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“DPT” Cocktail: Time for Rational and Safe Alternatives
Clinical Pharmacology
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Lyticl"DPT" Cocktail: Time for Rational and Safe Alternatives
Wayne R. Snodgrass, MD, PhD, * and Warren F. Dodge, MDt
Lytic cocktail, also known as DPT cocktail or cardiac cocktail, is a mixture consisting of a combination of meperidine (Oemerol) 25 mg per ml, promethazine (Phenergan) 6.5 mg per ml, and chlorpromazine (Thorazine) 6.5 mg per ml (i.e., "OPT"). Initially described as a premedication for children p.rior to cardiac catheterization and then for use prior to other procedures, the usual dose of this mixture is 0.1 ml per kg administered in tramuscularly. However, owing to the frequent occurrence of orthostatic hypotension, ventilatory (respiratory) depression, we no longer recommend using the OPT/lytic cocktail combination of drugs. This article will review 1) the goals of anesthetic premedication in children, 2) physiologic considerations in pediatric premedication, 3) toxicities of certain premedication drug regimens, ahd 4) alternatives to the use of OPT/lytic cocktail. Because of the frequent occurrence of orthostatic hypotension, ventilatory (respiratory) depression, and also because of sound pharmacologic and physiologic principles of medical practice, we no longer recommend using the OPT/ lytic cocktail combination of drugs . .Regardless of the agent(s) used, dose monitoring of respiratory and cardiovascular status is mandatory in all infants and children given sedatives, narcotic analgesics, or combinations of these agents. Guidelines for the safe and appropriate use of these drugs are difficult to define, due primarily to the lack of published controlled clinical trials or comparative studies of different regimens in children. Thus, much of what we state herein represents only our opinion. Obviously, prospective controlled studies of sedation and analgesia in infants and children administered for a variety of invasive procedures and indications are clearly needed. *Head, Clinical Pharmacology-Toxicology Unit, Departments of Pediatrics and PharmacologyToXicology, University of Texas Medical Branch, Galveston, Texas tClinical Pharmacology-Toxicology Unit, Departments of Pediatrics and PharmacologyToXicology, University of Texas Medical Branch, Galveston, Texas
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GOALS OF ANESTHETIC PREMEDICATION IN CHILDREN The goals of pharmacologic anesthetic premedication are many and include 6 1. The elimination of preoperative pain 2. To minimize unwanted effects of anesthetic agents via avoidance of their use 3. To supplement anesthesia 4. To allay anxiety and thus purposeless body movements facilitating performance of the surgical procedure
The ideal premedication agent or combination of agents for use in infants and children is yet to be identified. Such a regimen should produce consistent and predictable results, be associated with good patient acceptance, be completely or partially reversible, and be free of adverse effects. Additional desirable characteristics may depend on the procedure anticipated. In pediatric dental procedures performed in an outpatient (office) environment, the patient should remain conscious and responsive to commands while the protective laryngeal reflexes remain intact. 1 In other procedures (e. g., cardiac catheterization) more sedation may be desirable and appropriate. Thus, analgesic activity, sedative-hypnotic effects, or antisialogogue (anticholinergic) effects may be desirable for some procedures. 2
PHYSIOLOGIC CONSIDERATIONS Aspiration of gastric contents into the lung is an important complication associated with the administration of the DPT/lytic cocktail andlor other anesthetic premedications. There is general agreement that aspiration risk is greater when the pH of the gastric contents is less than 2.5 with a volume greater than 0.4 ml per kg.3, 19 Also, small children may show very rapid and significant vagal responses to manipulation of the airway; even passing a nasogastric tube may cause significant bradycardia. For these reasons, many physicians have included an anticholinergic drug (e.g., atropine) in the premedication regimen. Nevertheless, for many pediatric procedures there is no apparent need to include an anticholinergic drug. Similar considerations may apply regarding the decision to include or omit the narcotic or sedative component of a premedication regimen.
