Pharmacology Midazolam for
Outpatient Sedation
Donna L. Betcher, RN, MS, PNP and Nora Burnham, PharmD oncology patients P EDIATRIC undergo variety
are
required to
of invasive procedures during their diagnostic workups and treatments. Procedures such as bone marrow aspirations and lumbar punctures may be required on a regular basis. Considerable discomfort and anxiety may be experienced with these procedures. Discomfort and anxiety may be decreased or alleviated with the use of appropriate pharmacological sedation. Midazolam (Versed; Roche Laboratories, blutley, J) is a rapid-onset, shortduration benzodiazepine that can be used for preoperative sedation, conscious sedation, and induction of general anesthesia. In this article, the authors will examine the use of midazolam for conscious sedation in children during oncolt
a
ogy
procedures.
Mechanism of Action Midazolam was the first water-soluble benzodiazepine when it became commercially available in the 1980s z Midazolam belongs to the group of benzodiazepines called imidazobenzodiazepines, which differ from the traditional family by the presence of an imidazole ring fused at position 1 and 2 of the benzodiazepine nucleus 3 The imidazole ring allows midazolam to form salts readily, which increases its water solubility and stability compared with other benzodiaz-
epines (Fig 1 ). The pH of the surrounding environment affects the structure of midazolam. At an acidic pH, midazolam’s imidazole ring will open. But at a physiological pH (7.4), the ring remains intact or closed. This form of midazolam is more lipid ~
~
~
z
From Mayo Comprehensive Cancer Center, Rochester, MN. Address reprint requests to Donna L Betcher, RN, MS, PNP, Mayo Clinic, 200 First St SW, E-12, Rochester, MN 55905. © 1992 by Association of Pediatric Oncology Nurses.
1043-454219210903-0005$03.00I0
soluble and allows the agent to cross the bloodbrain barrier. That midazolam readily crosses this barrier has been demonstrated in the animal model. The exact mode and sites of action of the benzodiazepines are unknown. Researchers believe their effects are mediated through inhibition of a neurotransmitter, gamma-animobutyrie.3 Benzodiazepines appear to act at the limbic, thalamic, and hypothalamic levels of the central nervous system. All benzodiazepines function to some degree as an anxiolytic, sedative, hypnotic, skeletal muscle relaxant, or anticonwlsant. All of them can produce all levels of central nervous system depression from mild sedation to coma. Midazolam is a short-acting benzodiazepine that has no accumulation of major metabolites 4 It has a sedative potency that is 3 to 4 times that of diazepam 3 Midazolam does not cause car-
diorespiratory instability.4 Kinetics Midazolam undergoes hepatic conversion to 1-hydroxymethyl midazolam, with 45% to 57% of the dose excreted in the urine as the metabolite 2 The drug is highly protein bound (94% to
97%). Normal patients have an elimination half-life of 1.2 to 12.3 hours, with the majority of patients eliminating half their dose by 21/2 hours.1 Plasma levels decline rapidly with intravenous (N) administration due to the high lipid solubility of the agent. Maximum blood levels achieved with intramuscular (IM) administration occur within 30 minutes.5 Administration 1M produces excellent blood levels because midazolam has a mean absolute bioavailability of 87% when given by that route. 6 Kretz et ah compared rectal administration of midazolam with the IM and N routes. They administered 1 mg/kg rectally, 0.15 mg/kg IM, and
136
Downloaded from jpo.sagepub.com at FLORIDA INTERNATIONAL UNIV on July 11, 2015
137
mulations, none of which have been approved yet by the Food and Drug Administration (FDA). The oral form is bitter. Partially melted commercially available &dquo;Popsicles&dquo; have been used to mask the bitterness.9 The British version is a raspberry-flavored syrup with 3 mg/mL midazolam that is freshly prepared the previous day.10 Rosen and Rosen9 developed a sweetened flavored gelatin as the preferred vehicle for oral midazolam. Researchers at the Medical University of South Carolina developed a nonflavored syrup as an oral preparation of 2.5 mg/mL midazolam.&dquo; They studied its stability and found it stable for 56 days at room temperature. The syrup contains benzyl alcohol as a preservative.
FIGURE 1. Chemical structure of midazolam.
