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FENTANYL/DROPERIDOL

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Innovar is an intravenous neuroleptanalgesic containing a fixed ratio combination of droperidol (Anapsine(R)), a butyrophenone (a phenothiazine like neuroleptic) and fentanyl (Sublimaze(R)), a narcotic analgesic. Fentanyl is a controlled substance that may be habit-forming.

Specific Substances

    A) DROPERIDOL
    1) Dehydrobenzperidol
    2) R 4749
    3) CAS 548-73-2
    FENTANYL
    1) Phentanyl
    2) R 4263
    3) CAS 437-38-7
    4) CAS 990-73-8 (citrate)

Available Forms Sources

    A) FORMS
    1) It comes in 2 and 5 mL ampules, with each mL containing 0.05 mg fentanyl and 2.5 mg droperidol.
    2) Fentanyl is available in a transdermal system for management of chronic pain (Duragesic(R)). The fentanyl content of each patch varies from 2.5 to 10 milligrams.
    3) STRENGTH CONVERSION: 0.1 mL of fentanyl = 10 mg morphine = 100 mg meperidine. No equivalents have been established for droperidol.
    B) USES
    1) Innovar(R) is a fixed combination drug consisting of a short acting narcotic (fentanyl citrate) and a long acting major tranquilizer (droperidol).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) WITH THERAPEUTIC USE
    1) Fentanyl/droperidol should not be used in patients with Parkinson's disease or patients who have received MAO inhibitors within 14 days.
    2) OBSERVATION CRITERIA - Respiratory depression may last longer than the analgesic effect. Patients should be monitored for respiratory depression, bradycardia, and hypotension for 4 hours after dosing.
    B) WITH POISONING/EXPOSURE
    1) Fentanyl/droperidol overdose clinical effects include respiratory depression, hypotension, and CNS disturbances. Patient must be observed and treated for these effects for 24 hours postingestion.
    2) OBSERVATION CRITERIA - Respiratory depression may last longer than the analgesic effect. Patients should be monitored for respiratory depression, bradycardia, and hypotension for 4 hours after dosing.
    a) Overdoses require monitoring for 24 hours post-dosage for the above plus CNS disturbances. An opioid antagonist, resuscitative and intubation equipment, and oxygen should be readily available.
    3) INHALATION - Volatilization and inhalational abuse of fentanyl patches has been reported. Symptoms would be expected to be the same as an oral overdose, but due to greater absorption, overdoses may be expected sooner and possibly at lower concentrations.
    4) SIGNS/SYMPTOMS OF FENTANYL/DROPERIDOL OVERDOSE may include the following:
    1) RESPIRATORY DEPRESSION
    2) BRADYCARDIA
    3) HYPOTENSION
    4) HYPERTENSION
    5) MIOSIS
    6) MYDRIASIS
    7) DYSTONIC REACTIONS
    0.2.3) VITAL SIGNS
    A) WITH POISONING/EXPOSURE
    1) Overdoses usually result in hypoventilation, hypotension and bradycardia. Monitoring should be maintained for 4 hours after normal dose and 24 hours after overdose.
    0.2.4) HEENT
    A) WITH THERAPEUTIC USE
    1) Miosis or mydriasis may occur.
    0.2.5) CARDIOVASCULAR
    A) WITH THERAPEUTIC USE
    1) Hypertension (rare) and dysrhythmias may occur.
    B) WITH POISONING/EXPOSURE
    1) Bradycardia and hypotension are common.
    0.2.6) RESPIRATORY
    A) WITH THERAPEUTIC USE
    1) Respiratory depression, recurrent apnea, and respiratory arrest may occur.
    0.2.7) NEUROLOGIC
    A) WITH THERAPEUTIC USE
    1) Altered mental status, including coma, may occur. Dystonic reactions have been reported.
    0.2.15) MUSCULOSKELETAL
    A) WITH THERAPEUTIC USE
    1) Truncal rigidity is a common and serious adverse effect occurring during rapid intravenous infusion or high doses.
    0.2.20) REPRODUCTIVE
    A) Fentanyl is in pregnancy category B* (Risk Factor D if used for prolonged periods or in high doses at term.) and Droperidol is in category C.