SIDE EFFECTS OF CERTAIN PREMEDICATION DRUG REGIMENS The DPT/lytic cocktail, given parenterally at a dose of 0.02 to 0.2 ml per kg, studied prospectively in 95 pediatric patients undergoing various procedures caused severe respiratory depression in 4 patients. 14 The lowest respiratory rate ranged from 8 to 18 breaths per minute at 1 to 3 hours after the dose was administered. One patient given 0.07 ml per kg experienced ventilatory arrest within 30 minutes following administration
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of the dose. An additional patient required the use of naloxone (Narcan) to reverse ventilatory depression. In addition to these important, life-threatening reactions noted above, about two thirds of the 95 pediatric patients Were sedated for longer than 7 hoursY No relationship between dose administered and duration of sedation could be obtained from the data. It is well known that narcotics (e.g., meperidine [Demerol]) and phenothiazines (e.g., promethazine and chlorpromazine) lower the seizure threshold and thus increase the risk for the development of seizures. 8 This may be of importance particularly in patients with an underlying seizure disorder. Seizures resulting in death have been reported following the administration of the DPT/lytic cocktai},5 In addition, dystonic (extrapyramidal) reactions also may occur, primarily because of the chlorpromazine (phenothiazine) component of the DPT/lytic cocktail mixture. In those clinical situations in which significant analgesia is desired (e.g., bone marrow aspiratibn/biopsies) a narcotic analgesic may be required. Despite this relatiVely common clinical need, little experience is available in children comparing the relative efficacy and safety of morphine, meperidine (Demerol), or the newer synthetic narcotics nalbuphine (Nubain), buprenorphine (Buprenex), and butorphanol (Standol). In general, morphine remains the standard to which other narcotic analgesics are compared; morphine appears to offer the most substantial pain relief in usual therapeutic doses but its effectiveness may be limited by a relatively narrow therapeutic index. Published data in adults show 1. A greater "ceiling effect" to reach ventilatory depression (i.e., larger margin of safety*) with the new synthetic narcotics compared to morphine and meperidine. 17 2. Nalbuphine (Nubain) produces significantly fewer and less frequent adverse hemodynamic (cardiovascular) effects in postoperative cardiac patients compared to morphine. 10 3. In laboratory animals nalbuphine does not appear to stimulate the release of histamine whereas morphine has been shown to result in a transient, 50-fold increase in plasma histamine concentration, which may be the cause for the decrease in blood pressure often seen with morphine administrationY Additionally, this increase in circulating histamine concentration also has been implicated in prolonging the time necessary to wean certain patients from the mechanical ventilators. 4. Butorphanol may increase pulmonary artery pressure, 18 an undesirable effect in infants and children undergoing cardiac catheterization. 5. Buprenorphine (Buprenex) ventilatory depreSSion, in one case, was not reversed by naloxone administration. 11 6. Nalbuphine, and possibly other narcotics, may produce amnesia, a highly desirable clinical effect in many situations for which anesthetic premedications are prescribed. 16
Despite the relative widespread use of meperidine, morphine is preferred to meperidine in infants and children. First, seizures may occur following chronic dosing with meperidine owing to accumulation of its primary metabolite normeperidine. 9 Increased seizure activity has been *Margin of safety (MS) may be defined as the ratio of the lethal dose in 1 per cent (LDI) of a particular study population divided by the effective dose in 99 per cent (ED99) of that same study group. MS = LDIIED99. Acetaminophen has an MS of about 15; digoxin has an MS of about 2. No pediatric MS data for sedatives or narcotics are published to our knowledge.)
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reported in oncology patients when meperidine is the primary analgesic employed. 9 Furthermore, there seems to be little difference in the risk of ventilatory depression with equally analgesic doses of morphine or meperidine in children. In light of all of this information, we have discontinued our use of meperidine.
ALTERNATIVES TO DPT/LYTIC COCKTAIL The search for a safe and effective single agent or combination regimen that combines the desired degrees of sedation, analgesia, and, for selected procedures, anticholinergic activity in infants and children continues. Although the DPT/lytic cocktail has been used extensively in pediatrics, more rational alternatives do exist. The following alternative premedication regimens are listed in order of potential safety and appear, at the present, to offer equally effective and probably safer sedation and analgesia than the DPT/lytic cocktail for many procedures. 1. Midazolam 0.1 mg per kg plus morphine 0.1 mg per kg (one may substitute nalbuphine 0.1 mg per kg for morphine), given together as a single mixture per rectum or by intramuscular injection. 2. Diazepam 0.5 mg per kg plus morphine 0.15 mg per kg plus atropine (if indicated) 0.01 mg per kg per rectum, given as a mixture in a propylene glycol suspension. 12 3. Diazepam 0.2 mg per kg plus meperidine 1.5 mg per kg (or preferably morphine 0.15 mg per kg) plus atropine (if indicated) 0.02 mg per kg, given orally as a suspension in a dose of 0.25 ml per kg!
