Diprivan

Uses

Induction and maintenance of general anaesthesia. Sedation during intensive care. Sedation for surgical and diagnostic procedures.

Diprivan is a highly lipid soluble, short-acting intravenous general anaesthetic. Onset of general anaesthesia occurs in most patients within 30-60 seconds. Most patients return to consciousness rapidly and recover without confusion or nausea. They are usually completely orientated within only a few minutes from recovery, and fit for discharge after only a few hours. Contrary to many other anaesthetic agents, propofol is not clinically significantly accumulated during maintenance dosage. It is therefore most suitable for sedation during intensive care.

Its distribution can best be described by a three compartment open model: rapid distribution from blood to tissues (half-life 2-3 minutes), rapid metabolic elimination from blood (half-life 30-60 minutes), and a slower final phase, during which propofol is eliminated from poorly perfused tissue. The rapid onset of action is based on the fact that propofol, as a lipid-soluble substance, easily passes the blood-brain barrier and is distributed to the central nervous system. The dosage, blood concentrations and duration of anaesthesia are directly interrelated on recommended dosages. Diprivan is metabolized in the liver to inactive glucuronide and sulphate conjugates, which are excreted in urine.

Diprivan is also used to associated treatment for these conditions: Induction of anesthesia therapy, Maintenance of anesthesia therapy, Monitored anesthesia care sedation, Sedative therapy

How Diprivan works

The action of propofol involves a positive modulation of the inhibitory function of the neurotransmitter gama-aminobutyric acid (GABA) through GABA-A receptors.

Dosage

Diprivan dosage

Adults:

Induction of general anaesthesia: The dosage of Diprivan should be titrated individually against the response of the patient. The ordinary initial dosage in adults is 40 mg (4 ml) by slow intravenous bolus injection at intervals of 10 seconds until the clinical signs show the onset of anaesthesia. The ordinary induction dose in healthy patient below 55 years of age is 2.2-2.5 mg/kg. A dose of 1.0-1.5 mg/kg is often sufficient for older patient. Lower doses, most often 20 mg (2 ml) at intervals of 10 seconds, are recommended for patient of ASA grades 3 and 4.

Maintenance of general anaesthesia: Anaesthesia can be maintained by administering Diprivan either by continuous infusion or by repeat bolus injections to maintain sufficient anaesthesia.

Continuous infusion: The required rate of infusion varies considerably between patients. At the onset of anaesthesia (during roughly the first 10-20 minutes), some patient may require a slightly higher infusion rate (8-10 mg/kg/h). However, sufficient anaesthesia is normally achieved by infusing 4-6 (up to 12) mg/kg/h of Diprivan. Repeat bolus injections: 25-50 mg (2.5-5.0 ml) bolus injections, depending on response.

Sedation during intensive care: A bolus injection of 1.0-2.0 mg/kg should be given first, followed by continuous infusion adjusted according to required degree of sedation. An infusion rate of 0.3-4 mg/kg/h is usually sufficient.

Sedation for surgical and diagnostic procedures: Dosages shall be adjusted individually. Sufficient sedation for surgical and diagnostic procedures can usually be achieved by administering initially 0.5-1 mg/kg during 1-5 minutes, and maintained by continuous at a rate of 1-4.5 mg/kg/h. Bolus dose of 10-20 mg can be given in addition, should deeper sedation be suddenly required. Lower doses of Diprivan are often sufficient for patient of ASA grades 3 and 4, and for older patient.

Children:

Diprivan is not recommended for use in children less then 3 years of age as its safety has not been demonstrated.

Induction of general anaesthesia: Dosage of Diprivan in children shell be adjusted for weight and age. The mean induction dosage in children over 8 years is 2.5 mg/kg, given by slow intravenous injection until the clinical signs show the onset of anaesthesia. Younger children may need slightly higher doses of propofol per kilogram of weight. Lower dosages are recommended for children of ASA grades 3 and 4.

Maintenance of general anaesthesia: Anaesthesia can be maintained by administering Diprivan either by continuous infusion or by repeat bolus injections. Dosage shall be adjusted individually, but an infusion rate of 9-15 mg/kg/h is usually sufficient to achieve satisfactory anaesthesia.

