COLLECTIVE REVIEW ketamine

Ketamine Sedation for Pediatric Procedures: Part 2, Review and Implications [Green SM, Johnson NE: Ketamme sedation for pediatric procedures: Part 2, review and implications. Ann Emerg Med September 1990;19:1033-1046.] INTRODUCTION Emergency physicians frequently perform procedures that can be painful. Ketamine hydrochloride can be valuable in these circumstances; when administered IV or IM, it rapidly produces profound sedation and analgesia, allowing performance of procedures under optimum conditions. Spontaneous breathing and protective airway reflexes are maintained without intubation, and recovery to a degree suitable for emergency department discharge typically occurs in 30 to 120 minutes. Use of ketamine for various pediatric applications has been extensively documented in numerous studies of more than 11,000 children as having outstanding safety and efficacy. 1-9z Despite frequent recommendations for use of this agent in the ED,3S,98-1oo reports of ED applications are few and of limited scope. 31 34 Structurally derived from the street drug phencyclidine in 1963 and introduced into general clinical practice in 1970, ketamine is a unique combination of sedative, amnesic, and analgesic. Unlike narcotics and inhalational agents, which suppress the reticular activating system, ketamine generates a functional and electrophysiological dissociation between the cortical and limbic systems.4a, let to4 This trancelike cataleptic state was first described as "dissociative anesthesia" by Corssen and Domino in 1966. 45 Analgesia and amnesia are no less apparent than in the use of narcotic and inhalational anesthetics; however, unlike these agents, ketamine does not impair laryngeal reflexes and independent airway maintenance.6,2o,2h45,49,so,85,86,102 Muscle tone is uninhibited, and purposeful movements may occur unrelated to painful stimuli. Eyes remain open with~a " d i s c o n n e c t e d " stare, and n y s t a g m u s is almost universally noted.2O, le2, lo4 Hallucinatory emergence reactions frequently seen in adults are extremely rare in children.3,43,ss,-~7,6e,62,82,94 Generally recognized contraindications to the use of ketamine are listed (Figure). Despite a common perception that it is a general anesthetic, the unique clinical state induced by ketamine is distinctly different from the generalized relaxation produced by traditional anesthetic agents. Consensus conferences have defined general anesthesia as "unconsciousness, accompanied by partial or complete loss of protective reflexes, including the inability to independently maintain an airway. 'qo54os The dissociated state induced by ketamine cannot be equated with this definition of general anesthesia because protective airway reflexes are maintained without clinical respiratory depression.6,2o,27,45,49,so,85,86, m2 Furthermore, the effects of ketamine do not correlate with the classic stages and planes of anesthesia as described by Geudel 20,22,1e9 The dissociated state induced by ketamine is unique and cannot be compared on equal terms with that induced by general anesthetics.

Steven M Green, MD* Loma Linda, and Riverside, California N Eric Johnson, MD, MPH, FACEPt Loma Linda, California From the Department of Emergency Medicine, Riverside General Hospital, Riverside, California;* California Emergency Physicians Medical Group, Oakland, California;* and the Department of Emergency Medicine, Loma Linda University Medical Center, Loma Linda, California2 Received for publication May 1, 1989. Revisions received September 7, 1989, and April 9, 1990. Accepted for publication May 2, 1990. Address for reprints: Steven M Green, MD, Department of Emergency Medicine, Riverside General Hospital, 9851 Magnolia Avenue, Riverside, California 92503.

REVIEW OF CLINICAL EXPERIENCE Regular use for 20 years has established ketamine as a safe and efficacious agent. Numerous large investigations involving both IV and IM routes substantiate this concensus; all series-style reports that could be

19:9 September 1990

Annals of Emergency Medicine

1033/131

KETAMINE SEDATION Green & Johnson

TABLE 1. Summarization of 97 published reports detailing 11,589 pediatric administrations of ketamine*

Procedural Indications Bronchoscopy Burn w a r d p r o c e d u r e s Cardiac catheterization Dentistry or oral s u r g e r y

No. of Reports

No. of Pediatric Patients

Dose (mg/kg) IM

IV

1

5

10

3,415

1.5 - 13

11

8

579

7 - 13

11

673

1

2 -- 5

2-11 12 - 19

12

0.25 - 2.2

20 - 30

2

0.25 - 2

31 - 35

5

39

0.5

Ear, nose, and throat p r o c e d u r e s

5

653

2

11

Gastroenterology procedures

3

88

4

8

Minor or m a j o r s u r g e r y

23

3,285

Ophthalmology procedures

12

637

Pediatric minor p r o c e d u r e s t

4

338

Radiology procedures

3

35I

8 - 12

12

1,526

2.7 - 16

Radiation t h e r a p y

1

... 1 - 2.2

ED

0.4 - 2.2 2

4 - 17 5 - 13 2.5-

Reference

10

3

36

40

41

43

1 - 11

44 - 66

1 - 4

67 - 78

1 -2

79 - 82

1 - 2.2 1

83 - 85 86 - 97

*Includes all published series that could be located on the use of ketamine as a primary sedating agent in children. Excluded are reports in which patients were intubated. More specific information regarding each study is detailed in a summary table compiled by the authors and available to those providing a stamped, addressed, legal-size envelope. tProcedures such as bone marrow aspiration, lumbar puncture, and thoracentesis, among others, performed in a pediatric ward or clinic.

F I G U R E . Contraindications to the

use of ketamine.