Laboratory Monitoring

    A) Fentanyl or droperidol levels are not clinically useful.
    B) Monitor arterial blood gases to assess ventilation as needed.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MONITOR ARTERIAL BLOOD GAS or tidal volume to assess adequacy of respirations. Watch carefully for prolonged respiratory depression or biphasic respiratory effects.
    B) NALOXONE - Administer naloxone (Narcan(R)) 0.4 to 2 mg IV in adults and children. Repeat if necessary.
    C) HYPOTENSION: Infuse 10 to 20 mL/kg isotonic fluid. If hypotension persists, administer dopamine (5 to 20 mcg/kg/min) or norepinephrine (ADULT: begin infusion at 0.5 to 1 mcg/min; CHILD: begin infusion at 0.1 mcg/kg/min); titrate to desired response.
    D) AVOID EPINEPHRINE for hypotension as unopposed beta stimulation may worsen hypotension.
    E) DYSTONIC REACTION: ADULT: BENZTROPINE: 1 to 4 mg once or twice daily IV or IM (max, 6 mg/day); 1 to 2 mg of the injection will usually provide quick relief in emergency situations, OR DIPHENHYDRAMINE: ADULT: 10 to 50 mg IV at a rate not exceeding 25 mg/minute or deep IM (max, 100 mg/dose; 400 mg/day). CHILDREN: Diphenhydramine: 5 mg/kg/day or 150 mg/m(2)/day IV divided into 4 doses at a rate not to exceed 25 mg/min, or deep IM (max,, 300 mg/day). Not recommended in premature infants and neonates.
    F) BRADYCARDIA - Ensure adequate oxygenation and administer naloxone as needed.
    1) ATROPINE: ADULT DOSE: BRADYCARDIA: BOLUS: 0.5 mg IV may repeat every 3 to 5 min. Maximum: 3 mg. PEDIATRIC DOSE: 0.02 mg/kg IV/IO (0.04 to 0.06 mg/kg ET). Repeat once, if needed. Minimum dose: 0.1 mg. Maximum single dose: Child: 0.5 mg; Adolescent: 1 mg. Maximum total dose: Child: 1 mg; Adolescent: 2 mg.
    G) ACUTE LUNG INJURY: Maintain ventilation and oxygenation and evaluate with frequent arterial blood gases and/or pulse oximetry monitoring. Early use of PEEP and mechanical ventilation may be needed.

Range Of Toxicity

    A) Insufficient data in the literature to determine range of toxicity.
    B) The induction dose used to produce neuroleptanalgesia is 1 mL/9 to 12 kg IV.

Clinical Effects

Neurologic

    3.7.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Altered mental status, including coma, may occur. Dystonic reactions have been reported.
    3.7.2) CLINICAL EFFECTS
    A) COMA
    1) WITH THERAPEUTIC USE
    a) Altered mental status, including sedation and unconsciousness, may occur (Eckstein et al, 1977; Bassuh & Schoonover, 1977).
    B) SEIZURE
    1) WITH THERAPEUTIC USE
    a) MYOCLONUS may occur (Eckstein et al, 1977; Bassuh & Schoonover, 1977).
    b) Previous reports of grand mal seizure activity (Rao et al, 1982; Safwat & Daniel, 1983; Hoien, 1984) may have misinterpreted nonpurposeful motor activity and truncal rigidity for grand mal seizures.
    c) No EEG documentation was provided in these cases (Murkin et al, 1984).
    d) In one case myoclonus was documented and the EEG showed no cortical seizure activity (Scott & Sarnquist, 1985).
    C) EXTRAPYRAMIDAL DISEASE
    1) WITH THERAPEUTIC USE
    a) SYNDROMES - Parkinsonism and acute dystonic reactions including oculogyric crisis, torticollis, hand tremor, and hyperextension of the hands have all been reported (DuPre & Stieglitz, 1980; Arrowsmith & Gams, 1980; Merridew & Keefe, 1994).
    b) ONSET occurred 30 minutes after intravenous droperidol injection, in doses of 2.5 to 5 milligrams in three patients (Arrowsmith & Gams, 1980).
    D) DYSKINESIA
    1) WITH THERAPEUTIC USE
    a) Acute dyskinetic reactions have been reported after single doses of droperidol, and include limb and trunk spasm and involuntary movements, choreoathetoid movements, and muscular rigor (Taylor, 1969) DeSilva et al, 1973; (Graham et al, 1974).
    E) HYPERACTIVE BEHAVIOR
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - AKATHISIA is reported following chronic use (2 months) of epidural infusions of droperidol added to morphine therapy in a cancer patient. The akathisia disappeared within 72 hours of discontinuation of droperidol (Athanassiadis & Karamanis, 1992).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea, vomiting, and dysphagia have been reported (Prod Info, 1987).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) PRIAPISM
    1) WITH THERAPEUTIC USE
    a) Priapism has been reported following premedication with Innovar(R) (Chin & Sharpe, 1983).

