VA Class:RE900

AHFS Class:

• Respiratory and CNS Stimulants 28:20.32

Generic Name(s):

• Doxapram Hydrochloride

Doxapram hydrochloride is a monohydrated pyrrolidinone-derivative CNS stimulant.

Doxapram hydrochloride has been used in conjunction with supportive measures to hasten arousal and to treat respiratory depression associated with overdosage of CNS depressant drugs (e.g., barbiturates, opiate analgesics, general anesthetics); acute respiratory insufficiency associated with chronic obstructive pulmonary disease; or respiratory depression in the postoperative recovery period that is not caused by skeletal muscle relaxants. However, because of its questionable benefit, transient action, and high potential for toxicity, doxapram has a limited role in the contemporary management of these conditions.128 In the management of respiratory depression associated with overdosage of CNS depressant drugs, doxapram and other analeptic drugs have largely been abandoned in favor of intensive supportive care (e.g., mechanical ventilation, oxygenation, cardiovascular support) and treatment with specific antidotes (e.g., pure opiate antagonists).135 Use of doxapram in the management of postoperative respiratory depression has declined because of the availability of safer and shorter-acting anesthetic agents.128 Most experts state that respiratory stimulants such as doxapram should not be used for the treatment of acute respiratory failure in patients with chronic obstructive pulmonary disease unless other supportive measures (e.g., noninvasive ventilation using either negative- or positive-pressure devices) are unavailable or not indicated.132,133,134

Doxapram hydrochloride also has been used for the treatment of neonatal apnea†,100,101,102,103,104,105,106,107,108,120,121,123,124,125 principally in combination with theophylline104,105,106,120 or caffeine107 when the response to therapy with one of the latter drugs alone was inadequate; however, further evaluation is needed to determine the efficacy, safety, and optimum dosage of doxapram in the treatment of this condition.100,101,102,103,104,105,106,107,108 Limited evidence suggests that doxapram may improve apnea in preterm infants within the first 48 hours of treatment; however, no firm conclusions regarding efficacy for this indication can be made because of the relatively small number of patients included in the studies.131 Furthermore, no apparent therapeutic advantage for doxapram over IV methylxanthines has been observed.128,130 In addition, because the commercially available doxapram hydrochloride injection is preserved with benzyl alcohol, the manufacturers state that this preparation should not be used in neonates.109,127,136 (See Cautions: Pediatric Precautions.)

Administration

Doxapram hydrochloride may be administered by IV injection or infusion. An adequate airway and oxygenation should be established before administering the drug, and care should be taken to prevent vomiting and aspiration of vomitus. Monitoring of blood pressure, heart rate, and deep tendon reflexes is recommended to prevent overdosa dosage or rate of infusion should be adjusted on the basis of these parameters. Arterial blood gases should be monitored prior to and at 30-minute intervals during administration of doxapram to guard against the development of respiratory acidosis; the drug should be discontinued if arterial carbon dioxide tension increases, oxygen tension decreases, or mechanical ventilation is initiated. The drug also should be discontinued if sudden hypotension or dyspnea occurs.127 Because narcosis may recur after administration of doxapram, close observation of the patient should be continued until the patient has been fully alert for 30 minutes to 1 hour.127 If recurrence of unconsciousness or respiratory depression occurs, supportive care should be provided as required.127 Doxapram is not an antagonist to muscle relaxant drugs nor a specific opiate antagonist.127 When doxapram is used to manage respiratory depression following anesthesia, adequacy of ventilation should be assessed with specific tests (e.g., peripheral nerve stimulation, airway pressures, head lift, pulse oximetry, end-tidal carbon dioxide) prior to administration.127

For IV infusion, a doxapram hydrochloride solution containing approximately 1 mg/mL can be prepared by adding 250 mg of doxapram hydrochloride (12.5 mL of the commercially available injection) to 250 mL of 5 or 10% dextrose or 0.9% sodium chloride injection. A solution containing a final concentration of 2 mg/mL can be prepared by adding 400 mg of doxapram hydrochloride (20 mL of the commercially available injection) to 180 mL of 5 or 10% dextrose or 0.9% sodium chloride injection.127

Dosage

Because doxapram has a narrow margin of safety, the minimum effective dosage should be used and maximum recommended dosages should not be exceeded. Analeptic use of doxapram hydrochloride is strongly discouraged by most clinicians.