A g e of 3 m o n t h s or less

l o c a t e d (both p r o s p e c t i v e and retrospective) on the use of k e t a m i n e as the p r i m a r y sedating agent in the uni n t u b a t e d pediatric p a t i e n t are summ a r i z e d (Table 1). ~ 97 N i n e t y - s e v e n series i n v o l v i n g 17,550 a d m i n i s t r a tions (at least 11,589 are specified as pediatric) d e m o n s t r a t e a wide range of a p p l i c a t i o n s and an e x c e p t i o n a l margin of safety. O u t p a t i e n t k e t a m i n e sedation was p e r f o r m e d e x c l u s i v e l y in 26 of the 97 reports and in s o m e cases in 20 o t h e r reports. T h e s e s t u d i e s docum e n t that recovery typically requires 30 to 120 minutes, m a k i n g k e t a m i n e quite suitable for outpatient

Active p u l m o n a r y infection or d i s e a s e

P r o c e d u r e s involving stimulation of the posterior p h a r y n x *

1.1Se. 20-37,39-44,48,51, ,54,62-64, 67, 71,72, 75, 78, 79,81,87-96

Also n o t e w o r t h y is the p a u c i t y of m o n i t o r i n g d e v i c e s ; 14 a u t h o r s reported that their only " m o n i t o r i n g " m o d a l i t y was clinical observation (ie, a physician or nurse closely watching t h e p a t i e n t ) , to,21 23,29,36,60,77,78,82, ~7 90 Pulse and cardiac m o n i t o r s were n o t r e g u l a r l y used; in a s u b s t a n t i a l n u m b e r of cases, e v e n v i t a l s i g n s were n o t m e a s u r e d . T h e absence of increased respiratory or cardiac comp l i c a t i o n s in t h e s e r e p o r t s fails to 132/1034

History of a i r w a y instability, tracheal surgery, or tracheal stenosis C a r d i o v a s c u l a r disease, including angina, heart failure, a n e u r y s m , or uncontrolled hypertension H e a d injury a s s o c i a t e d with loss of c o n s c i o u s n e s s or altered m e n t a l status* CNS m a s s lesions,* h y d r o c e p h a l u s , or other c o n d i t i o n s a s s o c i a t e d with intracranial h y p e r t e n s i o n G l a u c o m a or a c u t e g l o b e injury* Prior a d v e r s e reaction to k e t a m i n e Psychosis Thyroid d i s o r d e r or m e d i c a t i o n * Porphyria* *Use of ketamine is not recommended in these situations; however, supporting literature evidence is contradictory or controversial.

support the suggestion that extensive m o n i t o r i n g d e v i c e s are m a n d a t o r y w h e n k e t a m i n e is used. In the 22 reports in w h i c h use of cardiac m o n itoring is described (eight were exclusively reporting children undergoing cardiac catheterization), dysrhythmias were e x t r e m e l y rare and considered to be secondary to catheter stimAnnals of Emergency Medicine

ulation.

1,3,5,11,12 19,37,53,56,57,59,75,

76,91,95,96

The reports of Phillips et al 5~ and Walker 6~ describe a single physician acting as both surgeon and anesthetist who used IM ketamine successfully to perform major and m i n o r surgical procedures on patients in rem o t e Pacific islands. D e s p i t e t h e s e 19:9 September 1990

harrowing conditions, they report m i n i m a l c o m p l i c a t i o n s in 886 cases (both pediatric and adult). O n l y two p a t i e n t s r e q u i r e d i n t u b a t i o n - an underweight neonate who experienced laryngospasm and a 15-monthold w i t h e x t e n s i v e p n e u m o n i a w h o b e c a m e apneic.5:~,6t These cases represent established contraindications to the use of k e t a m i n e (Figure). Because of its s i m p l i c i t y and efficacy, k e t a m i n e is of great v a l u e in b a t t l e f i e l d or d i s a s t e r s i t u a t i o n s in w h i c h the lack of facilities and t i m e disallow the use of general anesthetics.110, l l 1 Soon after the G u a t e m a l a e a r t h q u a k e of 1976, Roy Wilson and a second anesthesiologist a d m i n i s t e r e d k e t a m i n e IV to f a c i l i t a t e 150 unint u b a t e d surgical cases during a 36hour period. M o n i t o r i n g consisted of visual observation with infrequent b l o o d pressure m e a s u r e m e n t s . Wilson concluded, " N o t h i n g in m y wilde s t d r e a m s of m i n i m a l e q u i p m e n t ever a p p r o a c h e d the s i m p l i c i t y and safety of the k e t a m i n e technique under these true test conditions. ''112

PHARMACOLOGY L a b o r a t o r y e x p l o r a t i o n of p h e n c y c l i d i n e v a r i a t i o n s led to the synthesis in 1963 of CI-581 (initial design a t i o n of ketamine), a chloroketone analogue of the hallucinogen, ml The r a c e m i c f o r m of k e t a m i n e u s e d in clinical practice contains equal a m o u n t s of t w o r e s o l v a b l e o p t i c a l i s o m e r s or e n a n t i o m e r s . l ~ 3 : 1 4 Despite being water soluble at c o m m e > cial c o n c e n t r a t i o n s , k e t a m i n e possesses e x c e l l e n t lipid s o l u b i l i t y and can quickly cross the blood-brain barrier.~tt,t~,% ll6 K e t a m i n e is painless and n o n i r r i t a t i n g after parenteral injection. 99 Ketamine induces a dissociation b e t w e e n the t h a l a m o n e o c o r t i c a l and limbic systems, preventing the h i g h e r c e n t e r s f r o m p e r c e i v i n g visual, auditory, or painful s t i m u l i 3 m A s s o c i a t i o n areas of the c o r t e x and t h a l a m u s are depressed and create a "sensory isolation."48, m4 The mecha n i s m by w h i c h k e t a m i n e p r o d u c e s this effect is uncertain. K e t a m i n e has been found to bind to c e n t r a l n e r v o u s s y s t e m (CNS) N-methyl-D-aspartate (NMDA) recept o r s in a m a n n e r s i m i l a r to t h a t achieved by p h e n c y c l i d i n e and sigma o p i a t e s ; in a d d i t i o n , it i n h i b i t s release of the N M D A t r a n s m i t t e r glut a m i n e . 117-119 It has been h y p o t h e 19:9 September 1990