Regimen I, midazolam plus morphine (or nalbuphine), contains drugs that display a greater margin of safety when compared with other combinations published in adult studies. Midazolam, a benzodiazepine that differs from diazepam (e.g., Valium) in its short duration of effect (approximately 30 to 45 minutes),20 possesses greater water solubility and 'produces a greater degree of sedation. Greater water solubility allows much more predictable absorption following intramuscular injection and minimizes the often associated local irritation. 15 In its parenteral water-soluble preparation (buffered to an acidic pH of 3.5) midazolam can be mi~ed physically with other drugs, including morphine, nalbuphine, atropine, D5W, normal saline, and lactated Ringer's solution. Like other berizodiazepine drugs, midazolam produces amnesia, a desirable effect in children undergoing procedures. 15 A further advantage of midazolam, shared py diazepam, is that a specific benzodiazepine antagonist, flumazenil (now in clinical trials in the United States), soon will be clinically available. This antagonist has been shown to reverse coma due to midazolam, similar to the reversal of narcotic depression by naloxone. Thus, both midazolam and morphine (or naIbuphine) in regimen I can be reversed by specific antagonists. Nalbuphine, described earlier, is a newer synthetic narcotic that certain studies in adults suggest may have advantages over morphine and meperidine. The recommended dosing for nalbuphine is the same as that for morphine. Nalbuphine appears to possess a greater "ceiling effect" for
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ventilatory (respiratory) depression than other available narcotics. Beyond three to five times usual analgesic doses, nalbuphine produces little further ventilatory depression whereas morphine continues to depress the respiratory rate in a dose response manner. 10. 17 Also, morphine has been reported to produce a euphoric effect that is thought to contribute to its analgesic effect. Nalbuphine may lack this effect and this may not provide as complete a feeling of pain relief as morphine; however, this possible difference remains to be proven in children. Nevertheless, the practice of administering nalbuphine followed by morphine should be avoided because of the risk of dysphoric reactions. As a partial antagonist of the narcotic mu receptor, nalbuphine may permit the sigma (dysphoric effects) receptor stimulation by morphine to predominate. It should be obvious from the above that a clear need exists for doubleblind controlled clinical trials evaluating premedicant regimens for use in children. Specifically, critical studies should be undertaken in children to compare regimen I to DPT/lytic cocktail as premedication for specific procedures. In lieu of such data, the adult data cited herein, along with classic pharmacologic considerations, strongly suggest this combination may be a preferred regimen for many, if not most, pediatric procedures requiring a sedative-analgesic premedication. Regimen II, a mixture of diazepam, morphine and atropine, is administered per rectum. Evaluation of a similar regimen (hyoscine, i. e., scopolamine, was used in place of atropine) in 20 children undergoing minor surgery showed this regimen to produce satisfactory sedation but not analgesia. 12 Using this regimen, morphine plasma concentrations of only 10 to 20 jJ-g per liter were achieved. Previous studies have suggested that morphine plasma concentrations below 65 jJ-g per liter are associated with unpredictable or poor pain relief in children. 4 Thus, from this study it would appear possible to achieve adequate pain relief if larger doses of morphine were administered. However, additional study is necessary to assess the relationship between rectal morphine dose and analgesic response. Regimen III, a mixture of diazepam, meperidine, and atropine given orally, evaluated in a prospective, double-blind study of 159 healthy children (average age 5.5 years) admitted for outpatient pediatric surgery, produced significantly less secretions and a significantly lower incidence of crying (20 per cent versus 34 per cent, p < 0.05) upon arrival in the operating room compared to children in the placebo group. 2 The frequency of laryngospasm and postoperative crying tended to be less in the premedicated group than in the placebo group but was not statistically different. Onset of effect was described as rapid, approximating 10 minutes. 2 In our opinion, morphine (or nalbuphine) may be preferred instead of meperidine owing to the documented seizure risk of chronic meperidine.
SUMMARY These therapeutic approaches to the premedication of children, in our opinion, offer a more rational, probably safer, and at least equally efficacious
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treatment regimen as the DPT/lytic cocktail. It is understood that controlled, double-blind comparative clinical trials in children are needed of these or other potential premedicant regimens for specific pediatric procedures (e. g., cardiac catheterization, CT scans, bone marrow aspiration, gastrointestinal endoscopy, pleural taps, etc.) to establish the premedication treatment(s) with the greatest benefit-to-risk ratio. Until these data are available, we must maintain prudence in the selection (design) of premedicant regimens and carefully monitor all children receiving these "cocktails. "