Respiratory Depression Following Anesthesia

For the management of respiratory depression following anesthesia, the manufacturers suggest an initial IV injection of 0.5-1 mg/kg. Single doxapram hydrochloride doses should not exceed 1.5 mg/kg. When repeated IV injections are administered, the initial dose may be repeated at 5-minute intervals, if necessary, but the total dose should not exceed 2 mg/kg. Alternatively, IV infusions containing approximately 1 mg/mL may be administered at an initial rate of 5 mg/minute. When the desired response is obtained or if adverse effects appear, the infusion rate may be reduced to 1-3 mg/minute. The recommended dose by IV infusion is 0.5-1 mg/kg; the total dose administered by IV infusion should not exceed 4 mg/kg (approximately 300 mg for an average adult).127 The manufacturers state that the total dose of doxapram hydrochloride administered in a 24-hour period should not exceed 3 g.127

Acute Hypercapnia Associated with Chronic Obstructive Pulmonary Disease

For the management of acute respiratory failure associated with chronic obstructive pulmonary disease, the manufacturer recommends infusion of a doxapram hydrochloride solution containing 2 mg/mL. Initially, the rate of infusion is 1-2 mg/minute; if necessary, the rate of infusion may be increased to a maximum of 3 mg/minute. The infusion should not be administered for longer than 2 hours and should be discontinued if arterial blood gases show evidence of deterioration. The manufacturers warn that it is especially important that the rate of infusion not be exceeded in debilitated patients in an attempt to lower pCO₂ because of the associated increased work in breathing.

Adverse Effects

Doxapram hydrochloride has a narrow margin of safety. Excessive increases in blood pressure; tachycardia and other arrhythmias; skeletal muscle hyperactivity including increased deep tendon reflexes, muscle spasticity, and involuntary movements; and dyspnea have occurred and may be considered early signs of overdosage. More serious symptoms of overdosage include clonus and generalized seizures. Postictal depression may intensify any existing coma. Seizures may be treated with IV injection of an anticonvulsant (e.g., diazepam or a short-acting barbiturate); oxygen and resuscitative equipment should be readily available.

Other adverse central and autonomic nervous system effects reported in patients receiving doxapram include headache, dizziness, apprehension, disorientation, pupillary dilation, positive bilateral Babinski signs, hyperpyrexia, flushing, sweating, pruritus, and paresthesia such as a feeling of warmth, or burning and hot sensations, especially in the area of the perineum and genitalia. Adverse cardiovascular effects such as lowered T waves, sudden hypotension (which should prompt discontinuance of the drug), chest pain, and tightness in the chest have been reported. Mild to moderate increases in blood pressure occur commonly and may be of concern in patients with a severe cardiovascular disease. Sneezing, coughing, laryngospasm, bronchospasm, hiccups, tachypnea, and rebound hypoventilation have also been reported, but coughing, gagging, and laryngospasm are probably manifestations of protective reflexes which follow arousal. Nausea, vomiting, diarrhea, a desire to defecate, and urinary retention or stimulation of the urinary bladder with spontaneous voiding may also occur.

In vitro studies have shown that doxapram hydrochloride injection produces hemolysis of erythrocytes. Thrombophlebitis, hemolysis, and local reactions can be minimized by administering dilute solutions of the drug at a slow rate and by avoiding extravasation or repeated use of a single injection site.

Changes in laboratory test results including decreases in hemoglobin, hematocrit, and erythrocyte count; a further decrease in leukocyte count in a patient with leukopenia; and increases in BUN and albuminuria have been observed following administration of doxapram to patients receiving multiple drugs concomitantly (e.g., general anesthetics, CNS depressants). The importance of these findings is not yet known, but the possibility that they may be related to doxapram should be considered.