sized t h a t N M D A r e c e p t o r s constit u t e a s u b g r o u p of s i g m a o p i a t e r e c e p t o r s and t h a t the analgesic effect of k e t a m i n e is m e d i a t e d in this m a n n e r , ll7,12° T h e s i g n i f i c a n c e of this a c t i v i t y r e m a i n s controversial, h o w e v e r ; one i n v e s t i g a t o r n o t e d a p a r t i a l r e v e r s a l of k e t a m i n c w i t h naloxone, ~2° and, although the same doses were used, another investigator did not. 121 Rat s t u d i e s suggest t h a t w h i l e n a l o x o n e reverses the analgesic effects of k e t a m i n e at c l i n i c a l doses (0.23 mg/kg), even high doses (3 mg/kg) have no effect on its dissoc i a t i v e properties. ~2¢ In addition, it appears t h a t o n l y the ( + ) - i s o m e r of k e t a m i n e binds to these N M D A rec e p t o r s : t7 K e t a m i n e p h a r m a c o k i n e t i c s are very similar in adults and children. 116,123 125 Peak c o n c e n t r a t i o n s o c c u r w i t h i n o n e m i n u t e after IV injection, and rapid absorption by the highly perfused cerebral tissue allows a l m o s t i m m e d i a t e induction of clinical effects. ~,5 K e t a m i n e then slowly redistributes into the peripheral tissues; t h i s d e c r e a s e in C N S l e v e l s correlates w i t h r e t u r n of coherence, g e n e r a l l y a v e r a g i n g 15 m i n u t e s if n o a d d i t i o n a l i n j e c t i o n s a r e given..~5,79, to2,104,115, 116 P e a k l e v e l s o c c u r five m i n u t e s after a 5 to 10-mg/kg IM i n j e c t i o n w i t h equal onset of effect; however, recovery t i m e is more prolonged and v a r i a b l e t h a n w i t h IV a d m i n i s t r a tion. D i s s o c i a t i o n t y p i c a l l y persists for 15 to 30 m i n u t e s w i t h coherence and p u r p o s e f u l n e u r o m u s c u l a r act i v i t y r e t u r n i n g in 30 to 120 m i n u t e s . 10,48,51,60,62,86,87,92,102,104 T h e e l i m i n a t i o n half-life of k e t a m i n e is two to three hours in adults;ll6,123, 124 c h i l d r e n m e t a b o l i z e k e t a m i n e more quickly, w i t h a half-life of one to two hours. ~23,125 The overall m e t a b o l i c fate of keta m i n e is c o m p l e x and poorly understood; there are scores of m e t a b o l i t e s w i t h c h e m i c a l s t r u c t u r e s and pharmacological activities that r e m a i n to be established. ~26 K e t a m i n e is first N - d e m e t h y l a t e d by the hepatic cytoc h r o m e P4so s y s t e m to f o r m n o r k e t a m i n e , w h i c h possesses a dissociative p o t e n c y of as m u c h as one third that of ketamine.l~l, ~a6 In children, this e n z y m a t i c transformation occurs more rapidly than in adults. 123 F r o m t h i s p o i n t , n o r k e t a m i n e is subjected to m u l t i p l e branching degAnnals of Emergency Medicine

radation paths; certain enantioselective enzymes more rapidly metabolize one isomer and others construct second chiral centers w i t h resulting diastereoisomers.t26 Thus, the degradation of k e t a m i n e quickly becomes q u i t e c o m p l i c a t e d , a n d l i t t l e is k n o w n of the pharmacological activi t y of t h e m e t a b o l i t e s , t26 Rat a n d m o n k e y s t u d i e s of t r i t i u m - l a b e l e d k e t a m i n e show that the m a j o r i t y of b r e a k d o w n p r o d u c t s are e v e n t u a l l y p a s s e d in the u r i n e or, to a m u c h lesser extent, in the feces, lo2, ~~l, ~7 C o a d m i n i s t r a t i o n of drugs requiring h e p a t i c m e t a b o l i s m w i l l e x t e n d the half-life of k e t a m i n e by competing for d e g r a d a t i o n e n z y m e s ; I l l , 12s concurrent benzodiazepines and barbiturates have been shown to prolong c l i n i c a l r e c o v e r y in c h i l d r e n by app r o x i m a t e l y ,30%. ~l t, 12a H i g h e r k e t a m i n e doses are necessary w i t h oral or r e c t a l a d m i n i s t r a t i o n b e c a u s e a substantial first-pass hepatic metabol i s m occurs. 111,129 The dextro-( + )-isomer of k e t a m i n e has a p p r o x i m a t e l y threefold to fourfold the d i s s o c i a t i v e p o t e n c y of t h e ievo-(- )-isomer, whereas the ( - ) - i s o m e r manifests a higher rate of emergence r e a c t i o n s and agitated behavior.l13,tt4,117, ~3° Thus, a pure prepar a t i o n of t h e ( + ) - i s o m e r a p p e a r s superior to the current racemic mixture; h o w e v e r , this f o r m u l a t i o n is not c o m m e r c i a l l y available. 11l, ~~3 A v a i l a b l e f o r m u l a t i o n s of k e t a m i n e are 10, 50, or 100 mg/mL; the 10 m g / m L solution is preferred for IV a d m i n i s t r a t i o n and the 100 m g / m L s o l u t i o n is preferred for IM administration in older children to m i n i m i z e v o l u m e - r e l a t e d injection site discomfort.I;gl CLINICAL EFFECTS