Summary Of Exposure

    A) WITH THERAPEUTIC USE
    1) Fentanyl/droperidol should not be used in patients with Parkinson's disease or patients who have received MAO inhibitors within 14 days.
    2) OBSERVATION CRITERIA - Respiratory depression may last longer than the analgesic effect. Patients should be monitored for respiratory depression, bradycardia, and hypotension for 4 hours after dosing.
    B) WITH POISONING/EXPOSURE
    1) Fentanyl/droperidol overdose clinical effects include respiratory depression, hypotension, and CNS disturbances. Patient must be observed and treated for these effects for 24 hours postingestion.
    2) OBSERVATION CRITERIA - Respiratory depression may last longer than the analgesic effect. Patients should be monitored for respiratory depression, bradycardia, and hypotension for 4 hours after dosing.
    a) Overdoses require monitoring for 24 hours post-dosage for the above plus CNS disturbances. An opioid antagonist, resuscitative and intubation equipment, and oxygen should be readily available.
    3) INHALATION - Volatilization and inhalational abuse of fentanyl patches has been reported. Symptoms would be expected to be the same as an oral overdose, but due to greater absorption, overdoses may be expected sooner and possibly at lower concentrations.
    4) SIGNS/SYMPTOMS OF FENTANYL/DROPERIDOL OVERDOSE may include the following:
    1) RESPIRATORY DEPRESSION
    2) BRADYCARDIA
    3) HYPOTENSION
    4) HYPERTENSION
    5) MIOSIS
    6) MYDRIASIS
    7) DYSTONIC REACTIONS

Vital Signs

    3.3.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Overdoses usually result in hypoventilation, hypotension and bradycardia. Monitoring should be maintained for 4 hours after normal dose and 24 hours after overdose.
    3.3.4) BLOOD PRESSURE
    A) WITH THERAPEUTIC USE
    1) HYPERTENSION may occur rarely, and occurs almost exclusively in patients with pheochromocytoma (Bitter, 1979; (Feingold & Ivanhovic, 1969; Sumikawa & Yoshikuni, 1977).
    B) WITH POISONING/EXPOSURE
    1) HYPOTENSION is commonly reported in overdose (Anon, 1974; Anon, 1981) Russell, 1994).
    3.3.5) PULSE
    A) WITH THERAPEUTIC USE
    1) TACHYCARDIA may occasionally occur (Mark & Greenberg, 1983).
    B) WITH POISONING/EXPOSURE
    1) BRADYCARDIA is commonly reported in overdose (Anon, 1974; Anon, 1981; Marshall & Wollman, 1980) Whitman & Russell, 1971).

Heent

    3.4.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Miosis or mydriasis may occur.
    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) MIOSIS may occur secondary to the narcotic effects, especially with fentanyl.
    2) MYDRIASIS may occur secondary to the anticholinergic effects of droperidol.

