598 PEDIATRICS Vol. 95 No. 4 April 1995

AMERICAN ACADEMY OF PEDIATRICS

Reappraisal of Lytic Cocktail/Demerol, Phenergan, and Thorazine (DPT)for the Sedation of Children

Committee on Drugs

The importance of premedication for pediatric pa-tients undergoing surgical procedures dates to theclassic work of Waters,’ who believed that childrenwere as entitled as adults to have premedication. Therecommended premedication was morphine withscopolamine. Later, phenothiazines were believed tobe useful as anesthetic premedications because oftheir sedative and vasodilator effects.2’� These obser-vations led to the combination of a narcotic with aphenothiazine, which induced deep sedation (sleep-ing) in the child and allowed easy separation fromhis or her parents before administration of the anes-thetic. The narcotic provided a base of analgesiawhereas the phenothiazine lowered the blood pres-sure and blunted the pressor responses to surgicalstimulation.

The combination of meperidine (Demerol),promethazine (Phenergan), and chiorpromazine(Thorazine), commonly referred to as DPT, has beenused for more than 20 years as a sedative and anal-gesic cocktail for pediatric patients.2 Although thecombination of a narcotic with phenothiazine wasfirst developed to provide preanesthetic sedation forpatients about to undergo general anesthesia, its pri-mary use in children has been outside of the operat-ing room. The DPT combination has been used as aprimary sedative for infants and young children Un-dergoing radiologic procedures (computed tomogra-phy, magnetic resonance imaging, and contrast stud-ies). It has been used as a sedative/analgesic forinvasive procedures (suturing, bone marrow aspira-tions, cardiac catheterization, and renal biopsy).

The precise mixture of constituents in the cocktailused for children varies somewhat from institutionto institution.3’4 Original descriptions refer to a for-mulation including 25 mg/mL of meperidine, 6.5mg/mL of promethazine, and 6.5 mg/mL of chlor-promazine, with a recommended dose of 0.1 mL/kgof body weight. Recent sources refer to a formulationconsisting of a 2:1:1 mixture, with what amounts to al-mL/kg dosage recommendation.3’4 In fact, dosagerecommendations may vary by a factor of 10.� Noproprietary mixtures are available, so the solutionmust be prepared locally. Intramuscular injection hasbeen the most common route of administration; how-

The recommendations in this statement do not indicate an exclusive course

of treatment or procedure to be followed. Variations, taking into account

individual circumstances, may be appropriate.PEDIATRICS (ISSN 0031 4005). Copyright © 1995 by the American Acad-

emy of Pediatrics.

ever, intravenous administration (without dosagemodification) has been gaining in popularity. Fewadmonitions concerning dosage modification withrespect to age or underlying disease have been pub-lished. Thus, despite the scarcity of data concerningits efficacy and safety in children, the DPT lytic cock-tail has found widespread use in pediatrics.

PHARMACOLOGY OF THE CONSTITUENTS OF

LYTIC COCKTAIL6

Studies in adult patients have served as the basisfor the use of this drug combination in children.Unless stated otherwise, the references cited containdata obtained with adult patients. No comparablepediatric studies exist.

Meperidine

Meperidine is a synthetic opioid with an analgesicpotency about 10% of that of morphine. It has a morerapid onset and a shorter duration of action thanmorphine, but usual doses may be ineffective in upto 5% of patients. No rigorous studies have definedthe pharmacokinetics or pharmacodynamics of me-peridine in children. Common adverse reactions in-dude dizziness, nausea, and vomiting. In compara-tive studies, meperidine was found to be moresedating and to have equivalent respiratory depres-sant effects when compared with equianalgesicdoses of morphine.

Meperidine does not allay anxiety or induce retro-grade amnesia. It is metabolized, at least in part, viaN-demethylation, yielding normeperidine, whichhas a relatively long haff-life. This active metabolitehas been implicated as a cause of seizures in patientswho receive meperidine in high doses or have renalfunctional impairment. It also has been found toaccumulate in patients receiving concomitant chior-promazine therapy?

Promethazine

Promethazine has moderate sedating propertiesand pronounced antihistaminic activity. It achievedwidespread use in adults as a preanesthetic medica-tion because its sedating properties were not associ-ated with respiratory depressant effects. Some stud-ies found this even when the drug was administeredwith morphine or meperidine. Another attractive at-tribute of promethazine is its modest, centrally me-diated antiemetic activity.