Airway Maintenance Endotracheal i n t u b a t i o n is unnecessary w i t h k e t a m i n e . S p o n t a n e o u s respiration and m u s c u l a r tone of the tongue and pharynx are preserved.6,20,27,45,49,so, 'q~,s6 P r o t e c t i v e a i r w a y r e f l e x e s s u c h as c o u g h i n g , sneezing, and swallowing are not rep r e s s e d and m a y be s l i g h t l y exaggerated.6,20,27,45,48-so,ss,s6 R e s p i r a t o r y d e p r e s s i o n is e x t r e m e l y rare; it has b e e n r e p o r t e d w h e n k e t a m i n e is pushed by rapid IV bolus;2°,24,48,55,58,62,63,132 w h e n exceptionally high doses are used; 20,44 w h e n C N S injuries, masses, or abn o r m a l i t i e s a r e p r e s e n t ; 7s,133-t36 1035/133

KETAMINE SEDATION Green & Johnson

TABLE 2. Pooled data incidence of emesis in fasting and rlonfasting patients* Fasting Five Hours or More "Empty Stomachs" No. of Hours No. of Vomiting Reference Fasting Patients No. %

Total

Fasting Four Hours or Less "Full Stomachs" No. of Hours No. of Vomiting Reference Fasting Patients No. %

22

6+

18

6

33

3

1

131

1

24

6+

46

2

4

15

3

40

0

0.7 0

29

6

20

4

20

21

0

146

60

41

30

5

43

2

5

22

0

7

1

14

37

6+

81

7

9

32

0

30

2

7

43

6+

26

0

0

80

4

80

4

5

60

6+

115

2

2

82

3

100

3

3

62

6+

122

40

33

87

0

160

3

2

81

6

22

0

0

92

3

436

0

0

89

6+

17

0

0

90

6+

29

0

0

539

63

12

1,130

74

7

*Overall incidence of emesis is compared in reports requiring fasting for five hours or more (empty stomachs) with those requiring four hours or less (full stomachs). Nineteen of the 97 reports summarized in Table 1 specified the period of fasting and the incidence of emesis for pediatric patients.

or when administered to ill neonates.16,51,53,137 It is recommended that IV doses be given over at least 60 seconds. TM Although initial studies suggested that respiratory drive is unaffected by ketamine, l.38,139 subsequent reports have demonstrated a mild dose-related respiratory depression.t40 142 In children, the respiratory rate, tidal volume, end-tidal CO a tension, and minute ventilation are unaffected by ketamine; 140,143 however, respiratory response to hypercapnia is depressed by 15% to 22%. 14° A d u l t s have nearly i d e n t i c a l r e a c t i o n s ; 141 the CO2-response curve is shifted to the right, but its slope r e m a i n s unchanged.t40,141 Thus, h y p e r c a r b i c respiratory stimulation remains intact at clinical doses but requires a slightly higher P c o a to achieve the same response. While not of major clinical significance, this may explain reported cases of respiratory depression at very high doses. 2°,44 Ketamine stimulates salivary and tracheobronchial secretions.~O,43,sh 60,63,82,114,144-146 Most authors recommend administering a concurrent anticholinergic such as atropine or glycopyrrolate to inhibit these secretions and minimize the necessity of suctioning. 20,43,57,60,63,82,114,131, 134/1036

144 146 In addition, excessive salivation has been postulated as a precipitant of laryngospasm.15 Despite these concerns, ketamine has been successfully and extensively used without these adjuncts.31, 5s,66,87 Atropine and glycopyrrolate appear to be equally efficacious; 144 the typically recommended dose of atropine is 0.01 mg/kg (maximum total dose, 0.5 rag), the equivalent glycopyrrolate dose is 0.005 mg/kg (maximum total dose, 0.25 mg). 63,131,144,147,148 Either anticholinergic can be combined with ketamine in a single 1M injection. 86 Concerns have been raised regarding potential aspiration when using a powerful sedating agent such as ketamine without the guaranteed airway protection of intubation; however, the risk of a clinical aspiration synd r o m e w i t h k e t a m i n e is m i n i ma1.10~,104,lll Despite the apparent functionality of the swallowing and coughing mechanisms, several somewhat-conflicting studies have suggested that a degree of possibly doserelated reflex impairment can occur. After placement of radiopaque dye on the tongues of adults given ketamine 2 m g / k g IV, radiographs d e m o n strated endobronchial contrast in six of 11 patients, 149 seven of seven, 15° Annals of Emergency Medicine

and 12 of 17.151 A fourth author, who used unspecified quantities in 20 adults, noted tracheal contamination in only one patient, who received a "very large" dose as well as concurrent diazepam. 15~ Children appear to have better laryngeal reflexes with k e t a m i n e ; similar i n v e s t i g a t i o n s have shown endobronchial contrast in one of ten children who received 6 mg/kg IM 153 and none of eight who received 4 mg/kg IV. is4 The clinical significance of these contrast studies may be questionable, however, as silent gastric regurgitation has been reported in 4% to 26% of patients receiving general anesthetics, with tracheal contamination in as m a n y as 76%. 155 More than 20 years of continual use have produced only two case reports of k e t a m i n e - a s s o c i a t e d aspiration in non-neonates. One case occurred in an infant known to have a full stomach; the age, ketamine dose, method of administration, and clinical outcome were not given# 37 The second report describes a 6-year-old boy with a brain t u m o r (a relative contraindication to ketamine) who vomited soon after induction and developed radiographic infiltrates postoperatively. No fever or symptomatology developed, and there was no clinical 19:9 September 1990