REFERENCES Brandt SK, Bugy JL: Problems of medication with the pediatric patient. Dental Clin North Am 28:563, 1984 2. Brzustowicz RM, Nelson DA, Betts EK, et al: Efficacy of oral premedication for pediatric outpatient surgery. Anesthesiology 60:475, 1984 3. Cote CJ, Goudsouzian NG, Liu LMP, et al: Assessment of risk factors related to the acid aspiration syndrome in pediatric patients: gastric pH and residual volume. Anesthesiology 56:70, 1982 4. Dahlstrom B, Bolme P, Feychting H, et al: Morphine kinetics in children. Clin Pharmacol Ther 26:354, 1979 5. EI-Kadre D, Giordano C: The lytic cocktail induces recurrence of fits in the treatment of eclampsia. Am J Obstet GynecoI151:143, 1985 6. Feychting H: Premedication and psychological preparation. Clin Anaesthesiol 3:505, 1985 7. GrafJD, Phillips OC, Bensen DW, et al: Factors in pediatric anesthesia mortality. Anesth Analg 43:407, 1964 8. Gilman AG, et al (eds): Goodman and Gilman's The Pharmacological Basis of Therapeutics, Ed 7. New York, Macmillan Publishing, 1985, p 386, p 500 9. Hursey LA: Meperidine and central neural toxicity. Ann Intern Med 98:548, 1983 10. Lake CL, Duckworth EN, DiFazio CA, et al: Cardiovascular effects of nalbuphine in patients with coronary or valvular heart disease. Anesthesiology 57:498, 1982 11. Lewis JW: Buprenorphine. Drug Alcohol Dependence 14:363, 1985 12. Lindahl S, Olsson AK, Thomson D: Rectal premedication in children. Anaesthesia 36:376, 1981 13. Muldoon SM, Donlon MA, Todd R, et al: Plasma histamine levels in nalbuphine and morphine treated dogs. Fed Proc 42:904, 1983 14. Nahata MC, Clotz MA, Krogg EA: Adverse effects of meperidine, promethazine and chlorpromazine combination for sedation anesthesia. Pediatr Res 19:177A, 1985 15. Reves JG, Fragen RJ, Vinik R, et al: Midazolam: pharmacology and uses. Anesthesiology 62:310, 1985 16. Rita L, Seleny F, Goodarzi M: Comparison of the calming and sedative effects of nalbuphine and pentazocine for pediatric premedication. Canad Anaesth Soc J 27:546, 1980 17. Romagnoli A, Keats AS: Ceiling effect for respiratory depression by nalbuphine. Clin Pharmacol Ther 27:478, 1980 18. Vandam LD: Butorphanol. N Engl J Med 302:381, 1980 19. Vandam LD: Aspiration of gastric contents in the operative period. N Engl J Med 273:1206, 1965 20. Vinik HR, Reves JG, Wright D: Premedication with intramuscular midazolam: A prospective randomized, double-blind controlled study. Anesth Analg 61:933, 1982
ADDITIONAL READING Anonymous: Sedation and analgesia for minor painful procedures. Med Lett Drugs Ther 19:26, 1977
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Aubuchon RW: Sedation liabilities in pedodontics. Pediatric Dentistry 4:171, 1982 Bejerstem A, Olsson GL, Palmer L: The influence of body weight on plasma concentration of atropine after rectal administration in children. Acta Anesthesiol Scand 29:782, 1985 Blom H, Schmidt JF, Rytlander M: Rectal diazepam compared to intramuscular pethidine/ promethazine/chlorpromazine with regard to gastric contents in pediatric anesthesia. Acta Anaesthesiol Scand 28:652, 1984 Booker PD, Chapman DH: Premedication in children undergoing day-care surgery. Br J Anaesth 51:1083, 1979 Carter AJ: Premedication for children. Anaesthesia 41:440, 1986 Clyburn P, et al: Effects of diazepam and midazolam on recovery from anesthesia in outpatients. Brit J Anaesth 58:872, 1986 Dhames MS: An evaluation of intramuscular midazolam as a preanesthetic medication. Anesth Analg 62:256, 1983 Forrest WH, et al: Subjective responses to six common preoperative medications. Anesthesiology 47:241, 1977 Freeman A, Bachman L: Pediatric anesthesia: an evaluation of preoperative medication. Anesth Analg 38:429, 1969 Grimes JG: Oral premedication in children. Anesth Analg 41:201, 1982 Heizmann P, et al: Pharmacokinetics and bioavailability of midazolam in man. Br J Clin Pharmacol 16:435, 1983 Hoffman EW, et al: The effects of midazolam on cerebral blood flow and oxygen consumption and its interaction with nitrous oxide. Anesth Analg 65:729, 1986 Israel R, Hohn AR, Black IFS, et al: Evaluation of sedation during cardiac catheterization of children. J Pediatr 70:407, 1967 Klotz U, et al: Physiologic and temporal variation in hepatic elimination of midazolam. Clin Pharmacol Ther 32:107, 1982 Kroll RG: The effect of premedication on handicapped children. J Dentistry Children 36:103, 1969 Mitchell AA, Louik C, Lacoutre P, et al: Risks to children from computed tomographic scan premedication. JAMA 247:2385, 1982 Moore RL, Carrel R, Binns WHo Sedation: a balanced oral sedation technique. J Dentistry Children 48:363, 1981 Morel D, et al: Comparative hemodynamic and respiratory effects of midazolam and flunitrazepam as induction agents in cardiac surgery. Arzneim Forsch 31:2264, 1981 Myers OR, Shoaf HK: The intramuscular use of a combination of meperidine, promethazine and chlorpromazine for sedation of the child dental patient. J Dentistry Children 44:453, 1977 Quaynor H, Corbey M, Bjorkman S: Rectal induction of anesthesia in children with methohexital. Br J Anaesth 57:573, 1985 Reitan JA, et al: Comparison of midazolam and diazepam for induction of anesthesia in highrisk patients. Anesthesiology 59:A378, 1983 Root B: Problems of evaluation effects of premedication in children. Anesth Analg 41:180, 1962 Ruble JW: Appraisal of drugs to premedicate children for dental procedures. J Dentistry