In adult patients, the side effects of promethazine

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AMERICAN ACADEMY OF PEDIATRICS 599

are limited. Sedation is prominent and extrapyrami-dal effects are uncommon. In contrast, significantconcerns have been raised about the use of prometh-azine in infants and young children.8’9 Case reportshave linked promethazine to apneic episodes in thisage group. No systematic pharmacokinetic or phar-macodynamic studies of promethazine have beenperformed in infants and children.

Chlorpromazine

Chlorpromazine is a phenothiazine antipsychoticagent with relatively low potency. It has been used inadults and children to treat a variety of disordersfrom intractable hiccoughs to paranoia. Althoughthis drug has a long history of efficacy, its clinicalpharmacology in children is largely unknown. As asingle agent, chlorpromazine has little if any sedativeor analgesic properties.

The disposition of chlorpromazine is complex,with more than 150 metabolites identified. In addi-tion, toxicity is common, with pronounced antia-drenergic and anticholinergic effects predominatingearly in therapy. The a-adrenergic blocking proper-ties can result in profound hypotension if chlorprom-azine is administered to individuals with a con-tracted vascular volume. Chlorpromazine may havedeleterious effects in patients with congenital heartdisease. In patients with cyanotic congenital heart

disease, such as tetralogy of Fallot, the lower sys-temic vascular resistance from the a-blocking effectcan cause profound obligatory right-to-left shuntingthrough the ventricular septal defect and therebyprecipitate a severe hypercyanotic spell. In patientswith left ventricular outflow tract obstruction (eg,aortic stenosis at any site or hypertrophic cardiomy-opathy), the a-blocking effect with hypotension canincrease the left ventricular-aortic gradient, resultingin decreased coronary blood flow, shock, and evendeath. In patients with seizure disorders or a predis-position to seizures, chlorpromazine lowers the sei-zure threshold. Moreover, chlorpromazine is antian-algesic and commonly produces dystonic reactions.

HISTORY OF THE ATARACTIC MIXTURE

An ataractic mixture is a combination of drugs thatcreates a feeling of “serenity” when administered topatients. Several developments in pharmacology and

anesthesiology contributed to the formulation of thelytic cocktail and its use as a sedative/analgesic. Inthe late 1940s, antihistaminic agents were demon-strated to potentiate the sedative effects of the bar-biturates.’#{176} This work was extended during the1950s, when chlorpromazine also was shown to po-

tentiate the hypnotic effects of barbiturates.” Theseanimal studies provided the preliminary data neces-sary to support the initiation of clinical trials in theseareas. A series of articles reported the adjuvant ef-fects of chlorpromazine in the treatment of moderateto severe pain when combined with opioids.’2’4These observations were confirmed by other investi-gators who demonstrated that chlorpromazine,while having little intrinsic analgesic activity, mark-edly augmented the analgesic activity of both mor-phine and meperidine.’5 This allowed one to obtain a

desired analgesic effect with lower doses of opioid.Therefore, either morphine or meperidine could beused in doses that were not associated with respira-tory depression but could, in the presence of chlor-promazine, result in “optimal” analgesia.

The toxicity of the combination of meperidine andchlorpromazine was also studied.7 Profound leth-argy that persisted long after the clearance of meper-idine was noted. This lethargy was accompanied bya decrease in respiratory rate (63% ± I I %), a decreasein systolic blood pressure (9% ± 2% supine and 28%

± 5% standing), and severe mental debilitation. Side-

effect profiles were not evaluated systematically us-ing the three-drug combination, although there wasample evidence that combining either promethazineor chiorpromazine with an opioid leads to enhancedtoxicity as well as enhanced hypnosis and analgesia.Early studies showed that promethazine increasedagitation and hyperventilation when administeredbefore anesthesia.’6”7 It was concluded that there was“no significant advantage to the combination ofpromethazine with an opiate.”6 In one study, a moreprofound respiratory depression was reported whenpromethazine was administered with mependine.’8

In another report in which complete lytic cocktail(DPi’) was used in the treatment of eclampsia, sei-zures recurred because of both a lowering of theseizure threshold and a reduction of cerebral bloodflow attributed to phenothiazines.’9

While all of this work on preanesthetic medica-lions was proceeding, the techniques of neuroleptan-algesia were also being developed.20 Neuroleptanal-gesia describes a state of “apparent indifference topain induced by the combination of a potent analge-sic with a neurolept or major tranquilizing drug.”2#{176}The approach grew out of the work of Laborit andHuguenard,2’ who first described the lytic cocktail toproduce a state of “artificial hibernation.” Even inthis first description of the use of lytic cocktail, thestate of artificial hibernation was associated withconsiderable cardiovascular instability and pro-

longed depression of consciousness.