sequelae. 156 Ketamine-associated asp i r a t i o n has been described in ill neonates; this drug is generally contraindicated in this age group.16,51,53,137 Some a u t h o r s have r e c o m m e n d e d that k e t a m i n e be avoided in patients w i t h full s t o m a c h s due to p o s s i b l e aspiration.14,157 T i m e of last meal is clearly a factor beyond a physician's control in the ED, and it is often unw i s e or h i g h l y i m p r a c t i c a l to w a i t four or m o r e hours to perform a necessary procedure. Several of the clinical series s u m m a r i z e d (Table 1) either ignored the "empty stomach" rule 21,22,32-34,56,66 or allowed oral intake w i t h i n four hours, tO,~5,80,82,86,92 w i t h i n one hour, 3,31 or i m m e d i a t e l y before administration. 87 For c o m p a r i s o n , the a u t h o r s have m a d e a r b i t r a r y d e s i g n a t i o n s of " e m p t y s t o m a c h s " as f a s t i n g five hours or m o r e and of "full s t o m a c h s " as fasting four hours or less. Overall c o m p a r i s o n of series requiring e m p t y s t o m a c h s w i t h those r e q u i r i n g full s t o m a c h s reveals no a p p a r e n t assoc i a t i o n of fasting state w i t h e m e s i s (Table 2), although the danger of establishing firm conclusions based on pooled data is recognized. Wide varia b i l i t y is n o t e d in b o t h categories; t h r e e of t h e f o u r s e r i e s w i t h an emesis rate of 10% or more were dent a l p a t i e n t s in w h o m s w a l l o w e d blood may have induced vomiting.21,~2, ~9 N o c a s e s of a s p i r a t i o n were reported in any of the 97 series from w h i c h this comparison was extracted. Thus, a fasting r e q u i r e m e n t for p a t i e n t s l a c k i n g o t h e r c o n t r a i n dications has no clear s u b s t a n t i a t i o n in the literature. Cases of transient stridor or laryngospasm have been reported in several series and are probably related to s t i m u l a t i o n of hypersensitized laryngeal reflexes. 16,36,44,48,59,75,80 A c t i v e respiratory infection is an often-identified a s s o c i a t e d factor and t h u s is considered a c o n t r a i u d i c a t i o n to the u s e o f k e t a m i n e . 44,48,53,75,8°,1°4, 158 16o Review of the 97 series (Table 1) reveals o n l y two cases of laryng o s p a s m s e v e r e e n o u g h to n e c e s s i tate i n t u b a t i o n in h e a l t h y children; the p r e s e n c e of r e s u l t i n g m o r b i d i t y was n o t specified in e i t h e r c i r c u m stance.18, 63 O n e of t h e s e e p i s o d e s was considered to be secondary to apparently unsuctioned hypersalivation.15 Thus, r e p o r t e d l a r y n g o s p a s m r e q u i r i n g a i r w a y i n t e r v e n t i o n is ext r e m e l y unusual; the pooled-data in19:9 September 1990

cidence is two cases in m o r e t h a n 11,589 a d m i n i s t r a t i o n s , or less t h a n 0.017%. Procedures that s t i m u l a t e the hyperactive gag reflex through either dir e c t i n s t r u m e n t a t i o n or s e c r e t i o n s are considered to entail a higher risk of laryngospasm, and use in these situ a t i o n s is n o t r e c o m m e n d e d . 2 Z , 36, 59,154,158,161 D e s p i t e t h e s e p r e c a u tions, it should be noted that the tons i l l e c t o m y 38 and m u l t i p l e dental seriesaO 30 failed to note clinically significant laryngospasm. Laryngospasm associated w i t h traditional general anesthetics has been e x t e n s i v e l y examined by Olsson and H a l l e n i n an i m m e n s e s e r i e s of 136,929 p a t i e n t s ; t h e o v e r a l l incid e n c e w a s 0.87%. 158 C h i l d r e n less than 10 years old were more susceptible (1.74%), and 1 to 3 - m o n t h - o l d infants had a risk of m o r e than threefold h i g h e r t h a n a v e r a g e (2.82%). Respiratory infection in children entailed a fivefold increase in risk (9.58%). Surprisingly, in t h e i r 1,197 observed cases of l a r y n g o s p a s m , serious sequelae such as hypoxia, aspiration, and cardiac arrest w e r e relat i v e l y u n u s u a l (3.2%, 1.1%, a n d 0.50%, respectively). N o o u t c o m e inf o r m a t i o n was specified for the six p a t i e n t s w i t h o b s e r v e d c a r d i a c arrests. Laryngospasm was significantly m o r e likely in children w i t h a s t h m a or undergoing esophageal endoscopy; curiously, it also was m o r e frequent in cases of a p p e n d e c t o m y , s k i n grafting, a n d h y p o s p a d i a s repair. ,58 S t u d i e s of e x p e r i m e n t a l l a r y n gospasm in animals have shown that hypoxia and hypercapnia sharply diminish the laryngospastic res p o n s e ; 158,162,163 t h u s , it h a s b e e n suggested that laryngospasm is selfl i m i t e d in nature because the occurrence of hypoxia or hypercapnia will r e s u l t in s p o n t a n e o u s r e l a x a t i o n of t h e glottis.162,163 D e s p i t e r a r i t y of airway complications, however, keta m i n e a d m i n i s t r a t i o n s h o u l d be restricted to a setting in w h i c h intubation could be quickly performed if required. Great care should be taken to identify and avoid patients w i t h resp i r a t o r y i n f e c t i o n s . As O l s s o n a n d Hallen observed, "It is evidently unsafe to regard ]aryngospasm as being of m i n o r importance. A n y hope that this c o m p l i c a t i o n m a y be i n n o c e n t and s e l f q i m i t i n g is n o t to be r e l i e d on in clinical practice. ''158 Annals of Emergency Medicine