Cardiovascular

    3.5.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Hypertension (rare) and dysrhythmias may occur.
    B) WITH POISONING/EXPOSURE
    1) Bradycardia and hypotension are common.
    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) Hypotension is commonly reported in overdose (Anon, 1974; Anon, 1981).
    B) BRADYCARDIA
    1) WITH POISONING/EXPOSURE
    a) Bradycarida may commonly occur in overdose (Anon, 1974; Anon, 1981; Marshall & Wollman, 1980) Whitman & Russell, 1971).
    C) VENTRICULAR ARRHYTHMIA
    1) WITH THERAPEUTIC USE
    a) Dysrhythmias are uncommon, unless the sympathetic nervous system is stimulated secondary to carbon dioxide accumulation in the presence of inadequate ventilation (AMA, 1983).
    D) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Hypertension has been reported occasionally, and almost exclusively in patients with pheochromocytoma (Bitter, 1979; (Feingold & Ivanhovic, 1969) Sumikawa & Yoshikuni, 1977).
    E) TACHYARRHYTHMIA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - Hypertensive crisis and tachycardia were reported in one patient after high-dose fentanyl (96 mcg/kg), morphine, diazepam, and scopolamine during cardiopulmonary bypass grafting (Mark & Greenberg, 1983).
    3.5.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) BRADYCARDIA
    a) ANIMAL STUDIES - Following an injection of fentanyl/droperidol in a dog with a previously normal heart rhythm, bradyarhythmias occurred, with ECG diagnosis of sinus arrest with escape complexes. The origin of the escape complexes were thought to be near th AV junction or His bundle (French, 1991).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) HEMOLYSIS
    1) WITH THERAPEUTIC USE
    a) High doses of fentanyl have been reported to result in increased serum free hemoglobin levels. Hemolysis is thought to be secondary to rapid administration of a large volume of hypotonic solution, and not related to fentanyl itself (Furuya & Okumura, 1986).

Musculoskeletal

    3.15.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Truncal rigidity is a common and serious adverse effect occurring during rapid intravenous infusion or high doses.
    3.15.2) CLINICAL EFFECTS
    A) INCREASED MUSCLE TONE
    1) WITH THERAPEUTIC USE
    a) Truncal rigidity is a common and serious adverse effect of fentanyl, usually occurring during rapid intravenous infusion and high-dose fentanyl anesthesia. Thoracic compliance is markedly decreased, impairing the ability to assist or control ventilation. Central venous pressure (CVP) may be transiently raised (Mets & James, 1992).
    b) TREATMENT - Skeletal muscle relaxants are effective in preventing and treating muscular rigidity (Prod Info, 1987). Naloxone (0.04 milligram) was effective in reversing muscle rigidity in 21 patients (Caspi et al, 1988).

Reproductive

    3.20.1) SUMMARY
    A) Fentanyl is in pregnancy category B* (Risk Factor D if used for prolonged periods or in high doses at term.) and Droperidol is in category C.
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    DRUGPREGNANCY CATEGORY
    FENTANYLB*
    DROPERIDOLC (rated by manufacturer)
    *(Risk Factor D if used for prolonged periods or in high doses at term.)
    Reference: Briggs et al, 1998.
    B) LACK OF EFFECT
    1) One report exists of respiratory depression in an infant whose mother received epidural fentanyl during labor; generally, however, infants exposed in utero to fentanyl during labor do not differ from unexposed infants (Briggs et al, 1998).

Respiratory

    3.6.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Respiratory depression, recurrent apnea, and respiratory arrest may occur.
    3.6.2) CLINICAL EFFECTS
    A) ACUTE RESPIRATORY INSUFFICIENCY
    1) WITH THERAPEUTIC USE
    a) Respiratory depression occurs frequently, and sometimes follows a biphasic pattern with recurrent apnea after apparent recovery (Becker et al, 1976; Adams & Pylus, 1978; Rich, 1982). Other investigators have reported no evidence of a biphasic pattern (Smedstat & Rigg, 1982).
    b) CASE SERIES - Delayed respiratory depression occurred 2 to 6 hours postoperatively in 7.6% of coronary bypass patients receiving high-dose fentanyl anesthesia (100 mcg/kg) (Caspi et al, 1988).
    c) Impaired responsiveness to hypercapnia may be prolonged. Intense muscular rigidity of the chest and abdominal walls may be severe enough to prevent spontaneous or artificial respiration (Comstock et al, 1981; Waller et al, 1981).
    d) Ventilation and ventilatory response to carbon dioxide are depressed significantly for up to 4 hours following administration of Innovar(R) (Smedstad & Rigg, 1982).
    B) LARYNGISMUS
    1) WITH THERAPEUTIC USE
    a) The inability to ventilate patients receiving large doses of fentanyl may be due to truncal rigidity, glottic aperture closure, or a combination of the two. Succinylcholine may provide relief (Arandia & Patil, 1987).
    C) ACUTE LUNG INJURY
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - Non-cardiogenic pulmonary edema developed in a 27-year-old male following administration of 100 mcg fentanyl and 0.5 mg atropine. Tachycardia, hypotension and hypoxemia initially occurred, and worsened, with auscultation revealing rales throughout his pulmonary fields. Chest x-ray showed diffuse pulmonary infiltrates and vascular congestion (Soto et al, 1992).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Fentanyl or droperidol levels are not clinically useful.
    B) Monitor arterial blood gases to assess ventilation as needed.
    4.1.2) SERUM/BLOOD
    A) ACID/BASE
    1) Monitor blood gases in patients with respiratory depression.
    4.1.3) URINE
    A) URINALYSIS
    1) Urine samples may be obtained for routine screening.
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) Monitor blood pressure and ventilatory ability in all patients.

