002340 Thiopental Sodium

DESCRIPTION

WARNING: MAY BE HABIT FORMING.

Thiopental is a thiobarbiturate, the sulfur analogue of sodium pentobarbital.

The drug is prepared as a sterile powder and after reconstitution with an appropriate diluent is administered by the intravenous route.

Thiopental is chemically designated sodium 5-ethyl-5- (1-methylbutyl)-2-thiobarbiturate.

The drug is a yellowish, hygroscopic powder, stabilized with anhydrous sodium carbonate as a buffer (60 mg/g of thiopental sodium).

Ready-To-Mix Syringes And Vials:

Sterile water for injection is a sterile, nonpyrogenic preparation of water for injection which contains no bacteriostat, antimicrobial agents or added buffers. The pH is 5.7 (5.0 to 7.0). Sterile water for injection is a pharmaceutic aid (solvent) for intravenous administration only after addition of a solute.

Water is chemically designated H2O. 0.9% sodium chloride injection is a sterile, nonpyrogenic, isotonic solution of sodium chloride and water for injection. Each ml contains sodium chloride 9 mg (308 mOsmol/liter calc). It contains no bacteriostat, antimicrobial agents or added buffers except for pH adjustment. May contain hydrochloric acid and/or sodium hydroxide for pH adjustment. pH is 5.7 (4.5 to 7.0). 0.9% sodium chloride injection is an isotonic vehicle for intravenous administration of another solute. Sodium chloride is chemically designated NaCl, a white crystalline compound freely soluble in water. The semi-rigid vial contained in List Nos. 3329, 6418, 6419, 6420 and 6435 is fabricated from a specially formulated polyolefin. It is a copolymer of ethylene and propylene. The safety of the plastic has been confirmed by tests in animals according to biological standards for plastic containers. The container requires no vapor barrier to maintain the proper labeled volume.

CLINICAL PHARMACOLOGY

Thiopental is an ultrashort-acting depressant of the central nervous system which induces hypnosis and anesthesia, but not analgesia. It produces hypnosis within 30 to 40 seconds of intravenous injection. Recovery after a small dose is rapid, with some somnolence and retrograde amnesia. Repeated intravenous doses lead to prolonged anesthesia because fatty tissues act as a reservoir; they accumulate thiopental in concentrations 6 to 12 times greater than the plasma concentration, and then release the drug slowly to cause prolonged anesthesia.

The half-life of the elimination phase after a single intravenous dose is three to eight hours. The distribution and fate of thiopental (as with other barbiturates) is influenced chiefly by its lipid solubility (partition coefficient), protein binding and extent of ionization. Thiopental has a partition coefficient of 580.

Approximately 80% of the drug in the blood is bound to plasma protein. Thiopental is largely degraded in the liver and to a smaller extent in other tissues, especially the kidney and brain. It has a pKa of 7.4. Concentration in spinal fluid is slightly less than in the plasma.

Biotransformation products of thiopental are pharmacologically inactive and mostly excreted in the urine.

Sterile water for injection serves only as a pharmaceutic aid for diluting or dissolving drugs prior to administration.

Water is an essential constituent of all body tissues and accounts for approximately 70% of total body weight. Average normal adult daily requirement ranges from two to three liters (1.0 to 1.5 liters each for insensible water loss by perspiration and urine excretion). Water balance is maintained by various regulatory mechanisms. Water distribution depends primarily on the concentration of dissociated electrolytes in the body compartments and sodium (Na+) plays a major role in maintaining a physiologic equilibrium between fluid intake and output.

0.9% sodium chloride injection serves only as an isotonic vehicle for drugs prior to administration.

Sodium chloride in water is an electrolyte solution of sodium (Na+) and chloride (Cl-) ions. These ions are normal constituents of the body fluids (principally extracellular) and are essential for maintaining electrolyte balance.

The distribution and excretion of sodium (Na+) and chloride (Cl-) are largely under the control of the kidney which maintains a balance between intake and output of these ions.

The small volumes of fluid and amounts of sodium chloride provided by 0.9% sodium chloride injection in Ready-to-Mix Syringes are unlikely to produce a significant effect on fluid or electrolyte balance.

INDICATIONS AND USAGE

Thiopental is indicated (1) as the sole anesthetic agent for brief (15 minute) procedures, (2) for induction of anesthesia prior to administration of other anesthetic agents, (3) to supplement regional anesthesia, (4) to provide hypnosis during balanced anesthesia with other agents for analgesia or muscle relaxation, (5) for the control of convulsive states during or following inhalation anesthesia, local anesthesia, or other causes, (6) in neurosurgical patients with increased intracranial pressure, if adequate ventilation is provided, and (7) for narcoanalysis and narcosynthesis in psychiatric disorders.