Lidocaine IV has been s h o w n to be helpful in the prevention and treatm e n t of extubation laryngospasm in children emerging from halothane a n e s t h e s i a ; 164 however, w e are u n aware of any reports of lidocaine use in the setting of k e t a m i n e - a s s o c i a t e d laryngospasm. N e o n a t e s and infants 3 m o n t h s old or younger w h o are given k e t a m i n e h a v e a h i g h e r i n c i d e n c e of a i r w a y c o m p l i c a t i o n s w i t h reports of laryngospasm,53,137 apnea, 16,53,137 coughing spells, 16 and aspiration.137 T h i s greater d i f f i c u l t y in m a i n t a i n i n g a patent airway m a y be due to the differences in airway a n a t o m y and laryngeal e x c i t a b i l i t y p e c u l i a r to that age g r o u p . 1°2,158A65,166 F o r t h e s e reasons, k e t a m i n e should be avoided i n i n f a n t s 3 m o n t h s old or y o u n ger.51,102,137,166

P u l m o n a r y Effects A s t h m a t i c patients given k e t a m i n e have d e m o n s t r a t e d d i m i n i s h e d bronc h o s p a s m and airway resistance; the m e c h a n i s m of this r e s p o n s e is considered to be a c o m b i n a t i o n of druginduced increase in circulating catechotamines, direct smooth muscle d i l a t a t i o n , a n d i n h i b i t i o n of v a g a l outflow.lOl,159,167,168 C o r s s e n et al reported clearance of wheezing in 19 of 22 active a s t h m a t i c s (86%) given ketamine during anesthesia. Interestingly, k e t a m i n e e l i m i n a t e d bronc h o s p a s m in three patients receiving h a l o t h a n e - a p o t e n t bronchodilator itself.t59 K e t a m i n e i n f u s i o n has been u s e d s u c c e s s f u l l y as a b r o n c h o d i l a t o r to avoid i n t u b a t i o n in severe a s t h m a t i c a t t a c k s . 169 R a p i d - s e q u e n c e i n t u b a tion of patients in status a s t h m a t i c u s has b e e n described using k e t a m i n e 1.5 m g / k g p u s h e d s i m u l t a n e o u s l y w i t h s u c c i n y l c h o l i n e . 168 K e t a m i n e has been given to v e n t i l a t o r patients in refractory b r o n c h o s p a s m with lifesaving results. ~59,17o, 171 Cardiovascular Effects K e t a m i n e is s y m p a t h o m i m e t i c b y i n h i b i t i n g r e u p t a k e of catecholamines a n d c a n t h u s p r o d u c e m i l d - t o - m o d e r a t e i n c r e a s e s in b l o o d pressure, heart rate, and cardiac output.9,12,18,104,132,145,172 T h i s h y p e r t e n s i v e r e s p o n s e is e x a g g e r a t e d b y rapid IV p u s h and is m i n i m a l w i t h I M i n j e c t i o n ; it is a l s o l e s s p r o n o u n c e d in children than in adults. 45 S y s t e m i c vascular r e s i s t a n c e is n o t 1037/135

KETAMINE SFDA]-ION Green & Johnson

significantly altered; the sympathetically m c d i a t e d v a s o c o n s t r i c t i o n is countered by drug-induced smooth m u s c l e r e l a x a t i o n . ~73 K e t a m i n e is frequently chosen by a n e s t h e s i o l o gists in the setting of hemorrhage or shock because of its unique cardiovascular stimulation. ~o z , ~ r4, ~ 75 Critical patients may exhibit paradoxical h y p o t e n s i o n due to the unopposed direct vasodilatory effect of ketamme if endogenous catecholanrine stores are exhausted, to2 Kctamine inhibits reuptakc of catecholamines in both circulation and the CNS in a dose-dependent lnanner and can thus potentiate the effects of both endogenous and exogenous catecholamines; this effect appears to be caused by the ( + )-isomer only. J76 ~7s Despite this, sympathomimetic drugs such as d e c o n g e s t a n t s , theophylline, and [3-agonists have not becn c o n s i d e r e d c o n t r a i n d i c a t i o n s to k e t a l n i n e u s e . 102,104,166,179,18() F u r t h e r m o r e , k c t a m i n e has becn used extensively in patients on asthmatic medications, and no reports of c o m p l i c a t i o n s due to p o t e n t i a t i o n of t h e s e a g e n t s c o u l d be l o cated. 159,l(,s-l r t Thus, standard doses of sympathomimetic medications are not identified as a contraindication to the use of ketamine. The effect of ketamine on cardiac r h y t h m is c o n t r o v e r s i a l . A n i m a l studies have demonstrated reversal of digitalis-induced dysrhythmiaslSl and, paradoxically, e i t h e r enhancen l e n t W T , 1 7 8 , 1 8 2 o r diminution~Zr, is3 of m y o c a r d i a l s e n s i t i v i t y to catccholamines. Koehntop et al noted prompt cessation of epinephrine-induced dysrhythmias during the first m i n u t e after IV ketamine, followed by a longer period of prodysrhythmic effect.Its T h i s suggests t h a t ketamine manifests a balance of both direct antidysrhythmic effect and augm e n t e d d y s r h y t h m o g e n i c i t y due to indirect sympathetic stimulation. Despite this controversy, experience in h m n a n b e i n g s has n o t p r o v e n problematic. Authors of multiple pediatric cardiac catheterization reports fail to note dysrhythmias induced by k e t a m i n e , J2 19 and it is g e n e r a l l y considered that this agent manifests weak antidysrhythmic propert i e s . i 2,15,102, l l 1,145,148