Stability and Storage
0.2 mg/kg IV. They determined the kinetics of rectal administration to be very similar to IM and N, with approximately 40% of the dose absorbed rectally. Blumer et alB studied 20 children ranging in age from 2 to 6 years. They used a dosing schedule with an initial IV bolus followed by IV doses of 25% of the initial dose every minute until the child slept. They studied four groups of five children each, and the initial N doses were 0.1 mg, 0.15 mg, 0.2 mg, and 0.25 mg/kg. The number of children who slept (responders) were two children in the first group, three children in the second group, four children in the third group, and only one child in the fourth group. The mean age was 4 years for responders and .3.2 years for nonresponders. Responders had a -serum midazolam concentration at sleep of 2.1 ....g/mL (range, 0.4 to 6.6 )JLg/mL) and 0.5 wg/mL at awakening (range, 0.015 to 1.7 f-lg/mL). These concentrations are seven times that found in adults on awakening.3
Availability and Formulation Roche Laboratories
sterile, clear, colorless
supplies
midazolam
as a
light yellow aqueous solution. The commercial product is the hydroto
chloride salt and also contains disodium edetate, sodium chloride, and benzyl alcohol. Each milliliter contains 0.14 mEq sodium. The commercial sizes are 5 mg/mL in 1-, 2-, 5-, and 10-mL vials and a 2-mL syringe. The 1 mg/mL strength is available in 2-, 5-, and 10-mL vials. Many researchers have investigated oral for-
Store midazolam at room temperature and protect it from light. Roche Laboratories states that midazolam is stable for 2 years from the date of manufacture. It is physically stable when frozen for 3
days
and allowed to thaw at
temperature 3
room ’
Midazolam is physically and chemically stable with 5% dextrose in water, normal saline, or lactated Ringer’s solution. When diluted to ~0.5 mg/mL, midazolam maintains its stability, for 24 hours when diluted with 5% dextrose in water or normal saline and for 4 hours when diluted with lactated Ringer’s solution. Midazolam is physically compatible with several other medications when mixed in the same syringe; check with your local pharmacist for specifics. -
Dosage
and Administration
..
As with many medications, the dosage of midazolam must be individualized. Although the manufacturer currently does not have recommended dosages for pediatric patients, specific dosing protocols for pediatric patients have been reported in the literature.10.12 For conscious sedation in the adult population, 0.1 to 0.2 mg/kg administered N is usually adequate.13.14 Additional dosages may be titrated slowly to the desired effect, with no more than 2.5 mg given over a period of at least 2 minutes.13.14 Increments of 25% may be used to maintain the desired effect. Midazolam can be used either alone or together with a narcotic. When given with a narcotic, dosages of midazolam should be lowered 25% to 30%. In the pediatric population, dosages of 0.05
Downloaded from jpo.sagepub.com at FLORIDA INTERNATIONAL UNIV on July 11, 2015
138
mg/kg as a single N dose have been administered. Additional doses of 0.05 mg/kg, with a maximum of 3 doses, were administered as needed.’ Pediatric sedation has also been accomplished with a single dosage of 0.05 mglkg of midazolam given in combination with either
rate, and blood pressure. 1.13 Respiratory reactions have included laryngospasm, bronchospasm, wheezing, shallow respirations, apnea, and airway obstruction. Cardiovascular reactions include a variety of dysrhythmias. Additional adverse reactions include nausea and
morphine (0.06 mg/kg) or fentanyl (0.6 p,gl kg).12,14 Opioids are administered N before midazolam.12.14 The midazolam is mixed with normal saline to a dilution of 1 mg/mL and administered slowly over 2 to 3 minutes through a freely flowing N infusion. Although presently midazolam is only approved by the FDA to be given N or IM, literature describing oral administration is available.’° Midazolam injectable solution is mixed in a flavored, dye-free oral solution.l° The oral syrup will be available commercially in the future. Rosen and Rosen9 have used a dose of 0.4 to 0.8 mg/kg orally and found an onset time of 10 to 20 minutes and sedation lasting 20 minutes
vomiting, headache, coughing, oversedation, drowsiness, and hypersensitivity. Local effects may be noted, such as tenderness, pain,’redness, induration, and phlebitis at the IV site.l.10,12,13 Flumazenil (Mazicon; Roche Laboratories, Nutley, NJ) is a benzodiazepine receptor antagonist that blocks the actions of benzodiazepines on the central nervous system. It has been administered to reverse the sedative effects of benzodiazepines administered for conscious sedation or general anesthesia and in the management
of suspected
benzodiazepine overdose.15 ’
Summary
to 3 hours.
Adverse Reactions Midazolam generally produces few adverse reactions. The most frequently reported reactions are fluctuations in respiratory rate, pulse
Midazolam appears to be a practical and safe pharmacological sedative that may be used to alleviate the discomfort and anxiety associated with invasive procedures in pediatric oncology
patients.