Children 19:22, 1952 Salem MR, Wong AY, Mani M, et al: Premedicant drugs and gastric juice pH and volume in pediatric patients. Anesthesiology 44:216, 1976 Samuelson PN, et al: Midazolam versus diazepam: Different effects of systemic vascular resistance. Arzneim Forsch 31:2268, 1981 Schulte-Sassa U, et al: Hemodynamic responses to induction of anesthesia using midazolam in cardiac surgical patients. Br J Anesth 54: 1053, 1982 Sjovall S, Kanto J, Iisalo E, et aI: Midazolam versus atropine plus pethidine (meperidine) as premedication in children. Anaesthesia 39:224, 1984 Smith C, Rowe RD, Vlad P: Sedation of children for cardiac catheterization. Canad Anesth Society J 6:35, 1958 Smith MT, et aI: The pharmacokinetics of midazolam in man. Europ J Clin Pharmacol 19:271, 1981 Tobias MG, Lipschultz DH, Album MM: A study of three preoperative sedative combinations. J Dentistry Children 42:453, 1975 Department of Pediatrics and PharmacologylToxicology University of Texas Medical Branch Galveston, TX 77550
0031-3955/89 $0.00
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.20
Lyticl"DPT" Cocktail: Time for Rational and Safe Alternatives
Wayne R. Snodgrass, MD, PhD, * and Warren F. Dodge, MDt
Lytic cocktail, also known as DPT cocktail or cardiac cocktail, is a mixture consisting of a combination of meperidine (Oemerol) 25 mg per ml, promethazine (Phenergan) 6.5 mg per ml, and chlorpromazine (Thorazine) 6.5 mg per ml (i.e., "OPT"). Initially described as a premedication for children p.rior to cardiac catheterization and then for use prior to other procedures, the usual dose of this mixture is 0.1 ml per kg administered in tramuscularly. However, owing to the frequent occurrence of orthostatic hypotension, ventilatory (respiratory) depression, we no longer recommend using the OPT/lytic cocktail combination of drugs. This article will review 1) the goals of anesthetic premedication in children, 2) physiologic considerations in pediatric premedication, 3) toxicities of certain premedication drug regimens, ahd 4) alternatives to the use of OPT/lytic cocktail. Because of the frequent occurrence of orthostatic hypotension, ventilatory (respiratory) depression, and also because of sound pharmacologic and physiologic principles of medical practice, we no longer recommend using the OPT/ lytic cocktail combination of drugs . .Regardless of the agent(s) used, dose monitoring of respiratory and cardiovascular status is mandatory in all infants and children given sedatives, narcotic analgesics, or combinations of these agents. Guidelines for the safe and appropriate use of these drugs are difficult to define, due primarily to the lack of published controlled clinical trials or comparative studies of different regimens in children. Thus, much of what we state herein represents only our opinion. Obviously, prospective controlled studies of sedation and analgesia in infants and children administered for a variety of invasive procedures and indications are clearly needed. *Head, Clinical Pharmacology-Toxicology Unit, Departments of Pediatrics and PharmacologyToXicology, University of Texas Medical Branch, Galveston, Texas tClinical Pharmacology-Toxicology Unit, Departments of Pediatrics and PharmacologyToXicology, University of Texas Medical Branch, Galveston, Texas
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GOALS OF ANESTHETIC PREMEDICATION IN CHILDREN The goals of pharmacologic anesthetic premedication are many and include 6 1. The elimination of preoperative pain 2. To minimize unwanted effects of anesthetic agents via avoidance of their use 3. To supplement anesthesia 4. To allay anxiety and thus purposeless body movements facilitating performance of the surgical procedure
The ideal premedication agent or combination of agents for use in infants and children is yet to be identified. Such a regimen should produce consistent and predictable results, be associated with good patient acceptance, be completely or partially reversible, and be free of adverse effects. Additional desirable characteristics may depend on the procedure anticipated. In pediatric dental procedures performed in an outpatient (office) environment, the patient should remain conscious and responsive to commands while the protective laryngeal reflexes remain intact. 1 In other procedures (e. g., cardiac catheterization) more sedation may be desirable and appropriate. Thus, analgesic activity, sedative-hypnotic effects, or antisialogogue (anticholinergic) effects may be desirable for some procedures. 2
PHYSIOLOGIC CONSIDERATIONS Aspiration of gastric contents into the lung is an important complication associated with the administration of the DPT/lytic cocktail andlor other anesthetic premedications. There is general agreement that aspiration risk is greater when the pH of the gastric contents is less than 2.5 with a volume greater than 0.4 ml per kg.3, 19 Also, small children may show very rapid and significant vagal responses to manipulation of the airway; even passing a nasogastric tube may cause significant bradycardia. For these reasons, many physicians have included an anticholinergic drug (e.g., atropine) in the premedication regimen. Nevertheless, for many pediatric procedures there is no apparent need to include an anticholinergic drug. Similar considerations may apply regarding the decision to include or omit the narcotic or sedative component of a premedication regimen.
