mg or more of ketorolac daily. However, Sucato and colleagues found no statistically significant differences in the nonunion rates between pediatric patients after major orthopedic surgery who received ketorolac and those who did not ( ; ; ; ). In addition, Kurmis concluded in a review of NSAIDs on acute-phase fracture healing that a short-duration NSAID regimen is a safe and effective supplement to postfracture pain control ( ).

The dose of ketorolac for neonates has not been established. Burd recommends 0.5 mg/kg per dose every 8 hours for up to 1 to 2 days ( ). Using the lowest effective dose is also recommended to reduce the risk for adverse cardiovascular and gastrointestinal effects. The recommended multidose treatment for infants 1 month of age and older to children younger than 2 years of age is 0.5 mg/kg every 6 to 8 hours for up to 48 to 72 hours ( ; ; ; ). For children 2 to 16 years of age and children older than 16 years who weigh less than 50 kg, the manufacturer recommends a single-treatment dose of 1 mg/kg IM with a maximum of 30 mg and 0.5 mg/kg IV with a maximum of 15 mg. Limited data on dosing recommendations for this age and weight group is available. Doses of 0.05 to 1 mg/kg IV and IM have been studied. Maunuksela found a median required single IV dose of 0.4 mg/kg ( ). Multiple-dose IM or IV treatment is 0.5 mg/kg every 6 hours for a maximum of 5 days ( ; ; ). For children older than 16 years of age who weigh over 50 kg, single IM dosing is 60 mg, and single IV dosing is 30 mg. For this age and weight group, multiple-dose IM and IV treatment is 30 mg every 6 hours with a maximum of 120 mg/day, although some centers also use a maximum of 15 mg/dose for this group.

Acetaminophen

Acetaminophen (paracetamol), N- acetyl- p- aminophenol, is a commonly used nonopioid analgesic and antipyretic in pediatric practice. It is also used as an alternative for the closure of patent ductus arteriosus in premature neonates ( ; ). It has been used as an analgesic and antipyretic since the 1940s and has been available in the United States without a prescription since 1955. It is available in oral, rectal, and intravenous forms.

Acetaminophen functions centrally and peripherally by blocking prostaglandin synthesis as a COX-3 inhibitor, activating descending serotonergic pathways, reducing substance P–induced hyperalgesia, and reducing nitric oxide in the spinal cord ( ; ; ). Acetaminophen’s analgesic properties may also be due to its cannabinoid agonist and NMDA antagonist properties ( ; ). Importantly, acetaminophen does not have antiplatelet or anti-inflammatory activity. Acetaminophen produces antipyresis through inhibition of the hypothalamic heat-regulating center. Plasma concentrations of 5 to 20 mcg/mL have been associated with analgesic and antipyretic effects ( ; ; ; ; ). Ideal analgesic concentrations remain unknown. Anderson and colleagues found that an acetaminophen concentration of 10 mg/L was associated with a pain score reduction of 2.6 out of 10 in children following tonsillectomy ( ). Patient characteristics, surgical procedure, and timing may play an important role in dosing and efficacy. Mian found that the clearance of acetaminophen was lower and the volume of distribution higher in children after cardiac surgery with cardiopulmonary bypass ( ). Obesity likely plays a role as well. Hakim found that in severely obese adolescents, a dose of 1000 mg IV acetaminophen resulted in undetectable serum concentration levels within 2 hours of administration ( ). Preemptive (prior to procedure) versus preventive dosing (at conclusion of the procedure) may also play a role in efficacy ( ).