THAM

General Administration Information
For storage information, see the specific product information within the How Supplied section.
-Tromethamine is administered by slow intravenous infusion, by addition to ACD blood for priming cardiac bypass equipment, and by direct injection into the ventricular cavity during cardiac arrest.

Route-Specific Administration

Injectable Administration
Intravenous Administration
Intermittent IV Infusion
-Administer intravenously over at least 1 hour if emergent correction is not required.
-For more rapid correction, 25-50% of the calculated dose may be given IV over 5-10 minutes, followed by the remainder of the calculated dose given IV over 1 hour. Use caution with accelerated administration; too rapid infusion may result in apnea and significant hypoglycemia.
-Take precautions to avoid extravasation. If infusing via peripheral vein, use a large needle in the largest antecubital vein or place an indwelling catheter in a large vein of an elevated limb to minimize irritation during infusion. Catheters are recommended.
-Individualize dosage based on severity and progression of acidosis; carefully monitor the patient to avoid alkalosis. Limit the dosage to the amount needed to increase blood pH to normal and to correct acid-base imbalances.

Other Injectable Administration
Intraventricular Administration
-During cardiac arrest, tromethamine should be administered at the same time that other standard resuscitative measures are being applied, including manual systole.
-If the chest is open, tromethamine may be administered into the intraventricular cavity.
-Do not inject into the cardiac muscle.

According to the manufacturer, adverse reactions to tromethamine therapy are generally infrequent.

Although data are lacking in humans, increases in coagulation time have been seen in animal studies of tromethamine.

Respiratory depression and apnea may occur with high dose tromethamine or with rapid administration due to increased blood pH and decreased CO2 concentration; slow administration and careful monitoring of acid/base status to avoid overcorrection is recommended. In an observational study including 100 infants who received tromethamine, 17% experienced respiratory depression during or within 2 minutes of injection. Neonates who had a history of spontaneous apnea had a greater sensitivity to the respiratory depressant effect of tromethamine. Of note, the solution was infused into the umbilical arterial catheter quickly (over 2-3 minutes) and neonates received either 10 ml of 0.3 M or 0.58 M tromethamine. The incidence of respiratory depression after the recommended method of administration (i.e. slow infusion) is not known. Respiratory depression is more likely to occur in patients who have chronic hypoventilation or in those who have been treated with drugs that depress ventilation. The dosage should be adjusted to ensure blood pH does not rise above normal. In patients with concomitant respiratory acidosis and metabolic acidosis, tromethamine should be administered with mechanical ventilation.

Transient, but sometimes prolonged, hypoglycemia may occur with tromethamine therapy. To reduce the risk of hypoglycemia, avoid rapid administration and use the lowest dose needed for the shortest duration of time to correct the existing acidosis. Simultaneous administration of a solution containing at least 5% glucose may decrease the incidence of hypoglycemia. Frequent blood glucose concentrations should be monitored during and after tromethamine administration.

Extreme care should be used when administering tromethamine injection to avoid extravasation, which may result in inflammation, local tissue damage, sloughing and necrosis. The risk of intravenous thrombosis and venospasm may be reduced by ensuring that the injection needle is placed well inside the largest available vein and that the solution is administered slowly. Other reactions that may occur due to technique of administration or because of the high osmolar load of the solution include chemical phlebitis extending from the site of injection extravasation, fever, and infection at the site of injection. If an adverse reaction develops during tromethamine therapy, discontinue the infusion, evaluate the patient and initiate appropriate medical therapy.

Hepatic necrosis and bladder necrosis has been reported with the infusion of earlier formulations of tromethamine via low-lying umbilical venous catheters. These effects are most likely associated with tromethamine's alkalinity and hyperosmolality. The 0.3 M solution with a pH adjusted to 8.6 has not been associated with these complications ; however, the possibility of these adverse events cannot be ruled out.

The use of tromethamine injection can cause fluid and/or solute overload resulting in dilution of serum electrolyte concentrations, overhydration, congestion, and pulmonary edema. Hyperkalemia has been reported after tromethamine use in patients with renal dysfunction. Serum electrolyte concentrations should be measured before, during, and after tromethamine therapy in all patients. In addition, the manufacturer recommends using tromethamine with caution in patients with renal impairment and only with electrocardiographic monitoring and frequent serum potassium determinations.