SIDE EFFECTS OF CERTAIN PREMEDICATION DRUG REGIMENS The DPT/lytic cocktail, given parenterally at a dose of 0.02 to 0.2 ml per kg, studied prospectively in 95 pediatric patients undergoing various procedures caused severe respiratory depression in 4 patients. 14 The lowest respiratory rate ranged from 8 to 18 breaths per minute at 1 to 3 hours after the dose was administered. One patient given 0.07 ml per kg experienced ventilatory arrest within 30 minutes following administration
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of the dose. An additional patient required the use of naloxone (Narcan) to reverse ventilatory depression. In addition to these important, life-threatening reactions noted above, about two thirds of the 95 pediatric patients Were sedated for longer than 7 hoursY No relationship between dose administered and duration of sedation could be obtained from the data. It is well known that narcotics (e.g., meperidine [Demerol]) and phenothiazines (e.g., promethazine and chlorpromazine) lower the seizure threshold and thus increase the risk for the development of seizures. 8 This may be of importance particularly in patients with an underlying seizure disorder. Seizures resulting in death have been reported following the administration of the DPT/lytic cocktai},5 In addition, dystonic (extrapyramidal) reactions also may occur, primarily because of the chlorpromazine (phenothiazine) component of the DPT/lytic cocktail mixture. In those clinical situations in which significant analgesia is desired (e.g., bone marrow aspiratibn/biopsies) a narcotic analgesic may be required. Despite this relatiVely common clinical need, little experience is available in children comparing the relative efficacy and safety of morphine, meperidine (Demerol), or the newer synthetic narcotics nalbuphine (Nubain), buprenorphine (Buprenex), and butorphanol (Standol). In general, morphine remains the standard to which other narcotic analgesics are compared; morphine appears to offer the most substantial pain relief in usual therapeutic doses but its effectiveness may be limited by a relatively narrow therapeutic index. Published data in adults show 1. A greater "ceiling effect" to reach ventilatory depression (i.e., larger margin of safety*) with the new synthetic narcotics compared to morphine and meperidine. 17 2. Nalbuphine (Nubain) produces significantly fewer and less frequent adverse hemodynamic (cardiovascular) effects in postoperative cardiac patients compared to morphine. 10 3. In laboratory animals nalbuphine does not appear to stimulate the release of histamine whereas morphine has been shown to result in a transient, 50-fold increase in plasma histamine concentration, which may be the cause for the decrease in blood pressure often seen with morphine administrationY Additionally, this increase in circulating histamine concentration also has been implicated in prolonging the time necessary to wean certain patients from the mechanical ventilators. 4. Butorphanol may increase pulmonary artery pressure, 18 an undesirable effect in infants and children undergoing cardiac catheterization. 5. Buprenorphine (Buprenex) ventilatory depreSSion, in one case, was not reversed by naloxone administration. 11 6. Nalbuphine, and possibly other narcotics, may produce amnesia, a highly desirable clinical effect in many situations for which anesthetic premedications are prescribed. 16
Despite the relative widespread use of meperidine, morphine is preferred to meperidine in infants and children. First, seizures may occur following chronic dosing with meperidine owing to accumulation of its primary metabolite normeperidine. 9 Increased seizure activity has been *Margin of safety (MS) may be defined as the ratio of the lethal dose in 1 per cent (LDI) of a particular study population divided by the effective dose in 99 per cent (ED99) of that same study group. MS = LDIIED99. Acetaminophen has an MS of about 15; digoxin has an MS of about 2. No pediatric MS data for sedatives or narcotics are published to our knowledge.)
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reported in oncology patients when meperidine is the primary analgesic employed. 9 Furthermore, there seems to be little difference in the risk of ventilatory depression with equally analgesic doses of morphine or meperidine in children. In light of all of this information, we have discontinued our use of meperidine.
ALTERNATIVES TO DPT/LYTIC COCKTAIL The search for a safe and effective single agent or combination regimen that combines the desired degrees of sedation, analgesia, and, for selected procedures, anticholinergic activity in infants and children continues. Although the DPT/lytic cocktail has been used extensively in pediatrics, more rational alternatives do exist. The following alternative premedication regimens are listed in order of potential safety and appear, at the present, to offer equally effective and probably safer sedation and analgesia than the DPT/lytic cocktail for many procedures. 1. Midazolam 0.1 mg per kg plus morphine 0.1 mg per kg (one may substitute nalbuphine 0.1 mg per kg for morphine), given together as a single mixture per rectum or by intramuscular injection. 2. Diazepam 0.5 mg per kg plus morphine 0.15 mg per kg plus atropine (if indicated) 0.01 mg per kg per rectum, given as a mixture in a propylene glycol suspension. 12 3. Diazepam 0.2 mg per kg plus meperidine 1.5 mg per kg (or preferably morphine 0.15 mg per kg) plus atropine (if indicated) 0.02 mg per kg, given orally as a suspension in a dose of 0.25 ml per kg!