Methods

    A) CHROMATOGRAPHY
    1) Plasma fentanyl levels have been measured with gas liquid chromatography (Kowalski et al, 1987) and radioimmunoassay (Michiels et al, 1977), however assays are not routinely available.
    2) An ion monitoring gas chromatography/mass spectrometry method is described to quantitate fentanyl in various biologic tissues, including blood, kidney and liver (Pare et al, 1987; Matejczyk, 1988; Chaturvedi et al, 1990).
    3) A sensitive method, utilizing gas-liquid chromatography, has been used to detect fentanyl metabolites in urine at concentrations as low as 2 nanograms/milliliter (Hammargren & Henderson, 1988).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients should be observed for the occurrence of respiratory depression for at least 4 hours after Innovar(R) administration (Smedstad & Rigg, 1982).

Monitoring

    A) Fentanyl or droperidol levels are not clinically useful.
    B) Monitor arterial blood gases to assess ventilation as needed.

Oral Exposure

    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) MONITOR RESPIRATORY FUNCTION in all patients. If compromised, monitor blood gases.
    2) Monitor pulse and blood pressure.
    B) NALOXONE
    1) THERAPEUTIC DOSES - Naloxone in doses of 0.08 to 0.24 milligram was effective in reversing respiratory depression in patients receiving high-dose fentanyl anesthesia (mean fentanyl dose of 25 micrograms/kilogram) (Bailey et al, 1987).
    2) OVERDOSE - The most frequently recommended initial naloxone dose for opioid overdose in a consensus of experts (Consensus, 1985) was as follows: 0.4 to 2 milligrams intravenous bolus in both children and adults.
    a) This dose may be given intralingually or endotracheally if intravenous access is unobtainable (Maio et al, 1987; Tandberg & Abercrombie, 1982).
    b) The intramuscular or subcutaneous route may be effective if hypoperfusion is not present.
    3) MAXIMUM DOSES - Repeat doses of 0.4 to 2 milligrams may be given to achieve or maintain a clinical effect. If no response is observed after 10 milligrams has been administered, the diagnosis of opioid-induced toxicity should be questioned.
    a) Single doses of up to 24 milligrams have been given to adults without adverse effect (Evans et al, 1973).
    4) NEONATES: Small doses (10 to 30 micrograms/kilogram intravenously) have been successful. There is no evidence that larger doses are required to reverse in-utero acquired narcosis.
    a) The risk of precipitating withdrawal in an addicted neonate should be considered. Naloxone appears to have a longer half-life (3 hours) in neonates (Moreland et al, 1980).
    5) MANUFACTURER RECOMMENDED PEDIATRIC DOSE -
    a) Initial recommended pediatric dose is 0.01 milligram/kilogram followed by 0.1 milligram/kilogram if no clinical improvement.
    C) AIRWAY MANAGEMENT
    1) HYPOVENTILATION/APNEA - Oxygen should be administered and respirations should be assisted or controlled as needed (Prod Info, 1987).
    2) TRUNCAL MUSCULAR RIGIDITY -
    a) Neuromuscular blocking agents and/or naloxone may be indicated to facilitate assisted or controlled ventilation. Naloxone alone was effective in reversing truncal rigidity and respiratory depression in 21 patients (Caspi et al, 1988).
    D) HYPOTENSIVE EPISODE
    1) EPINEPHRINE - May paradoxically decrease blood pressure in Innovar(R)-treated patients, due to the alpha-blocking effects of droperidol (Prod Info, 1987).
    2) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    3) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    4) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    E) DRUG-INDUCED DYSTONIA
    1) ADULT
    a) BENZTROPINE: 1 to 4 mg once or twice daily intravenously or intramuscularly; maximum dose: 6 mg/day; 1 to 2 mg of the injection will usually provide quick relief in emergency situations (Prod Info benztropine mesylate IV, IM injection, 2009).
    b) DIPHENHYDRAMINE: 10 to 50 mg intravenously at a rate not exceeding 25 mg/minute or deep intramuscularly; maximum dose: 100 mg/dose; 400 mg/day (Prod Info diphenhydramine hcl injection, 2006).
    2) CHILDREN