Pediatric Experience With Lytic Cocktail

Early experience with the combination of pheno-thiazine and a narcotic revealed a high incidence ofextrapyramidal movements and seizures, resultingfrom excessive doses of phenothiazine. The classiclytic DPT cocktail was formulated in response to theneed of pediatric cardiologists for a sedated andnarcotized patient. Previous attempts at preparingappropriate sedatives using combinations of barbitu-rates and narcotics had proven unsatisfactory. In1958, Smith et al2 examined three DPT combinations(Cardiac Mixtures 1-3) and found the most satisfac-tory to be the 2:1:1 ratio described above (0.1 mg/kgintramuscularly; a maximum of I .5 mL, with lowerdoses in cyanotic children). It is interesting that intheir series of 670 children, “only 17 patients ap-peared shocked,” whereas “three subjects developedserious respiratory depression” and one subject died“twenty minutes after returning to the ward.” De-spite these complications, this drug combination ful-ifiled an important need at the time.

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600 LYFIC COCKTAIL/DEMEROL, PHENERGAN, AND THORAZINE

The next citation of DPT in the pediatric literature

appeared in 1967 in a study of the effects of sedationon acid-base balance during cardiac catheterization.�The authors of the study stated that “all patientsreceived the widely used sedative mixture of 50 mg(1 cc) mependine, 12.5 mg (0.5 cc) chiorpromazineand 12.5 mg (0.5 cc) promethazine.” These doses,however, are twice as high as those previouslyreported.

In an effort to compare the relative efficacy andsafety of DPT with other potential sedative modali-ties, investigators in the late 1970s reported a ran-domized study comparing rectal thiopental with in-tramuscular DPT as sedation for computedtomographic scanning?�’ The lytic cocktail failed toproduce adequate sedation at standard doses in 14%of the children, compared with a 3% failure rateusing thiopental.

Two years later, the Pediatric Drug SurvefflanceProgram in Boston reported the risks of premedica-tion for computed tomographic scanning in cull-dren.24 Major adverse events were seen only with“Demerol Compound,” which was the Boston Chil-dren’s Hospital formulation of DPT lytic cocktail.The incidence of life-threatening adverse events was4%, which was four times that seen with other pa-tients monitored by the Pediatric Drug SurveillanceProgram. Similar results were reported by anothergroup of investigators,� who used the DPT cocktailfor a variety of procedures.

These experiences, as well as the anecdotal evi-dence of others, culminated in the 1989 admonitionagainst the use of lytic cocktail in children?� Never-theless, in 1990 a survey of emergency departmentsof member institutions of the National Association ofChildren’s Hospitals and Related Institutions re-vealed that DPT lytic cocktail remains the most com-monly used form of sedation for suturing in pediatricemergency departments. These results are surprisinggiven that only 22% of respondents reported thecocktail to be effective more than 90% of the time.3

These deficiencies have been highlighted by recentretrospective and prospective studies of DPT lyticcocktail from the pediatric emergency center in Syr-acuse, New York.27”-� Although the retrospectivestudy did not directly report efficacy, only 8 of 487patients required repeated sedation, whereas theprospective study demonstrated a 29% failure rate.Adverse events were rare in the two studies; how-

ever, patients required 19 ± 15 hours to return tonormal behavior.

CONSIDERATIONS FOR THE RATIONAL AND

SAFE SEDATION OF INFANTS AND CHILDREN

Whenever it is considered necessary to sedate apediatric patient, one must consider the type of pro-cedure planned (painful or nonpainful), the durationof the procedure (important in choosing the appro-priate sedative), the underlying medical condition ofthe patient (whether the patient has properly fasted,whether the blood volume is contracted, whether thepatient is taking other medications that may interactwith the sedative, and whether the patient is able toeliminate the drug), the need for anxiolysis or nar-

cosis, and experience with alternative techniques orroutes of administration.

The drugs used for the sedation of infants and

children should be selected from among those forwhich rational pediatric dosing guidelines are avail-able. Sedative effects should be titratable and con-trollable so that the duration of the effect of thedose does not exceed greatly the duration of theprocedure.

Opioid medications should be reserved for painfulprocedures (eg, angiography, cardiac catheterization,very large lacerations) and should not be adminis-

tered merely to sedate the child (eg, before undergo-ing computed tomography). Even when faced withpainful procedures (eg, bone marrow aspiration),

children may prefer the anxiolysis and amnesia pro-

duced by a benzodiazepine (midazolam) to the nar-cosis produced by a narcotic (fentanyl)?� The appro-priate use of local anesthetics is mandatory.