Regimen I, midazolam plus morphine (or nalbuphine), contains drugs that display a greater margin of safety when compared with other combinations published in adult studies. Midazolam, a benzodiazepine that differs from diazepam (e.g., Valium) in its short duration of effect (approximately 30 to 45 minutes),20 possesses greater water solubility and 'produces a greater degree of sedation. Greater water solubility allows much more predictable absorption following intramuscular injection and minimizes the often associated local irritation. 15 In its parenteral water-soluble preparation (buffered to an acidic pH of 3.5) midazolam can be mi~ed physically with other drugs, including morphine, nalbuphine, atropine, D5W, normal saline, and lactated Ringer's solution. Like other berizodiazepine drugs, midazolam produces amnesia, a desirable effect in children undergoing procedures. 15 A further advantage of midazolam, shared py diazepam, is that a specific benzodiazepine antagonist, flumazenil (now in clinical trials in the United States), soon will be clinically available. This antagonist has been shown to reverse coma due to midazolam, similar to the reversal of narcotic depression by naloxone. Thus, both midazolam and morphine (or naIbuphine) in regimen I can be reversed by specific antagonists. Nalbuphine, described earlier, is a newer synthetic narcotic that certain studies in adults suggest may have advantages over morphine and meperidine. The recommended dosing for nalbuphine is the same as that for morphine. Nalbuphine appears to possess a greater "ceiling effect" for
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ventilatory (respiratory) depression than other available narcotics. Beyond three to five times usual analgesic doses, nalbuphine produces little further ventilatory depression whereas morphine continues to depress the respiratory rate in a dose response manner. 10. 17 Also, morphine has been reported to produce a euphoric effect that is thought to contribute to its analgesic effect. Nalbuphine may lack this effect and this may not provide as complete a feeling of pain relief as morphine; however, this possible difference remains to be proven in children. Nevertheless, the practice of administering nalbuphine followed by morphine should be avoided because of the risk of dysphoric reactions. As a partial antagonist of the narcotic mu receptor, nalbuphine may permit the sigma (dysphoric effects) receptor stimulation by morphine to predominate. It should be obvious from the above that a clear need exists for doubleblind controlled clinical trials evaluating premedicant regimens for use in children. Specifically, critical studies should be undertaken in children to compare regimen I to DPT/lytic cocktail as premedication for specific procedures. In lieu of such data, the adult data cited herein, along with classic pharmacologic considerations, strongly suggest this combination may be a preferred regimen for many, if not most, pediatric procedures requiring a sedative-analgesic premedication. Regimen II, a mixture of diazepam, morphine and atropine, is administered per rectum. Evaluation of a similar regimen (hyoscine, i. e., scopolamine, was used in place of atropine) in 20 children undergoing minor surgery showed this regimen to produce satisfactory sedation but not analgesia. 12 Using this regimen, morphine plasma concentrations of only 10 to 20 jJ-g per liter were achieved. Previous studies have suggested that morphine plasma concentrations below 65 jJ-g per liter are associated with unpredictable or poor pain relief in children. 4 Thus, from this study it would appear possible to achieve adequate pain relief if larger doses of morphine were administered. However, additional study is necessary to assess the relationship between rectal morphine dose and analgesic response. Regimen III, a mixture of diazepam, meperidine, and atropine given orally, evaluated in a prospective, double-blind study of 159 healthy children (average age 5.5 years) admitted for outpatient pediatric surgery, produced significantly less secretions and a significantly lower incidence of crying (20 per cent versus 34 per cent, p < 0.05) upon arrival in the operating room compared to children in the placebo group. 2 The frequency of laryngospasm and postoperative crying tended to be less in the premedicated group than in the placebo group but was not statistically different. Onset of effect was described as rapid, approximating 10 minutes. 2 In our opinion, morphine (or nalbuphine) may be preferred instead of meperidine owing to the documented seizure risk of chronic meperidine.
SUMMARY These therapeutic approaches to the premedication of children, in our opinion, offer a more rational, probably safer, and at least equally efficacious
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treatment regimen as the DPT/lytic cocktail. It is understood that controlled, double-blind comparative clinical trials in children are needed of these or other potential premedicant regimens for specific pediatric procedures (e. g., cardiac catheterization, CT scans, bone marrow aspiration, gastrointestinal endoscopy, pleural taps, etc.) to establish the premedication treatment(s) with the greatest benefit-to-risk ratio. Until these data are available, we must maintain prudence in the selection (design) of premedicant regimens and carefully monitor all children receiving these "cocktails. "