Sedation during intensive care, surgical diagnostic procedures: Diprivan is not recommended for sedation in children as its efficacy and safety have not been demonstrated. Although no casual relationship has been established, serious adverse events (including fatalities) have been reported in cases, where propofol has been used against recommendations. Adverse events have most commonly been seen in children with respiratory tract infections given doses in excess of those recommended for adults.

Diprivan should not be mixed prior to intravenous injection with solutions or infusion fluids other than 5% dextrose or lidocaine 10 mg/ml injection.

Method of administration: In order to reduce pain on injection, the induction dose of propofol may be mixed immediately before injection in the palstic syringe with lidocaine 10 mg/ml injection, in a ratio of 1 part of lidocaine injection for 20 parts of Diprivan.

Diprivan can be administered either undiluted or diluted for infusion. Before injection or dilution, each ampoule or vial shall be ispected for any irregularity. Should any changes be observed, the product shall not be used. Suitable equipment shall be used to ensure correct rate of infusion. Volumetric infusion pumps and syringe pumps, for example, are suitable for this purpose. The ordinary infusion set used alone is not sufficient to prevent accidential overdosage reliably enough.

Compatibility: Diprivan may be diluted only with 5% dextrose infusion. Dilution shall not exceed 1 in 5 (containing 2 mg/ml Diprivan) and shall be prepared in a PVC infusion bag or glass infusion bottle. If a PVC infusion bag is used, the bag should be full and the dilution be prepared by withdrawing a volume of infusion fluid and replacing it with an equal volume of Diprivan. Special attention shall be paid to preparing the dilution aseptically, immediately before administration. Any diluted solution shall be used within 6 hours of preparation. Any remaining solution shall be discarded.

Side Effects

Local: Diprivan is normally well tolerated. Its most common undesirable effect is pain at the site of injection that can be reduced by mixing the preparation with lidocaine or by injecting it into one of the larger veins of the forearm or the intercubital fossa. Thrombosis and phlebitis are rare.

General: Hypotension and transient apnea may occur at the induction of anaesthesia, and may be severe especially in patients who are in a poor general condition. Epileptic movement, convulsions and dystonic reactions have been seen in rare cases. Pulmonary oedema has also been reported. Headache, nausea and, more rarely, vomiting may occur in some patients during recovery. Recovery may also be associated with another short period of impaired consciousness. Hypersensitivity has been reported in some cases, connected with anaphylactic symptoms such as marked hypotension, bronchospasm, oedema and facial erythema. Some cases of cardiac arrest have occurred in connection with the administration of propofol. In connection with long-term administration of propofol, green or reddish brown discolouration of urine may occur. This is caused by the quinol metabolites of propofol, and is not dangerous. As with other anaesthetics, altered sexual behaviour may occur.

Toxicity

Overdosage may increase pharmacologic and adverse effects or cause death.

IV LD₅₀=53 mg/kg (mice), 42 mg/kg (rats). Oral LD₅₀ (as a solution in soybean oil)=1230 mg/kg (mice), 600 mg/kg (rats)

Precaution

Diprivan and any equipment needed in its administration shall be treated strictly aseptically, since Diprivan contains no antimicrobial preservatives and as a lipid emulsion it supports the growth of bacteria and other micro-organisms. When Diprivan is to be aspirated, it must be drawn aseptically into a sterile syringe immediately after opening the ampoule or vial, and administered without delay. Any fluids to be given simultaneously with Diprivan shall be administered as close to the cannula site as possible. Diprivan must not be administered via a microbiological filter.

Diprivan and any equipment needed in its administration are for use in an individual patient, only. According to general recommendations related to the use of lipid emulsions, the infusion period of undiluted Diprivan shall not exceed 12 hours at a time. Any unused Diprivan and the infusion line shall be discarded at the end of infusion or not later then 12 hours from the start of infusion. Infusion may be repeated, if necessary.

Interaction

Diprivan has been used in association with spinal and epidural anaesthesia as well as with various types of premedicants, muscle relaxants, inhalation anaesthetics and analgetics. No pharmacological incompatibility has been observed. Lower doses of Diprivan may be sufficient in case Diprivan is used as an adjunct to local anaesthetic techniques. In doses applied clinically, propofol will not inhibit the synthesis of adrenocortical hormones. Simultaneous administration of opiates may potentiate respiratory depression caused by Diprivan.

Food Interaction

[Moderate] GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents.

Use in combination may result in additive central nervous system depression and
MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol.

Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

Diprivan Cholesterol interaction

[Moderate] Diprivan is formulated in an oil-and-water emulsion and elevated triglycerides can occur during extended therapy.

Diprivan should be administered cautiously in patients with lipid disorders such as primary hyperlipoproteinemia, diabetic hyperlipemia, and pancreatitis.

Each milliliter of propofol contains 0.1g of fat (1.1 kcal).

Diprivan Drug Interaction

Moderate: lorazepam, ciprofloxacin, hydromorphone, acetaminophen / hydrocodone, dexmedetomidine, diazepam, midazolam, alprazolam, ondansetronUnknown: epinephrine, diphenhydramine, diltiazem, glucose, furosemide, norepinephrine, acetaminophen, acetaminophen, cyanocobalamin, ascorbic acid, cholecalciferol

Diprivan Disease Interaction

Major: cardiovascular dysfunctionModerate: hyperlipidemia, renal dysfunction, seizure, zinc deficiency

Volume of Distribution

• 60 L/kg [healthy adults]

Elimination Route

Rapid - time to onset of unconsciousness is 15-30 seconds, due to rapid distribution from plasma to the CNS. Distribution is so rapid that peak plasma concentrations cannot be readily measured. Duration of action is 5-10 minutes.

Half Life

Initial distribution phase t_1/2α=1.8-9.5 minutes. Second redistirubtion phase t_1/2β=21-70 minutes. Terminal elimination phase t_1/2γ=1.5-31 hours.

Clearance

• 23 - 50 mL/kg/min
• 1.6 - 3.4 L/min [70 Kg adults]

Elimination Route

It is chiefly eliminated by hepatic conjugation to inactive metabolites which are excreted by the kidney.

Pregnancy & Breastfeeding use

Due to insufficient experience, propofol shall not be used during pregnancy. Diprivan is rapidly distributed to the foetus and shall therefore not be used for obstetric anaesthesia. Safety to the neonate has not been established in cases, where propofol has been administered to lactating women.

Contraindication

Allergy to propofol or any other ingredient in the preparation. Diprivan should only be given by specialists in anaesthesiology or under their supervision. The physician performing a surgical or diagnostic procedure should not administer propofol. Facilities for resuscitation in case of any complication should be available at the treatment unit. During the administration of Diprivan, patients shall be monitored continuously to observe possible hypotension, obstruction in the respiratory tract, hypoventilation or insufficient oxygen intake at a sufficiently early stage. Special attention shall be paid to patients sedated by Diprivan for a surgical or diagnostic procedure, who are not artificially ventilated. Caution shall be taken in administering Diprivan to patients with cardiac, respiratory, renal or hepatic insufficiency. Hypovolemic patients and those with poor general condition form another risk group.

Since propofol lacks vagolytic activity, bradycardia, even asystole, may occur. Intravenous administration of an anticholinergic agent before induction and during maintenance of anaesthesia should be considered, especially if propofol is used in conjunction with other agents likely to cause bradycardia and in situations where vagal tone is likely to predominate. Since Diprivan is a lipid emulsion, appropriate care should be applied in patients with severe disorders of fat metabolism such as pathological hyperlipidemia. If Diprivan is administered to a patient for whom excessive fat intake may be risky, blood lipid values shall be monitored and Diprivan dosage decreased if necessary. If the patient is receiving other paranteral lipid emulsions in addition to Diprivan, the amount of lipid in Diprivan (0.1 g/ ml) shall be taken into account, when calculating the total intake of fat. In epileptic patients, propofol may lead to convulsions. The analgetic effect of propofol as such is insufficient. Analgetics shall be used to ensure sufficient analgesia. Full recovery from general anaesthesia shall be confirmed prior to discharge. It shall be noted that the aftermath of general anaesthesia may impair the patient's ability to understand instructions given postoperatively.

Special Warning

Use in children: Diprivan is not recommended for use in children less then 3 years of age as its safety has not been demonstrated.

Acute Overdose

Overdosage may cause cardiorespiratory depression. Respiratory depression should be treated by artificial ventilation with oxygen, and cardiovascular depression by lowering of the patient's head and elevating of his/her legs. Pressor agents and plasma expanders or Ringer-type electrolyte solutions may be used, if necessary.

Storage Condition

Diprivan should be stored at a temperature not exceeding 25º C. It must not be frozen. Any unused solution shall be discarded.

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