References 1. Versed
package insert Roche Laboratories, Nutley, NJ,
October, 1990 2. Personal communication. Roche Laboratories, December 1991 3. AHFS Drug Information: Midazolam. Am Soc Hosp Pharm, 1992, pp 1345-1349 4. Dundee J; Halliday N, Harper K, et al: Midazolam: A review of its pharmacological properties and therapeutic effect Drugs 28:519-543, 1984 5. Crevoisier PC, Eckert M, Heizmann, et al: Relation between clinical effect and the pharmacokinetics of midazolam following IM and IV administration. Arzneim Forsh Drug Res 31:2211-2215, 1981 6. Gemperle M, Knapp W: Midazolam and anaesthesia. Br J Clin Pharmacol 16:1875-1905, 1983 7. Kretz F, Dorrah T, Heinemeier G, et al: Serum levels following IV, IM, or rectal applications in young children. Naunyn Schmiedeberg’s Arch Pharmacol 334:R12, 1986
(suppl) 8. Blumer
J, Weissman B,
Horwitz S, et al: Midazolam
sedation for CT in children: Pharmacokinetics and pharma-. codynamics, part 2. Acta Pharmacol Toxicol 59:75, 1986 9. Rosen D, Rosen K: A palatable gelatin vehicle for midazolam and ketamine. Anesthesiology 75:914-915, 1991 10. Payne K, Mattheyse F, Uebenberg D, et al: The pharmacokinetics of midazolam in paediatric patients. Eur J Clin Pharmacol 37:267-272, 1989 11. Steedman S, Koonce J, Brahen N, et al: Midazolam stability in a flavored dye-free oral solution. ASHP Midyear Meeting, New Orleans, December 1991 (abstr) 12. Sievers T, Yee JD, Foley M, et al: Midazolam for conscious sedation
Safety and
during pediatric oncology procedures:
recovery parameters. Pediatrics
88:1172-1178,
1991 13. (Jjjajni K, Sujit P: Use of midazolam hydrochloride in anesthesia. Clin Pharmacol 6:553-547, 1987 14. RevesJG, Fragen RJ, et al: Midazolam: Pharmacology and users. Anesthesiology 62:310-324, 1985 15. Mazicon package insert Roche Laboratories, Nutley, NJ, December 1991
Downloaded from jpo.sagepub.com at FLORIDA INTERNATIONAL UNIV on July 11, 2015
&dquo;
Outpatient Sedation
Donna L. Betcher, RN, MS, PNP and Nora Burnham, PharmD oncology patients P EDIATRIC undergo variety
are
required to
of invasive procedures during their diagnostic workups and treatments. Procedures such as bone marrow aspirations and lumbar punctures may be required on a regular basis. Considerable discomfort and anxiety may be experienced with these procedures. Discomfort and anxiety may be decreased or alleviated with the use of appropriate pharmacological sedation. Midazolam (Versed; Roche Laboratories, blutley, J) is a rapid-onset, shortduration benzodiazepine that can be used for preoperative sedation, conscious sedation, and induction of general anesthesia. In this article, the authors will examine the use of midazolam for conscious sedation in children during oncolt
a
ogy
procedures.
Mechanism of Action Midazolam was the first water-soluble benzodiazepine when it became commercially available in the 1980s z Midazolam belongs to the group of benzodiazepines called imidazobenzodiazepines, which differ from the traditional family by the presence of an imidazole ring fused at position 1 and 2 of the benzodiazepine nucleus 3 The imidazole ring allows midazolam to form salts readily, which increases its water solubility and stability compared with other benzodiaz-
epines (Fig 1 ). The pH of the surrounding environment affects the structure of midazolam. At an acidic pH, midazolam’s imidazole ring will open. But at a physiological pH (7.4), the ring remains intact or closed. This form of midazolam is more lipid ~
~
~
z
From Mayo Comprehensive Cancer Center, Rochester, MN. Address reprint requests to Donna L Betcher, RN, MS, PNP, Mayo Clinic, 200 First St SW, E-12, Rochester, MN 55905. © 1992 by Association of Pediatric Oncology Nurses.