CONTRAINDICATIONS

Absolute Contraindications:

Absence of suitable veins for intravenous administration

Hypersensitivity (allergy) to barbiturates

Variegate porphyria (South African) or acute intermittent porphyria

Relative Contraindications:

Severe cardiovascular disease

Hypotension or shock

Conditions in which the hypnotic effect may be prolonged or potentiated-excessive premedication, Addison's disease, hepatic or renal dysfunction, myxedema, increased blood urea, severe anemia, asthma, myasthenia gravis

Status asthmaticus.

Diluents in Pentothal Kits, Ready-to-Mix Syringes or Vials should not be used for fluid or sodium chloride replacement.

WARNINGS

KEEP RESUSCITATIVE AND ENDOTRACHEAL INTUBATION EQUIPMENT AND OXYGEN READILY AVAILABLE. MAINTAIN PATENCY of THE AIRWAY AT ALL TIMES.

THIS DRUG SHOULD BE ADMINISTERED ONLY BY PERSONS QUALIFIED IN THE USE of INTRAVENOUS ANESTHETICS.

Avoid extravasation or intra-arterial injection. WARNING: MAY BE HABIT FORMING.

Intravenous administration of sterile water for injection without a solute may result in hemolysis.

Use aseptic technique for preparing thiopental solutions when using Pentothal Kits, Syringes or Vials and during withdrawal from reconstituted single or multiple-use containers.

Administer only clear reconstituted solutions. Use within 24 hours after reconstitution. Discard unused portions.

PRECAUTIONS

General:

Care should be taken in administering the drug to patients with advanced cardiac disease, increased intracranial pressure, ophthalmoplegia plus, asthma, myasthenia gravis and endocrine insufficiency (pituitary, thyroid, adrenal, pancreas).

Nursing Mothers:

Pregnancy Category C:

Do not use unless solution is clear and container is undamaged.

Inspect reconstituted (mixed) solutions of thiopental for clarity and freedom from precipitation or discoloration prior to administration. Use Transfer Label in each Pentothal Kit and affix to container of reconstituted solution to show concentration and time of preparation.

DRUG INTERACTIONS

The following drug interactions have been reported with thiopental:

ADVERSE REACTIONS

Adverse reactions include respiratory depression, myocardial depression, cardiac arrhythmias, prolonged somnolence and recovery, sneezing, coughing, bronchospasm, laryngospasm and shivering.

Anaphylactic and anaphylactoid reactions to thiopental have been reported. Symptoms, (e.g., urticaria, bronchospasm, vasodilation and edema) should be managed by conventional means.

Rarely, immune hemolytic anemia with renal failure and radial nerve palsy have been reported.

Reactions which may occur because of the diluents, technique of preparation or mixing, or administration of reconstituted solutions of thiopental include febrile response or infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection and extravasation.

If an adverse reaction does occur, discontinue the injection, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of unused solution (or the used container or syringe) for examination if deemed necessary.

DRUG ABUSE AND DEPENDENCE

WARNING: MAY BE HABIT FORMING.

Thiopental sodium is classified as a Schedule III controlled substance.

OVERDOSAGE

Overdosage may occur from too rapid or repeated injections. Too rapid injection may be followed by an alarming fall in blood pressure even to shock levels. Apnea, occasional laryngospasm, coughing and other respiratory difficulties with excessive or too rapid injections may occur. in the event of suspected or apparent overdosage, the drug should be discontinued, a patent airway established (intubate if necessary) or maintained, and oxygen should be administered, with assisted ventilation if necessary. The lethal dose of barbiturates varies and cannot be stated with certainty. Lethal blood levels may be as low as 1 mg/100 mL for short-acting barbiturates; less if other depressant drugs or alcohol are also present.

Management of Overdosage:

Used as diluents for preparing solutions of thiopental the small volumes of administered fluid (from sterile water for injection in bottles and vials) and amounts of sodium chloride (from 0.9% sodium chloride injection in Ready-to-Mix Syringes) are unlikely to pose a threat of fluid or sodium chloride overload.

DOSAGE AND ADMINISTRATION

Thiopental is administered by the intravenous route only. Individual response to the drug is so varied that there can be no fixed dosage. The drug should be titrated against patient requirements as governed by age, sex and body weight. Younger patients require relatively larger doses than middle-aged and elderly persons; the latter metabolize the drug more slowly. Pre-puberty requirements are the same for both sexes, but adult females require less than adult males. Dose is usually proportional to body weight and obese patients require a larger dose than relatively lean persons of the same weight.

Premedication:

Ideally, the peak effect of these medications should be reached shortly before the time of induction.

Test Dose:

Use in Anesthesia:

Muscles usually relax about 30 seconds after unconsciousness is attained, but this may be masked if a skeletal muscle relaxant is used. The tone of jaw muscles is a fairly reliable index.

The pupils may dilate but later contract; sensitivity to light is not usually lost until a level of anesthesia deep enough to permit surgery is attained. Nystagmus and divergent strabismus are characteristic during early stages, but at the level of surgical anesthesia, the eyes are central and fixed. Corneal and conjunctival reflexes disappear during surgical anesthesia.