The duration of the planned procedure is also animportant consideration. It is not generally desirableto have the child sedated for much longer than the

duration of the procedure. The reported 19±15hours before return to normal after DVF administra-tion� is obviously excessive. Such prolonged seda-tion unnecessarily ties up nursing personnel and

complicates following the recommended guidelinesfor monitoring sedated children.�#{176} The clinician cannever be certain how long any given procedure wifilast, but most routine procedures can be predicted

within a reasonable time range, allowing a choice of

the appropriate drug or drug combination.Children are less likely to have a problem with

sedative-associated respiratory depression during a

painful procedure because discomfort stimulates res-piration. However, once the procedure is terminated

or before a procedure is begun, the child is at greatestrisk for becoming more deeply sedated because thereis no painful stimulus. Even when the child does notappear to be sedated at the end of the procedure, latesedation may develop from a variety of causes, suchas continued drug uptake, delayed excretion, phar-macodynamics, or the lack of external stimulation. Itis essential that the child be observed in an appro-priate recovery facility for a sufficient period beforedischarge.�#{176}

ALTERNATIVE AGENTS

Fortunately, a number of newer drugs are avail-able that may provide safe and effective sedation andanalgesia for children. These drugs include midazo-lam, a short-acting, water-soluble benzodiazepine;fentanyl, a short-acting, potent synthetic opioid; ket-amine, a dissociative anesthetic agent; and propofol,

a short-acting intravenous anesthetic. Detailed dis-cussion of these drugs is beyond the scope of thiscommentary. Practitioners who wish to use theseagents should become familiar with their respectiverisks and benefits and, with their colleagues in anes-thesiology or clinical pharmacology, should develop

safe protocols for their use.

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CONCLUSIONS

AMERICAN ACADEMY OF PEDIATRICS 601

The DPT lytic cocktail remains a widely used sed-ative and analgesic for pediatric patients. Neither thecombination itself nor its dosage is based on soundpharmacologic data. There is a high rate of therapeu-tic failure as well as a high rate of serious adversereactions, including respiratory depression anddeath, associated with its use.

Even when it is effective, DFT appears to lackmany of the desirable characteristics of a sedative

for children. Specifically, the dose cannot be ti-trated easily and individually, the onset of action issignificantly delayed (20 to 30 minutes), the dura-tion of sedation is protracted (5 to 20 hours), theduration of analgesia is much shorter (1 to 3hours), and no anxiolytic or amnestic propertiesexist.

RECOMMENDATIONS

In light of the available information, the AmericanAcademy of Pediatrics recommends the following.

I . The risks and potential benefits of DPT lytic cock-tail for each patient must be evaluated carefullybefore it is used. Alternative sedatives/analgesicsshould be considered.

2. If DPT lytic cocktail is used, all of the guidelinespertaining to deep sedation for monitoring andmanagement of pediatric patients during and af-ter sedation for diagnostic and therapeutic proce-dures should be followed.�#{176}

3. Careful monitoring of blood pressure and venti-

lation should accompany the standard monitoringof oxygen saturation.

4. Additional caution should be exercised when usinglytic cocktail in children with seizure disorders,other central nervous system abnormalities, or con-genital heart disease consisting of tetralogy of Fallot-type anatomy or of left ventricular outflow obstruc-tion, such as any type of aortic stenosis.

5. Criteria for discharge from the sedation-monitor-

ing area must be established with full recognitionof the “trance-like” state produced by this neuro-leptanalgesic technique.

COMMTI-rEE ON DRUGS, 1993 TO 1994

Cheston M. Berlin, Jr. MD, ChairpersonRichard L. Gorman, MDD. Gail May, MDDaniel A. Notterman, MDDouglas N. Weismann, MD

Geraldine S. Wilson, MDJohn T. Wilson, MD

LIMsoN REPRESENTATIvES

Donald R. Bennett MD, PhD, American MedicalAssociation

Joseph Mulinare, MD, MSPH, Centers for DiseaseControl and Prevention

Paul Kaufman, MD, Pharmaceutical Manufacturers’Association

Sam A. Licata, MD, Health Protection Branch, CanadaPaul Tomich, MD, American College of Obstetricians

and Gynecologists

Gloria Troendle, MD, Food and Drug AdministrationSumner J. Yaffe, MD, National Institutes of Health

AAP SECTION LIAISON

Charles J. Cot#{233},MD, Section on Anesthesiology

CONSULTANTS

Jeffrey L. Blumer, PhD, MDRalph E. Kauffman, MDAnthony R. Temple, MD

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1995;95;598Pediatrics Committee on Drugs

Sedation of ChildrenReappraisal of Lytic Cocktail/Demerol, Phenergan, and Thorazine (DPT) for the

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