    a) DIPHENHYDRAMINE: 5 mg/kg/day or 150 mg/m(2)/day intravenously divided into 4 doses at a rate not to exceed 25 mg/min, or deep intramuscularly; maximum dose: 300 mg/day. Not recommended in premature infants and neonates (Prod Info diphenhydramine hcl injection, 2006).
    F) BRADYCARDIA
    1) Evaluate for hypoxia and ensure adequate oxygenation; administer naloxone as needed.
    2) ATROPINE/DOSE
    a) ADULT BRADYCARDIA: BOLUS: Give 0.5 milligram IV, repeat every 3 to 5 minutes, if bradycardia persists. Maximum: 3 milligrams (0.04 milligram/kilogram) intravenously is a fully vagolytic dose in most adults. Doses less than 0.5 milligram may cause paradoxical bradycardia in adults (Neumar et al, 2010).
    b) PEDIATRIC DOSE: As premedication for emergency intubation in specific situations (eg, giving succinylchoine to facilitate intubation), give 0.02 milligram/kilogram intravenously or intraosseously (0.04 to 0.06 mg/kg via endotracheal tube followed by several positive pressure breaths) repeat once, if needed (de Caen et al, 2015; Kleinman et al, 2010). MAXIMUM SINGLE DOSE: Children: 0.5 milligram; adolescent: 1 mg.
    1) There is no minimum dose (de Caen et al, 2015).
    2) MAXIMUM TOTAL DOSE: Children: 1 milligram; adolescents: 2 milligrams (Kleinman et al, 2010).
    G) DIAZEPAM
    1) Diazepam may be additive to the CNS depressant effect of fentanyl, and as such should be used with caution in a seizing patient.
    H) ACUTE LUNG INJURY
    1) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases.
    2) NON-PHARMACOLOGIC TREATMENT: The treatment of acute lung injury is primarily supportive (Cataletto, 2012). Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FIO2 is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 mL/kg) is preferred if ARDS develops (Haas, 2011; Stolbach & Hoffman, 2011).
    a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)
    3) FLUIDS: Crystalloid solutions must be administered judiciously. Pulmonary artery monitoring may help. In general the pulmonary artery wedge pressure should be kept relatively low while still maintaining adequate cardiac output, blood pressure and urine output (Stolbach & Hoffman, 2011).
    4) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998).
    5) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
    6) CALFACTANT: In a multicenter, randomized, blinded trial, endotracheal instillation of 2 doses of 80 mL/m(2) calfactant (35 mg/mL of phospholipid suspension in saline) in infants, children, and adolescents with acute lung injury resulted in acute improvement in oxygenation and lower mortality; however, no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was noted. Adverse effects (transient hypoxia and hypotension) were more frequent in calfactant patients, but these effects were mild and did not require withdrawal from the study (Wilson et al, 2005).
    7) However, in a multicenter, randomized, controlled, and masked trial, endotracheal instillation of up to 3 doses of calfactant (30 mg) in adults only with acute lung injury/ARDS due to direct lung injury was not associated with improved oxygenation and longer term benefits compared to the placebo group. It was also associated with significant increases in hypoxia and hypotension (Willson et al, 2015).

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DERMAL DECONTAMINATION
    1) TRANSDERMAL - Remove patch from skin. If gel from the patch's drug reservoir accidentally contacts skin, wash with copious amounts of water (do not use soap, alcohol, or other solvents) (Prod Info Duragesic(R), fentanyl citrate, 1991).
    6.9.2) TREATMENT
    A) SKIN ABSORPTION
    1) Remove the patch and physically and verbally stimulate the patient. If necessary, administer specific antagonist (naloxone).
    B) NALOXONE
    1) Repeated administration of naloxone may be necessary since the duration of hypoventilation following an overdose may exceed the antagonists' action. Reversal of narcotic effect may result in acute onset of pain (Prod Info Duragesic(R), fentanyl citrate, 1991).
    C) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Range Of Toxicity

Summary

    A) Insufficient data in the literature to determine range of toxicity.
    B) The induction dose used to produce neuroleptanalgesia is 1 mL/9 to 12 kg IV.