Ketamine increases coronary perfusion, w h e r e a s s i m u l t a n e o u s enhancement of contractility produces a parallel rise in myocardial oxygen 136/1038

c o n s u m p t i o n , ts4 K e t a m i n e r a i s e s puhnonary arterial pressurcs somewhat more than systemic pressures and may exacerbate pre-existing conditions of puhnonary hypertension or congestive heart failure. Is N e u r o n m s c u l a r Effects Skeletal muscle hypertonicity and r i g i d i t y are often seen w h e n ketamine is used. Random movement of the head or extremities unrelated to painful stimuli is also frequent; however, these features are rarely of sufficient intensity to interfere with perf o r m a n c e of procedures.5"s, ma, I°4 Muscular hypertonicity becomes extreme at high doses; one unusual report describes two cases of opisthotonus after administration of 14 and 19 mg/kg IV. Is5 Brief, s o m e t i m e s i n t e n s e myoclonus and t w i t c h i n g may be confused with seizure activity;59,c'o,s2,=8c', ~s7 h o w e v e r , t h e s e spasms are benign and not associated w i t h EEG changes, m2 Several authors have reported prompt cessation of convulsions when k e t a m i u e was administered,4s,sz, sa,~ss,~s9 and ketamine IM has been proposed as a rapid t h e r a p e u t i c m o d a l i t y in the seizing child w i t h o u t vascular access. lss EEG research in animals and human beings has demonstrated that at clinical doses ketamine possesses s i g n i f i c a n t a n t i c o n v u l s a n t properties. 190-193 Ketamine elevates intracranial pressure through cercbral vasodilation and increased s y s t e m i c perfusion pressure. 1o2,~94 The average increase in h e a l t h y adults is approxi m a t e l y 20 m m Hg; however, pressure elevations of 25 to 82 m m Hg have been reported in those with abnormal cerebrospinal fluid flow dynamics or other intracranial pathology.84,195 197 A n i m a l s t u d i e s have s h o w n t h a t c o a d m i n i s t e r e d benz o d i a z e p i n e s a t t e n u a t e this rise in intracranial pressure, t94 Conditions of potentially elevated intracerebral pressure (eg, significant head trauma, hydrocephalus, intracerebral masses) are t h u s r e l a t i v e contraindications to the use of keta m i n e , as apnea due to p r e s u m e d medullary compression has been reported.g2,97, ~33,L~4 Despite these concerns, k e t a m i n e has been used in h u n d r e d s of b r a i n t u m o r r a d i o therapy cases without problein.86-s8,90,92,93,95-97 In addition, paAnnals of Emergency Medicine

tients with congenital abnormalities of the CNS such as m i c r o c e p h a l y , meningocoele, or cerebal cysts have been noted to require substantially higher doses of ketamine to achieve the s a m e effect,55, w~ and use in these p a t i e n t s has been a s s o c i a t e d w i t h r e s p i r a t o r y depression,~,~6 apnca, 133,134 and laryngospasm. 75 Interestingly, k e t a n r i n e may exhibit ncuroprotective properties. Studies of rat hippocampal slices exposed to experimental anoxia have shown that ketamine prevents early release of calcium from intracellular stores through its N M D A receptor binding; this increase in c y t o s o l i c calcium is a known mechanism of ischemic damage. 1~)9 K e t a m i n e - i n d u c e d ataxia can be pronounced, and attempts at ambulat i o n d u r i n g r e c o v e r y m u s t be aw)ided. Mild d i s e q u i l i b r i u m m a y persist for one to four hours after a d m i n i s t r a t i o n , n e c e s s i t a t i n g close p a r e n t a l p r e c a u t i o n s a g a i n s t independent ambulation in children.21,22,26, i02 Emergence Phenomena The ability of ketamine to stinrulate dreaming is poorly understood. A n i m a l studies demonstrate depression of the inferior c o l l i c u l u s and medial geniculate -- centers crucial for transmission of auditory information. 200 The d i s s o c i a t i v e state also "disconnects" vision, dermal sensation, and proprioccption; this loss of external stimuli induces a sense of bodily detachment that may contribu t e to t h e p s y c h i c r e a c t i o n s or "weird trips" that are occasionally seen in the recovery phase. 1°3,104 T h e i n c i d e n c e of h a l l u c i n a t o r y p h e n o m e n a has been r e p o r t e d in from 0% to 50% of adults 63,201,202 a n d f r o m 0% to 10% of c h i l dren.3,32, 63,202 M a n i f e s t a t i o n s of these experiences are highly variable and include vivid reports of psychedelic colors, suspension in midair or outer space, floating down a kaleidoscope, rides in spaceships, out-ofbody experiences, or seeing faceless p e r s o n s w a l k i n g a r o u n d t h e bed. Some patients report the dreams as e x t r e m e l y f r i g h t e n i n g ; o t h e r s describe t h e m as pleasant, joyful, fascinating, or bizarre.~7,ss,203 207 R e p o r t e d risk factors for emergence reactions include age of more than 10 years, female sex, rapid IV administration, excessive noise 19:9 September 1990