The safety and efficacy of tromethamine in pediatric patients is based on over 30 years of clinical experience that has been documented in the literature and through safety surveillance. Robust clinical trial data are not available in pediatric patients.

Tromethamine is contraindicated for use in patients with uremia and/or anuria (anuric renal failure). Tromethamine is excreted by the kidneys and should be used cautiously in patients with renal disease, renal impairment, and in patients with reduced urinary output due to the potential for hyperkalemia and the possibility of decreased excretion and retention of tromethamine. If tromethamine is used in patients with renal insufficiency, ECG monitoring and frequent serum potassium measurements are recommended.

Tromethamine is contraindicated in newborns with chronic respiratory acidosis. In patients with concomitant respiratory acidosis with metabolic acidosis, tromethamine should be administered with the assistance of mechanical ventilation. Respiratory depression, including apnea, may occur after rapid tromethamine administration and with high doses of tromethamine secondary to increased blood pH and decreased CO2 concentration. Respiratory depression is more likely to occur in patients who have chronic hypoventilation or in those who have been treated with drugs that depress ventilation.

Tromethamine is contraindicated in neonates with chronic respiratory acidosis or salicylate intoxication. Because of the osmotic effects of tromethamine and the large continuous doses that are typically needed, sodium bicarbonate is generally preferred over tromethamine for acidotic neonates and infants with respiratory distress syndrome (RDS); however, tromethamine is beneficial for selected patients. When tromethamine is used in neonates, particularly premature neonates, monitor carefully and take appropriate precautions to avoid low blood glucose.

Take precautions to avoid extravasation of tromethamine; inflammation, necrosis, and tissue sloughing may occur. Administer tromethamine slowly and in the largest available vein to minimize the risk of perivascular infiltration and venospasm.

Tromethamine may cause hypoglycemia. Overdosage and rapid administration may cause prolonged hypoglycemia; infuse slowly and in amounts sufficient only to correct acidosis. Avoid overcorrection. Monitor blood glucose during and after therapy in all patients; frequent monitoring may be necessary for patients at high risk of hypoglycemia (e.g. newborns). Because of the risk for hypoglycemia, some experts recommend the coadministration of a dextrose-containing solution when tromethamine is administered to infants.

Tromethamine can cause fluid and/or solute overload resulting in volume overload and dilution of serum electrolyte concentrations, which may worsen existing electrolyte imbalance, congested states (e.g., congestive heart failure ), or pulmonary edema. Monitor serum electrolyte concentrations before, during, and after tromethamine therapy.

Description: Tromethamine, also known as THAM, is a parenteral, highly alkaline, sodium-free solution used for the short-term treatment of metabolic acidosis. It is used for the prevention and correction of systemic metabolic acidosis associated with cardiac bypass surgery, acidity from acid citrate dextrose, and cardiac arrest. Tromethamine is hypertonic and generally can be used only for a short period of time without risking solute and fluid overload. While sodium bicarbonate is usually preferred for the treatment of metabolic acidosis, tromethamine is sometimes used as an alternative to treat patients with severe cases of metabolic acidosis with concurrent respiratory acidosis because it does not raise PCO2. Tromethamine is also used in neonates and infants with hypernatremia and metabolic acidosis to avoid the additional sodium associated with sodium bicarbonate administration. Tromethamine has also been used off-label as a component of cardioplegia solutions, particularly at times of sodium bicarbonate shortages. Tromethamine is FDA-approved for use in neonates and infants.

General dosing information
-Monitor blood pH, PCO2, serum bicarbonate, serum glucose, serum electrolyte concentrations, and urinary output before, during, and after tromethamine therapy.
-Because of the risk for hypoglycemia, some experts recommend the coadministration of a dextrose-containing solution for neonates receiving tromethamine.
-Clinical experience with tromethamine has been limited to short-term use; therefore, tromethamine should not be administered for more than 24 hours except in life-threatening situations.