Therapeutic Dose

    7.2.1) ADULT
    A) PREMEDICATION
    1) RECOMMENDED DOSE: 0.5 to 2.0 mL of fentanyl/droperidol given intramuscularly 45 to 60 minutes prior to surgery with or without atropine (Prod Info Innovar(R) (fentanyl citrate and droperidol), 1995).
    B) INDUCTION OF ANESTHESIA
    1) RECOMMENDED DOSE: Without a general anesthetic in diagnostic procedures: 0.5 to 2 mL fentanyl/droperidol, (0.05 mg fentanyl and 2.5 mg droperidol/mL) 45 to 60 minutes prior to the procedure. To prevent the possibility of accumulation of the longer-acting droperidol component, fentanyl alone should be given in increments of 0.025 to 0.05 mg to maintain analgesia. In prolonged procedures, however, additional 0.5 to 1 mL doses of fentanyl/droperidol can be given intravenously if changes in the patients' condition indicate lightening of tranquilization and analgesia (Prod Info Innovar(R) (fentanyl citrate and droperidol), 1995).
    C) MAINTENANCE OF SURGICAL ANESTHESIA
    1) RECOMMENDED DOSE: Fentanyl/droperidol is not indicated as the sole agent for maintenance of surgical anesthesia (Prod Info Innovar(R) (fentanyl citrate and droperidol), 1995) Fentanyl alone should be administered to maintain analgesia in patients initially given fentanyl/droperidol as an adjunct. However, in prolonged operations, additional doses of fentanyl/droperidol (0.5 to 1 mL) may be given intravenously if changes in the patients condition indicate lightening of tranquilization and analgesia (Prod Info Innovar(R) (fentanyl citrate and droperidol), 1995).
    7.2.2) PEDIATRIC
    A) PREMEDICATION
    1) RECOMMENDED DOSE: Premedicant doses are 0.25 mL fentanyl/droperidol (0.05 mg fentanyl and 2.5 mg droperidol/mL) per 9 kg of body weight given intramuscularly, 45 to 60 minutes prior to surgery, with or without atropine (Prod Info Innovar(R) (fentanyl citrate and droperidol), 1995).
    B) ANESTHESIA
    1) RECOMMENDED DOSE: The manufacturer's recommendations are unclear, indicating that the total combined dose for induction and maintenance of anesthesia in children should average 0.5 mL/9 kg of body weight. Following induction of anesthesia with fentanyl/droperidol, fentanyl alone in doses of 1/4 to 1/3 of that recommended for adults should be administered when indicated to avoid the possibility of excess accumulation of droperidol (Prod Info Innovar(R) (fentanyl citrate and droperidol), 1995).

Minimum Lethal Exposure

    A) GENERAL/SUMMARY
    1) No toxic ranges have been established. This is probably due to the fact that Innovar overdosages are often complicated by the use of nitrous oxide and other general anesthetics.
    2) Individual sensitivities to anesthetics and narcotics further account for the wide variations in dosage.

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) SPECIFIC SUBSTANCE
    a) FENTANYL/THERAPEUTIC -
    1) Unconsciousness occurred at mean peripheral venous fentanyl plasma concentrations of 34 nanograms/milliliter during infusions of 300 micrograms/minute (Lunn et al, 1979).
    2) Most patients become responsive at fentanyl plasma levels of 8 to 9 nanograms/milliliter and can be extubated when levels decrease to 2.9 nanograms/milliliter (Mather, 1983).
    b) FENTANYL/TOXIC OVERDOSE -
    1) Significant respiratory depression has been reported at fentanyl plasma levels of 1 to 3 nanograms/milliliter; respiratory effects become insignificant below plasma levels of 0.7 nanogram/milliliter, but there is no predictable relationship between PCO2 and plasma fentanyl concentrations (Mather, 1983).
    2) One report of a fatal overdose listed fentanyl concentrations postmortem of 4 micrograms/liter in blood and 13 micrograms/liter in urine (Matejczyk, 1988).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Pharmacologically, fentanyl is similar to any other narcotic and droperidol is very similar to another butyrophenone, haloperidol.
    1) Used in combination intravenously, neither drug potentiates the other's effects, and the total effect does not exceed the sum effect of each drug alone.
    B) Fentanyl: Is a selective mu agonist with 70 to 100 times the potency of morphine. High doses affect dopaminergic transmission in the striatum, producing muscular rigidity.
    C) Droperidol: Is a neuroleptic that has adrenergic-blocking, antiemetic, antifibrillatory, and anticonvulsant actions, and it enhances the effects of other CNS depressants.