1043-454219210903-0005$03.00I0
soluble and allows the agent to cross the bloodbrain barrier. That midazolam readily crosses this barrier has been demonstrated in the animal model. The exact mode and sites of action of the benzodiazepines are unknown. Researchers believe their effects are mediated through inhibition of a neurotransmitter, gamma-animobutyrie.3 Benzodiazepines appear to act at the limbic, thalamic, and hypothalamic levels of the central nervous system. All benzodiazepines function to some degree as an anxiolytic, sedative, hypnotic, skeletal muscle relaxant, or anticonwlsant. All of them can produce all levels of central nervous system depression from mild sedation to coma. Midazolam is a short-acting benzodiazepine that has no accumulation of major metabolites 4 It has a sedative potency that is 3 to 4 times that of diazepam 3 Midazolam does not cause car-
diorespiratory instability.4 Kinetics Midazolam undergoes hepatic conversion to 1-hydroxymethyl midazolam, with 45% to 57% of the dose excreted in the urine as the metabolite 2 The drug is highly protein bound (94% to
97%). Normal patients have an elimination half-life of 1.2 to 12.3 hours, with the majority of patients eliminating half their dose by 21/2 hours.1 Plasma levels decline rapidly with intravenous (N) administration due to the high lipid solubility of the agent. Maximum blood levels achieved with intramuscular (IM) administration occur within 30 minutes.5 Administration 1M produces excellent blood levels because midazolam has a mean absolute bioavailability of 87% when given by that route. 6 Kretz et ah compared rectal administration of midazolam with the IM and N routes. They administered 1 mg/kg rectally, 0.15 mg/kg IM, and
136
Downloaded from jpo.sagepub.com at FLORIDA INTERNATIONAL UNIV on July 11, 2015
137
mulations, none of which have been approved yet by the Food and Drug Administration (FDA). The oral form is bitter. Partially melted commercially available &dquo;Popsicles&dquo; have been used to mask the bitterness.9 The British version is a raspberry-flavored syrup with 3 mg/mL midazolam that is freshly prepared the previous day.10 Rosen and Rosen9 developed a sweetened flavored gelatin as the preferred vehicle for oral midazolam. Researchers at the Medical University of South Carolina developed a nonflavored syrup as an oral preparation of 2.5 mg/mL midazolam.&dquo; They studied its stability and found it stable for 56 days at room temperature. The syrup contains benzyl alcohol as a preservative.
FIGURE 1. Chemical structure of midazolam.
Stability and Storage
0.2 mg/kg IV. They determined the kinetics of rectal administration to be very similar to IM and N, with approximately 40% of the dose absorbed rectally. Blumer et alB studied 20 children ranging in age from 2 to 6 years. They used a dosing schedule with an initial IV bolus followed by IV doses of 25% of the initial dose every minute until the child slept. They studied four groups of five children each, and the initial N doses were 0.1 mg, 0.15 mg, 0.2 mg, and 0.25 mg/kg. The number of children who slept (responders) were two children in the first group, three children in the second group, four children in the third group, and only one child in the fourth group. The mean age was 4 years for responders and .3.2 years for nonresponders. Responders had a -serum midazolam concentration at sleep of 2.1 ....g/mL (range, 0.4 to 6.6 )JLg/mL) and 0.5 wg/mL at awakening (range, 0.015 to 1.7 f-lg/mL). These concentrations are seven times that found in adults on awakening.3
Availability and Formulation Roche Laboratories
sterile, clear, colorless
supplies
midazolam
as a
light yellow aqueous solution. The commercial product is the hydroto
chloride salt and also contains disodium edetate, sodium chloride, and benzyl alcohol. Each milliliter contains 0.14 mEq sodium. The commercial sizes are 5 mg/mL in 1-, 2-, 5-, and 10-mL vials and a 2-mL syringe. The 1 mg/mL strength is available in 2-, 5-, and 10-mL vials. Many researchers have investigated oral for-
Store midazolam at room temperature and protect it from light. Roche Laboratories states that midazolam is stable for 2 years from the date of manufacture. It is physically stable when frozen for 3
days
and allowed to thaw at
temperature 3
room ’
Midazolam is physically and chemically stable with 5% dextrose in water, normal saline, or lactated Ringer’s solution. When diluted to ~0.5 mg/mL, midazolam maintains its stability, for 24 hours when diluted with 5% dextrose in water or normal saline and for 4 hours when diluted with lactated Ringer’s solution. Midazolam is physically compatible with several other medications when mixed in the same syringe; check with your local pharmacist for specifics. -
Dosage
and Administration
..