By reducing arterial carbon dioxide tension, doxapram may produce cerebral vasoconstriction and decreased cerebral circulation which may lead to respiratory alkalosis and possibly apnea. These adverse effects should be considered, especially in patients with barbiturate intoxication.

Precautions and Contraindications

Doxapram should be used with caution in patients with a history of bronchial asthma, severe tachycardia, or cardiac arrhythmias and in those with acute respiratory failure secondary to chronic obstructive pulmonary disease, since hypoxia may predispose a patient to arrhythmia.127 Doxapram also should be used with caution in patients with substantial hepatic or renal impairment, since alterations in drug metabolism and excretion may affect response to the drug.127 The drug should be used with caution, if at all, in patients with cerebral edema or increased CSF pressure, hyperthyroidism, pheochromocytoma, or profound metabolic disorders. Doxapram is contraindicated in patients with epilepsy or other seizure disorders or evidence of a head injury; cardiovascular disorders including coronary artery disease, frank uncompensated heart failure, severe hypertension including that associated with hyperthyroidism or pheochromocytoma, or cerebrovascular accidents; and respiratory failure or incompetence secondary to neuromuscular disorders, muscle paresis, flail chest, airway obstruction, suspected or confirmed pulmonary embolism, pneumothorax, or restrictive respiratory diseases such as pulmonary fibrosis.127 The drug is also contraindicated in patients with acute bronchial asthma or extreme dyspnea or whenever hypoxia is not associated with hypercapnia. Doxapram should not be used in patients with a history of hypersensitivity to the drug or in conjunction with mechanical ventilation.

Pediatric Precautions

Safe use of doxapram hydrochloride in children younger than 12 years of age has not been established.

Each mL of doxapram hydochloride injection contains 9 mg of benzyl alcohol as a preservative.109 Although a causal relationship has not been established, administration of injections preserved with benzyl alcohol has been associated with toxicity in neonates.109,110,111,112,113,114,115,116,117,122 Toxicity appears to have resulted from administration of large amounts (i.e., 100-400 mg/kg daily) of benzyl alcohol in these neonates.111,112,113,114,115,116,117,122 Because doxapram hydrochloride dosages (0.5-2.5 mg/kg per hour) that have been suggested for the treatment of neonatal apnea† would result in benzyl alcohol dosages ranging from 5.4-27 mg/kg daily (using the preparation commercially available in the US),117,119,121 it is recommended that this preparation not be used for the treatment of this condition.110,117,118,120 A preservative-free preparation currently is not commercially available in the US.109,118,127,136

Pregnancy

Pregnancy

The safety of doxapram in pregnant women has not been established. The manufacturer recommends that the drug be used during pregnancy only when clearly needed.

Doxapram should be used with caution in patients who are receiving sympathomimetic drugs or monoamine oxidase inhibitors, because a synergistic pressor effect may occur. Doxapram also should be used with caution in those who have received muscle relaxants because doxapram may temporarily mask their residual effects. Because animal studies show that doxapram causes an increase in epinephrine release and because self-limiting arrhythmias have been noted in patients receiving doxapram and general anesthetics known to sensitize the myocardium to catecholamines, the manufacturer recommends that administration of doxapram be delayed until the anesthetic has been excreted.127 Concomitant use of doxapram and theophyllines (e.g., theophylline, aminophylline) may increase skeletal muscle activity, agitation, and hyperactivity.127

Pharmacology

Doxapram hydrochloride stimulates all levels of the CNS, augmenting descending CNS impulses in a dose-related manner.127,128 The drug's stimulant effects appear to be stronger than those of nikethamide. Doxapram transiently increases the volume and, to a lesser extent, the rate of respiration by directly stimulating medullary respiratory centers. The drug may also stimulate respiration through reflex activation of carotid and aortic or other peripheral chemoreceptors.127,128 Despite increased respiratory rate and volume, arterial oxygenation is rarely improved because doxapram usually increases the work of breathing with subsequent increases in oxygen consumption and carbon dioxide production.