For the prevention and correction of metabolic acidosis:
-for the treatment of severe metabolic acidosis:
Intravenous dosage:
Neonates and Infants: For metabolic acidosis associated with respiratory distress syndrome, the initial dosage should be approximately 1 ml/kg IV for each pH unit below 7.4. Administer further dosages based on clinical condition and changes in PaO2, pH, and PCO2. Alternatively, some experts recommend calculating the dose of tromethamine using the following formula: Dose (ml) of 0.3 M tromethamine solution = body weight (kg) x base deficit (mEq/L). A maximum daily dose of 5-7 mmol/kg has been recommended for neonates with normal renal function to prevent accumulation.
Children and Adolescents: Used as an alternative to sodium bicarbonate in select patients. Dose depends on weight and buffer base deficit. When the deficit is known, the manufacturer recommends the following formula:
Dose (ml) of 0.3 M tromethamine solution = body weight (kg) x base deficit (mEq/L) x 1.1
Carefully monitor blood pH, PCO2, PO2, blood glucose, electrolytes, and renal function to determine the need for subsequent doses. Generally limit the dosage to an amount sufficient to return blood pH to the normal range (7.35-7.45) and correct acid-base derangement. Although a maximum dosage for children and adolescents has not been clearly defined, the dosage is generally limited to 15 mmol/kg/24 hours in adults.
-for the treatment of metabolic acidosis associated with cardiopulmonary bypass surgery:
Intravenous dosage:
Children and Adolescents: The dosage should be based on the clinical judgement of the clinician. A dose of 9 ml/kg (324 mg/kg) IV has been used in clinical studies. A single dose of 500 ml is considered adequate for most adults; however, doses up to 1000 ml have been used for cases of severe metabolic acidosis. Individual doses should not exceed 500 mg/kg over a period of not less than 1 hour (e.g., for a 70 kg patient, the dose should not exceed 35 g/hr [1078 ml of a 0.3 M solution]). Careful monitoring of pH and other clinical observations should be used as a guide to determine the need for subsequent doses.
-for the correction of acidity of ACD blood during cardiopulmonary bypass surgery:
Extracorporeal dosage:
Children and Adolescents: Clinical experience indicates that 62 ml (2 g) tromethamine per 500 ml of ACD blood is usually sufficient to correct the acidity of ACD blood used for priming the pump-oxygenator. The pH of stored blood ranges from 6.22 to 6.80 depending upon the duration of storage. The amount of tromethamine solution used to correct this acidity ranges from 0.5 to 2.5 g (15 to 77 ml of a 0.3 M solution) per 500 ml of ACD blood used for priming the pump-oxygenator.

Maximum Dosage Limits:
-Neonates
Dosage is dependent on clinical response and acid-base status. Some experts have recommended a maximum dose of 7 mmol/kg/day IV for the treatment of respiratory distress syndrome in neonates.
-Infants
Dosage is dependent on clinical response and acid-base status. Some experts have recommended a maximum dose of 7 mmol/kg/day IV for the treatment of respiratory distress syndrome in infants.
-Children
Dosage is dependent on clinical response and acid-base status. Maximum dosage for children is not clearly defined; some experts recommend a usual maximum of 15 mmol/kg/24 hours for adult patients.
-Adolescents
Dosage is dependent on clinical response and acid-base status. Maximum dosage for adolescents is not clearly defined; some experts recommend a usual maximum of 15 mmol/kg/24 hours for adult patients.

Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; use caution as elimination of the drug is likely decreased. Do not use in uremic or anuric patients.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Tromethamine prevents or corrects acidosis by binding hydrogen ions (H+). It binds cations of fixed or metabolic acids and also hydrogen ions of carbonic acid, resulting in an increase in bicarbonate anion (HCO3-). A significant portion (30% at pH 7.4) of tromethamine is not ionized and is capable of reaching equilibrium in total body water. This nonionized portion may penetrate cells and neutralize acidic ions in the intracellular fluid. Tromethamine also acts as an osmotic diuretic, increasing urine flow, urinary pH, and excretion of fixed acids, carbon dioxide, and electrolytes.

Pharmacokinetics: Tromethamine is administered intravenously, by injection into the ventricular cavity during cardiac arrest, and by addition to ACD blood or other priming fluids during cardiac bypass surgery. Tromethamine distributes slowly into cells and intracellular uptake is increased at a more alkaline pH, when more tromethamine is unprotonated. The beta-elimination half-life is 5.6 hours. Tromethamine is rapidly eliminated by the kidney. Eight hours after administration, 75% or more of the tromethamine dose appears in the urine. Urinary excretion continues over 3 days. Renal elimination is mostly by glomerular filtration.

Affected cytochrome P450 isoenzymes: none


-Special Populations
Renal Impairment
No specific pharmacokinetic data are available; however, tromethamine is substantially excreted by the kidneys. Renal impairment would be expected to decrease elimination and result in adverse consequences. Do not use tromethamine if uremia or anuria are present.