As with many medications, the dosage of midazolam must be individualized. Although the manufacturer currently does not have recommended dosages for pediatric patients, specific dosing protocols for pediatric patients have been reported in the literature.10.12 For conscious sedation in the adult population, 0.1 to 0.2 mg/kg administered N is usually adequate.13.14 Additional dosages may be titrated slowly to the desired effect, with no more than 2.5 mg given over a period of at least 2 minutes.13.14 Increments of 25% may be used to maintain the desired effect. Midazolam can be used either alone or together with a narcotic. When given with a narcotic, dosages of midazolam should be lowered 25% to 30%. In the pediatric population, dosages of 0.05
Downloaded from jpo.sagepub.com at FLORIDA INTERNATIONAL UNIV on July 11, 2015
138
mg/kg as a single N dose have been administered. Additional doses of 0.05 mg/kg, with a maximum of 3 doses, were administered as needed.’ Pediatric sedation has also been accomplished with a single dosage of 0.05 mglkg of midazolam given in combination with either
rate, and blood pressure. 1.13 Respiratory reactions have included laryngospasm, bronchospasm, wheezing, shallow respirations, apnea, and airway obstruction. Cardiovascular reactions include a variety of dysrhythmias. Additional adverse reactions include nausea and
morphine (0.06 mg/kg) or fentanyl (0.6 p,gl kg).12,14 Opioids are administered N before midazolam.12.14 The midazolam is mixed with normal saline to a dilution of 1 mg/mL and administered slowly over 2 to 3 minutes through a freely flowing N infusion. Although presently midazolam is only approved by the FDA to be given N or IM, literature describing oral administration is available.’° Midazolam injectable solution is mixed in a flavored, dye-free oral solution.l° The oral syrup will be available commercially in the future. Rosen and Rosen9 have used a dose of 0.4 to 0.8 mg/kg orally and found an onset time of 10 to 20 minutes and sedation lasting 20 minutes
vomiting, headache, coughing, oversedation, drowsiness, and hypersensitivity. Local effects may be noted, such as tenderness, pain,’redness, induration, and phlebitis at the IV site.l.10,12,13 Flumazenil (Mazicon; Roche Laboratories, Nutley, NJ) is a benzodiazepine receptor antagonist that blocks the actions of benzodiazepines on the central nervous system. It has been administered to reverse the sedative effects of benzodiazepines administered for conscious sedation or general anesthesia and in the management
of suspected
benzodiazepine overdose.15 ’
Summary
to 3 hours.
Adverse Reactions Midazolam generally produces few adverse reactions. The most frequently reported reactions are fluctuations in respiratory rate, pulse
Midazolam appears to be a practical and safe pharmacological sedative that may be used to alleviate the discomfort and anxiety associated with invasive procedures in pediatric oncology
patients.
References 1. Versed
package insert Roche Laboratories, Nutley, NJ,
October, 1990 2. Personal communication. Roche Laboratories, December 1991 3. AHFS Drug Information: Midazolam. Am Soc Hosp Pharm, 1992, pp 1345-1349 4. Dundee J; Halliday N, Harper K, et al: Midazolam: A review of its pharmacological properties and therapeutic effect Drugs 28:519-543, 1984 5. Crevoisier PC, Eckert M, Heizmann, et al: Relation between clinical effect and the pharmacokinetics of midazolam following IM and IV administration. Arzneim Forsh Drug Res 31:2211-2215, 1981 6. Gemperle M, Knapp W: Midazolam and anaesthesia. Br J Clin Pharmacol 16:1875-1905, 1983 7. Kretz F, Dorrah T, Heinemeier G, et al: Serum levels following IV, IM, or rectal applications in young children. Naunyn Schmiedeberg’s Arch Pharmacol 334:R12, 1986
(suppl) 8. Blumer
J, Weissman B,
Horwitz S, et al: Midazolam
sedation for CT in children: Pharmacokinetics and pharma-. codynamics, part 2. Acta Pharmacol Toxicol 59:75, 1986 9. Rosen D, Rosen K: A palatable gelatin vehicle for midazolam and ketamine. Anesthesiology 75:914-915, 1991 10. Payne K, Mattheyse F, Uebenberg D, et al: The pharmacokinetics of midazolam in paediatric patients. Eur J Clin Pharmacol 37:267-272, 1989 11. Steedman S, Koonce J, Brahen N, et al: Midazolam stability in a flavored dye-free oral solution. ASHP Midyear Meeting, New Orleans, December 1991 (abstr) 12. Sievers T, Yee JD, Foley M, et al: Midazolam for conscious sedation
Safety and
during pediatric oncology procedures:
recovery parameters. Pediatrics
88:1172-1178,
1991 13. (Jjjajni K, Sujit P: Use of midazolam hydrochloride in anesthesia. Clin Pharmacol 6:553-547, 1987 14. RevesJG, Fragen RJ, et al: Midazolam: Pharmacology and users. Anesthesiology 62:310-324, 1985 15. Mazicon package insert Roche Laboratories, Nutley, NJ, December 1991
Downloaded from jpo.sagepub.com at FLORIDA INTERNATIONAL UNIV on July 11, 2015
&dquo;