In doses greater than those required to stimulate respiration, the CNS stimulation produced by doxapram may result in tonic-clonic seizures. Limited studies indicate that the margin between doses that produce respiratory stimulation and those that produce seizures is greater with doxapram than with other analeptics including nikethamide and pentylenetetrazol.

Doxapram has no direct effect on peripheral blood vessels, but increases in blood pressure, pulse rate, heart rate, cardiac output, and pulmonary arterial pressure may occur due to a pressor response elicited by improved cardiac output and increased release of catecholamines.127,128 Doxapram antagonizes the respiratory depressant effects of opiates without interfering with their analgesic properties.127

Pharmacokinetics

Absorption

Doxapram has a rapid onset and short duration of action following IV administration.127,128 Following a single IV injection of doxapram, respiratory stimulation usually is evident within 20-40 seconds, is maximal at 1-2 minutes, and persists for about 5-12 minutes.127 In one study of postoperative patients receiving morphine sulfate and doxapram, increases in the minute volume of respiration occurred within 2 minutes and persisted for 5 minutes following a single IV dose of 14-56 mg of doxapram hydrochloride. IV infusion of doxapram results in more moderate but sustained respiratory stimulation than do direct IV injections.

Distribution

Doxapram and its metabolites are generally well distributed into tissues in animals.

Elimination

Doxapram is rapidly metabolized by hydroxylation to ketodoxapram, which is pharmacologically active.128,136 Most of the drug is excreted in urine and feces as metabolites within 24-48 hours following administration; small amounts of the metabolites continue to be excreted for up to 120 hours. Following IV injection of a single dose of doxapram hydrochloride, approximately 40-50% of the administered dose is excreted in urine as metabolites.128 The elimination half-life of doxapram in premature neonates receiving IV infusions of the drug has averaged 6.6-9.9 hours.124,125,126

Chemistry and Stability

Chemistry

Doxapram hydrochloride is a monohydrated pyrrolidinone-derivative CNS stimulant. The drug occurs as a white to off-white, odorless, crystalline powder and is soluble in water and sparingly soluble in alcohol. Commercially available doxapram hydrochloride injections contain benzyl alcohol as a preservative.127,136 The injections are sterile, nonpyrogenic solutions of the drug with a pH of 3.5-5.127,136

Stability

Doxapram hydrochloride injection should be stored at a controlled room temperature of 20-25°C.127,136

Doxapram hydrochloride appears to be physically compatible with most IV infusion fluids, but the manufacturer recommends dilution with 5% dextrose, 10% dextrose, or 0.9% sodium chloride injection.127,137 The drug is physically incompatible with sodium bicarbonate or other strongly alkaline drugs such as furosemide, aminophylline, or thiopental sodium, because of possible gas or precipitate formation.127,137 Doxapram hydrochloride exhibits a loss of potency when admixed with ticarcillin disodium (no longer commercially available in the US) and is incompatible with other drugs including ascorbic acid, cefoperazone sodium (no longer commercially available in the US), cefotaxime sodium, cefotetan sodium, cefuroxime sodium, folic acid, dexamethasone disodium phosphate, diazepam, hydrocortisone sodium phosphate, methylprednisolone sodium, and hydrocortisone sodium succinate.127 Since the compatibility of these and other admixtures of doxapram hydrochloride depends on several factors (e.g., concentration of the drugs, resulting pH, temperature), specialized references should be consulted for specific information.137

Only references cited for selected revisions after 1984 are available electronically.

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110. Food and Drug Administration. Parenteral drug products containing benzyl alcohol or other preservatives; intent and request for information. Notice of intent. [21 CFR Ch 1, Subchapter C; Docket No. 85N-0043] Fed Regist . 1985; 50:20233-5.

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