Toxicologic Mechanism

    A) TOXIC EFFECTS - On overdose, the clinical effects are those seen with both opioid and phenothiazines.
    B) RESPIRATORY - The opioid fentanyl causes profound respiratory depression and affects the dopaminergic transmission in muscle striata, producing muscular rigidity.
    1) Succinylcholine or other muscle relaxant may need to be administered to facilitate controlled ventilation.
    C) CARDIOVASCULAR - Droperidol causes mild alpha-adrenergic blockade and peripheral vascular dilatation. Hypovolemic hypotension may result, which is managed with parenteral fluid therapy.
    D) DRUG INTERACTIONS - Avoid using fentanyl/droperidol with MAO inhibitors and diazepam; titrate or lower the dose if given in conjunction with barbiturate anesthetics and other CNS depressants.

Physicochemical

Physical Characteristics

    A) Fentanyl is a crystalline powder with a bitter taste.

Molecular Weight

    A) Fentanyl: 528.6
    B) Droperidol: 379.43

Animal Toxicology

Clinical Effects

    11.1.3) CANINE/DOG
    A) NOT RECOMMENDED FOR USE in AUSTRALIAN TERRIERS. Effects consist of profound analgesia, generalized quiescence, and decreased motor activity.
    1) Used as preanesthetic or induction agent in procedures such as Caesarean sections, and useful alone for diagnostic manipulations (Prod Info, 1988).
    11.1.6) FELINE/CAT
    A) Fentanyl/droperidol is NOT RECOMMENDED FOR USE IN CATS.

Treatment

    11.2.1) SUMMARY
    A) GENERAL TREATMENT
    1) Reverse with naloxone: 1 milliliter (0.4 milligram) per 40 pounds body weight intramuscularly, or intravenously if patient is shocky or respiratory depression is severe.
    a) Extrapyramidal symptoms or seizures may be treated with small doses of intravenous sodium pentobarbital (7 milligrams/kilogram intravenously) (Plumb, 1989) Prod Info, 1988).

Range Of Toxicity

    11.3.1) THERAPEUTIC DOSE
    A) DOG
    1) Preanesthetic: 0.1 to 0.14 milliliter/kilogram intramuscularly; or 0.04 to 0.09 milliliter/kilogram intravenously.
    a) Concurrent use of atropine at 0.045 milligram/kilogram intramuscularly will help control bradycardia and salivation (Plumb, 1989).
    2) Dogs tolerate up to 6 to 8 times the therapeutic dose intramuscularly with few side effects (Prod Info, 1988).
    B) DRUG INTERACTIONS -
    1) Pentobarbital, tranquilizers, narcotic analgesics, and antitussives may cause additive CNS or respiratory depression when given with Innovar.
    11.3.2) MINIMAL TOXIC DOSE
    A) LACK OF INFORMATION
    1) No specific information on a minimal toxic dose was available at the time of this review.

Continuing Care

    11.4.1) SUMMARY
    11.4.1.2) DECONTAMINATION/TREATMENT
    A) GENERAL TREATMENT
    1) Reverse with naloxone: 1 milliliter (0.4 milligram) per 40 pounds body weight intramuscularly, or intravenously if patient is shocky or respiratory depression is severe.
    a) Extrapyramidal symptoms or seizures may be treated with small doses of intravenous sodium pentobarbital (7 milligrams/kilogram intravenously) (Plumb, 1989) Prod Info, 1988).

Sources

    A) GENERAL
    1) Innovar-Vet(R) contains 20 milligrams droperidol and 0.4 milligram fentanyl citrate per milliliter.

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