or stimulation during recovery, p r i o r p e r s o n a l i t y disorders, or subjects who normally dream freq u e n t l y . 14, ls,sg,ss, mz, 104,208 In a d d i tion, emergence reactions appear less c o m m o n w i t h IM a d m i n i s t r a t i o n t h a n w i t h Iv.3e,53,55,62, 97,131 Strong psychological factors appear to i n f l u e n c e t h e s e v e r i t y of e m e r gence reactions. Adults w i t h persona l i t y i n v e n t o r y scores suggesting psychotic or neurotic traits had a signific a n t l y h i g h e r r a t e of u n p l e a s a n t r e a c t i o n s . 205 A s e c o n d i n v e s t i g a t o r i n f o r m e d patients preoperatively that t h e y w o u l d d r e a m a b o u t a topic of their o w n choice while under the inf l u e n c e of k e t a m i n e ; e a c h s u b j e c t w a s e n c o u r a g e d to p l a n p l e a s a n t dreams in advance. W i t h the use of s u c h p o s i t i v e p s y c h o l o g y o n 90 adults, no u n p l e a s a n t reactions were observed. 2m U p s e t t i n g reactions are m u c h less c o m m o n in c h i l d r e n 10 to 15 years old than in adults and are e x t r e m e l y r a r e i n t h o s e l e s s t h a n 10 y e a r s old. 43,50,55,57,62,s6,sT,104 Review of the 49 r e p o r t s (Table 1 ) t h a t q u a n t i f y emergence p h e n o m e n a shows that 51 of 6,105 children (0.8%) had m i l d reactions and that eight others (0.1%) had episodes described as unpleasant. C h i l d r e n m a y dream during sedation, b u t these occurrences are usually not frightening.3,43,ss,s 7,60,6z,82,94 Arguably, not all pediatric patients are capable of reporting the specific nature of d r e a m s to researchers; however, the rare incidence of crying or agitation during recovery supports the benign nature of k e t a m i n e in this age group. U n u s u a l dreams or hallucinations that m i g h t prove disturbing to an adult do n o t always provoke distress in a " n a i v e " child w i t h fewer life experiences.94, mz Thus, c o n c e r n r e g a r d i n g f r i g h t e n i n g r e a c t i o n s or n i g h t m a r e s in c h i l d r e n s h o u l d n o t preclude the use of k e t a m i n e as these events are e x t r e m e l y unusual. T h e observation that reduction of s t i m u l i during the recovery phase (eg, d i m lighting, quiet location, avoidance of physical contact) appears to lessen the frequency of emergence reactions is widespread and universally r e c o m m e n d e d , yet unproven in controlled studies. 14,20,s5,82,87,202 A doserelated rate of reactions has not been e s t a b l i s h e d ; i s , z09 in fact, s o m e authors have described a surprising inverse r e l a t i o n of emergence reactions t o d o s e . ls,s3,87,2m P o s s i b l y a s u b 19:9 September 1990

dissociative condition allows painful s t i m u l i to reach the cortex with r e sultant psychic disturbance. Liang ct al report m i n i m i z a t i o n of emergence p h e n o m e n a w i t h lower doses; however, their reduction from 5% to 4% l a c k s s t a t i s t i c a l or p r a c t i c a l significance.21 l An a n t i c h o l i n e r g i c agent such as a t r o p i n e is u s u a l l y c o a d m i n i s t e r e d w i t h k e t a m i n e to s u p p r e s s h y p c r salivation. It has been suggested that glycopyrrolatc might be preferable to a t r o p i n e b e c a u s e of its d i m i n i s h e d C N S effect; a5 h o w e v e r , a d o u b l e blind comparison of the two agents d e m o n s t r a t e d no s i g n i f i c a n t differences in d r e a m i n g , u n p l e a s a n t reactions, or other side effects.t44 M u l t i p l e reports describe success with coadministered benzodiazepines or narcotics in suppressing k e t a m i n e emergence p h e n o m e n o n in a d u l t s . 27, to4,2°s,2 l°,212-2 t 5 U n f o r t u n a t e l y for o u t p a t i e n t p u r p o s e s , these agents also delay k c t a m i n e met a b o l i s m and prolong recovery. 111,tzs Delayed psychological effects have been reported. An ll-year-old boy w i t h an u n k n o w n CNS a b n o r m a l i t y received IM k e t a m i n e for p n e u m o e n c e p h a l o g r a p h y a n d e x p e r i e n c e d recurrent frightening h a l l u c i n a t i o n s of "blotches on the ceiling" for the next f i v e d a y s . z~6 A n o t h e r a u t h o r describes two previously serene 3-ycarolds w h o were noted to have t e m p e r tantrums and adverse personality changes p e r s i s t i n g for as long as 12 m o n t h s after r e c e i v i n g k e t a m i n e , z°e A p r o s p e c t i v e s t u d y c o m p a r e d keta m i n e w i t h standard h a l o t h a n e anesthesia in 107 children and found no significant differences in personality c h a n g e s r e p o r t e d by p a r e n t s for as long as one m o n t h postoperatively. 65 It is h i g h l y u n l i k e l y t h a t k e t a m i n e causes p e r m a n e n t changes in personality or intellectual function.~,m2,z~Tms

Other Clinical Effects R e v i e w of t h e r e p o r t s (Table 1) shows that rates of emesis vary from 0% to 43%; pooled data c o m p i l a t i o n of the 35 reports that quantify emesis s h o w s t h a t 284 of 3,358 c h i l d r e n (8.5%) vomited. When present, enresis ahnost always occurs late in the recovery phase w h e n the pat i e n t is a l e r t ; t h e a i r w a y is c o n sistently cleared without assist a n c e . 2 6 , 3 1 , 48,51,6 7, 71,s2,s3,s 7, go

Cmfflicting reports have n o t cornAnnals of Emergency Medicine

pletely resolved the issue of intraocular pressure elevation, with various reports concluding marked elevation, 7,~ slight elevation, ('