REFERENCES Brandt SK, Bugy JL: Problems of medication with the pediatric patient. Dental Clin North Am 28:563, 1984 2. Brzustowicz RM, Nelson DA, Betts EK, et al: Efficacy of oral premedication for pediatric outpatient surgery. Anesthesiology 60:475, 1984 3. Cote CJ, Goudsouzian NG, Liu LMP, et al: Assessment of risk factors related to the acid aspiration syndrome in pediatric patients: gastric pH and residual volume. Anesthesiology 56:70, 1982 4. Dahlstrom B, Bolme P, Feychting H, et al: Morphine kinetics in children. Clin Pharmacol Ther 26:354, 1979 5. EI-Kadre D, Giordano C: The lytic cocktail induces recurrence of fits in the treatment of eclampsia. Am J Obstet GynecoI151:143, 1985 6. Feychting H: Premedication and psychological preparation. Clin Anaesthesiol 3:505, 1985 7. GrafJD, Phillips OC, Bensen DW, et al: Factors in pediatric anesthesia mortality. Anesth Analg 43:407, 1964 8. Gilman AG, et al (eds): Goodman and Gilman's The Pharmacological Basis of Therapeutics, Ed 7. New York, Macmillan Publishing, 1985, p 386, p 500 9. Hursey LA: Meperidine and central neural toxicity. Ann Intern Med 98:548, 1983 10. Lake CL, Duckworth EN, DiFazio CA, et al: Cardiovascular effects of nalbuphine in patients with coronary or valvular heart disease. Anesthesiology 57:498, 1982 11. Lewis JW: Buprenorphine. Drug Alcohol Dependence 14:363, 1985 12. Lindahl S, Olsson AK, Thomson D: Rectal premedication in children. Anaesthesia 36:376, 1981 13. Muldoon SM, Donlon MA, Todd R, et al: Plasma histamine levels in nalbuphine and morphine treated dogs. Fed Proc 42:904, 1983 14. Nahata MC, Clotz MA, Krogg EA: Adverse effects of meperidine, promethazine and chlorpromazine combination for sedation anesthesia. Pediatr Res 19:177A, 1985 15. Reves JG, Fragen RJ, Vinik R, et al: Midazolam: pharmacology and uses. Anesthesiology 62:310, 1985 16. Rita L, Seleny F, Goodarzi M: Comparison of the calming and sedative effects of nalbuphine and pentazocine for pediatric premedication. Canad Anaesth Soc J 27:546, 1980 17. Romagnoli A, Keats AS: Ceiling effect for respiratory depression by nalbuphine. Clin Pharmacol Ther 27:478, 1980 18. Vandam LD: Butorphanol. N Engl J Med 302:381, 1980 19. Vandam LD: Aspiration of gastric contents in the operative period. N Engl J Med 273:1206, 1965 20. Vinik HR, Reves JG, Wright D: Premedication with intramuscular midazolam: A prospective randomized, double-blind controlled study. Anesth Analg 61:933, 1982
ADDITIONAL READING Anonymous: Sedation and analgesia for minor painful procedures. Med Lett Drugs Ther 19:26, 1977
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Aubuchon RW: Sedation liabilities in pedodontics. Pediatric Dentistry 4:171, 1982 Bejerstem A, Olsson GL, Palmer L: The influence of body weight on plasma concentration of atropine after rectal administration in children. Acta Anesthesiol Scand 29:782, 1985 Blom H, Schmidt JF, Rytlander M: Rectal diazepam compared to intramuscular pethidine/ promethazine/chlorpromazine with regard to gastric contents in pediatric anesthesia. Acta Anaesthesiol Scand 28:652, 1984 Booker PD, Chapman DH: Premedication in children undergoing day-care surgery. Br J Anaesth 51:1083, 1979 Carter AJ: Premedication for children. Anaesthesia 41:440, 1986 Clyburn P, et al: Effects of diazepam and midazolam on recovery from anesthesia in outpatients. Brit J Anaesth 58:872, 1986 Dhames MS: An evaluation of intramuscular midazolam as a preanesthetic medication. Anesth Analg 62:256, 1983 Forrest WH, et al: Subjective responses to six common preoperative medications. Anesthesiology 47:241, 1977 Freeman A, Bachman L: Pediatric anesthesia: an evaluation of preoperative medication. Anesth Analg 38:429, 1969 Grimes JG: Oral premedication in children. Anesth Analg 41:201, 1982 Heizmann P, et al: Pharmacokinetics and bioavailability of midazolam in man. Br J Clin Pharmacol 16:435, 1983 Hoffman EW, et al: The effects of midazolam on cerebral blood flow and oxygen consumption and its interaction with nitrous oxide. Anesth Analg 65:729, 1986 Israel R, Hohn AR, Black IFS, et al: Evaluation of sedation during cardiac catheterization of children. J Pediatr 70:407, 1967 Klotz U, et al: Physiologic and temporal variation in hepatic elimination of midazolam. Clin Pharmacol Ther 32:107, 1982 Kroll RG: The effect of premedication on handicapped children. J Dentistry Children 36:103, 1969 Mitchell AA, Louik C, Lacoutre P, et al: Risks to children from computed tomographic scan premedication. JAMA 247:2385, 1982 Moore RL, Carrel R, Binns WHo Sedation: a balanced oral sedation technique. J Dentistry Children 48:363, 1981 Morel D, et al: Comparative hemodynamic and respiratory effects of midazolam and flunitrazepam as induction agents in cardiac surgery. Arzneim Forsch 31:2264, 1981 Myers OR, Shoaf HK: The intramuscular use of a combination of meperidine, promethazine and chlorpromazine for sedation of the child dental patient. J Dentistry Children 44:453, 1977 Quaynor H, Corbey M, Bjorkman S: Rectal induction of anesthesia in children with methohexital. Br J Anaesth 57:573, 1985 Reitan JA, et al: Comparison of midazolam and diazepam for induction of anesthesia in highrisk patients. Anesthesiology 59:A378, 1983 Root B: Problems of evaluation effects of premedication in children. Anesth Analg 41:180, 1962 Ruble JW: Appraisal of drugs to premedicate children for dental procedures. J Dentistry Children 19:22, 1952 Salem MR, Wong AY, Mani M, et al: Premedicant drugs and gastric juice pH and volume in pediatric patients. Anesthesiology 44:216, 1976 Samuelson PN, et al: Midazolam versus diazepam: Different effects of systemic vascular resistance. Arzneim Forsch 31:2268, 1981 Schulte-Sassa U, et al: Hemodynamic responses to induction of anesthesia using midazolam in cardiac surgical patients. Br J Anesth 54: 1053, 1982 Sjovall S, Kanto J, Iisalo E, et aI: Midazolam versus atropine plus pethidine (meperidine) as premedication in children. Anaesthesia 39:224, 1984 Smith C, Rowe RD, Vlad P: Sedation of children for cardiac catheterization. Canad Anesth Society J 6:35, 1958 Smith MT, et aI: The pharmacokinetics of midazolam in man. Europ J Clin Pharmacol 19:271, 1981 Tobias MG, Lipschultz DH, Album MM: A study of three preoperative sedative combinations. J Dentistry Children 42:453, 1975 Department of Pediatrics and PharmacologylToxicology University of Texas Medical Branch Galveston, TX 77550