When thiopental is used for induction in balanced anesthesia with a skeletal muscle relaxant and an inhalation agent, the total dose of thiopental can be estimated and then injected in two to four fractional doses. With this technique, brief periods of apnea may occur which may require assisted or controlled pulmonary ventilation. As an initial dose, 210 to 280 mg (3 to 4 mg/kg) of thiopental is usually required for rapid induction in the average adult (70 kg). When thiopental is used as the sole anesthetic agent, the desired level of anesthesia can be maintained by injection of small repeated doses as needed or by using a continuous intravenous drip in a 0.2% or 0.4% concentration. (Sterile water should not be used as the diluent in these concentrations, since hemolysis will occur.) With continuous drip, the depth of anesthesia is controlled by adjusting the rate of infusion.

Use in Convulsive States:

Use in Neurosurgical Patients with Increased Intracranial Pressure:

Use in Psychiatric Disorders:

Management of Some Complications:

Laryngospasm may occur with light thiopental narcosis at intubation, or in the absence of intubation if foreign matter or secretions in the respiratory tract create irritation. Laryngeal and bronchial vagal reflexes can be suppressed, and secretions minimized by giving atropine or scopolamine premedication and a barbiturate or opiate. Use of a skeletal muscle relaxant or positive pressure oxygen will usually relieve laryngospasm. Tracheostomy may be indicated in difficult cases.

Myocardial Depression, proportional to the amount of drug in direct contact with the heart, can occur and may cause hypotension, particularly in patients with an unhealthy myocardium.

Arrhythmias may appear if PCO2 is elevated, but they are uncommon with adequate ventilation.

Management of myocardial depression is the same as for overdosage. Thiopental does not sensitize the heart to epinephrine or other sympathomimetic amines.

Extravascular Infiltration should be avoided. Care should be taken to insure that the needle is within the lumen of the vein before injection of thiopental. Extravascular injection may cause chemical irritation of the tissues varying from slight tenderness to venospasm, extensive necrosis and sloughing. This is due primarily to the high alkaline pH (10 to 11) of clinical concentrations of the drug. If extravasation occurs, the local irritant effects can be reduced by injection of 1% procaine locally to relieve pain and enhance vasodilatation. Local application of heat also may help to increase local circulation and removal of the infiltrate.

Intra-arterial injection can occur inadvertently, especially if an aberrant superficial artery is present at the medial aspect of the antecubital fossa. The area selected for intravenous injection of the drug should be palpated for detection of an underlying pulsating vessel. Accidental intra-arterial injection can cause arteriospasm and severe pain along the course of the artery with blanching of the arm and fingers.

Appropriate corrective measures should be instituted promptly to avoid possible development of gangrene. Any patient complaint of pain warrants stopping the injection. Methods suggested for dealing with this complication vary with the severity of symptoms. The following have been suggested:

1.

Dilute the injected thiopental by removing the tourniquet and any restrictive garments.

2.

Leave the needle in place, if possible.

3.

Inject the artery with a dilute solution of papaverine, 40 to 80 mg, or 10 mL of 1% procaine, to inhibit smooth muscle spasm.

4.

If necessary, perform sympathetic block of the brachial plexus and/or stellate ganglion to relieve pain and assist in opening collateral circulation. Papaverine can be injected into the subclavian artery, if desired.

5.

Unless otherwise contraindicated, institute immediate heparinization to prevent thrombus formation.

6.

Consider local infiltration of an alpha-adrenergic blocking agent such as phentolamine into the vasospastic area.

7.

Provide additional symptomatic treatment as required. Shivering after thiopental anesthesia, manifested by twitching face muscles and occasional progression to tremors of the arms, head, shoulder and body, is a thermal reaction due to increased sensitivity to cold. Shivering appears if the room environment is cold and if a large ventilatory heat loss has been sustained with balanced inhalation anesthesia employing nitrous oxide. Treatment consists of warming the patient with blankets, maintaining room temperature near 22°C (72°F), and administration of chlorpromazine or methylphenidate.

Preparation of Solutions:

Warning:

Compatibility:

Solutions of succinylcholine, tubocurarine or other drugs which have an acid pH should not be mixed with thiopental solutions. The most stable solutions are those reconstituted in water or isotonic saline, kept under refrigeration and tightly stoppered. The presence or absence of a visible precipitate offers a practical guide to the physical compatibility of prepared solutions of thiopental.

Reconstituted solutions of thiopental should be inspected visually for particulate matter and discoloration, whenever solution and container permit. Thiopental solutions should be administered only by intravenous injection and by individuals experienced in the conduct of intravenous anesthesia.

The volume and choice of diluent for preparing thiopental solutions for clinical use depends on the concentration and vehicle desired. Thiopental Kits provide only sterile water for injection as the diluent for individual or multi-patient use; Thiopental Ready-to-Mix Syringes provide only 0.9% sodium chloride injection as the diluent for individual patient use; vials provide only sterile water for injection as the diluent for individual patient use.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. (See PRECAUTIONS.)