Tris-Hydroxymethyl Aminomethane (THAM or tromethamine) is an amino alcohol that acts as a buffer base that unlike NaBicarb doesn't increase Na or release CO2–it actually lowers PaCO2. Sounds great, huh? It is unfortunately expensive and has some other issues we will discuss. In the USA, THAM was off the market in 2016, but is now it is being sold again. I wanted to bring in a pharm expert to bolster the discussion:
Our Guest
Patrick M. Wieruszewski, PharmD. Assistant Professor of Anesthesiology at Mayo Clinic School of Medicine.
Prior EMCrit Acid Base Shows
- EMCrit 44 – Acid Base – Part I
- EMCrit 45 – Acid Base – Part II
- EMCrit 46 – Acid Base – Part III
- EMCrit 50 – Acid Base – Part IV – Choose the Solution Based on the Problem
- EMCrit 96 – Acid Base – Part V – Enough with the Bicarb Already
- EMCrit 97 – Acid-Base – Part VI – Chloride-Free Sodium
- EMCrit 227 – Acid Base Part VII – Bicarb Updates, Quantitative Approach, and Prof. David Story
Mechanisms of Action of THAM
Takes a CO2 molecule and a H2O molecule and creates a bicarb and a pronated THAM complex that is secreted, unmetabolized, in the urine
or directly binds a proton
(equations poached from aliem.com)
From a Stewart Perspective
Adds new factor, BTOT which is a weak base
This has the effect of increased Base Excess
Dosing
In the US, THAM is available as
THAM Acetate (0.3 mol/L i.e. 300 mmol/l) in 500 mL bottles. This is 36 grams of THAM per liter.
Given in dosages ranging from 100 mL to 3700 mL
THAM has acetate in the vial, which will be metabolized to another bicarb
The initial loading dose of THAM acetate 0.3 mol/L in the treatment of acidaemia may be estimated as follows:
THAM (ml of 0.3 mol/L solution) = lean bodyweight (kg) × base deficit (mmol/L) x 1.1.
The maximum daily dose is 15 mmol/kg for an adult (3.5L of a 0.3 mol/L solution in a 70kg patient). [Drugs Paper]
A loading dose of 25 to 50% of the calculated dose is given intravenously over 5 to 10 minutes, and the balance is administered over 1 hour. In order to prevent rapid changes in plasma glucose or potassium levels, the rate of THAM administration should not exceed 2 mmol/kg in 30 minutes or 5 mmol/kg in 1 hour. The 24-hour dosage of THAM should be limited to 15 mmol/kg. [Drugs Paper]
In ApOx studies, it was administered at approx 0.5 mls/kg/min for up to 10 minutes [Ann NY Acad Sci 1961; 92 (2): 794-801 and DRUGS paper] Beyond that time, the rate of THAM infusion may be reduced by half, not to exceed 2 mmol/kg in 30 minutes or 5 mmol/kg in 1 hour.
In one ED, if the base deficit is unknown or the treatment is for hypercapnea, they empirically dose 500 mL and re-check venous or arterial blood gases after each bottle of THAM. The first 250 mL is given as a bolus, then slow down the infusion in an attempt to run the remaining 250 mL over 30 minutes. [Sooriyakumaran et al. from aliem.com]
Elimination
intra-cellular penetration is very slow, so THAM administration likely will create a gradient causing migration of CO2 out of the cells
Excreted in urine. if the patient is acidotic, it takes a Cl with it
Paper on Pharmacokinetics of THAM [7106159]
Effects of THAM
Osmolar Effects
THAM causes elevated plasma and ECF osmolality with an osmal gap and will acts as an osmotic diuretic
Osmolar Diuresis
Just like mannitol–but this may be a feature, not a bug depending on the pt
ICP
THAM is a better buffer in the CNS: THAM slowly crosses the intact blood-brain barrier to enter the CSF,[84,88,89] but rapidly decreases intracranial pressure (ICP),[57,137] most likely by decreasing paCO2. CSF pH rapidly adjusts to changes in arterial paCO2, but is slower to respond to alterations in arterial bicarbonate levels.[138-140] It is likely that THAM penetrates the traumatically injured, inflamed or disrupted bloodbrain barrier faster than when it is intact. [Drugs Paper] THAM lowers ICP [Anaesthetist 1989; 38 (4): 189-92] Initially, THAM 0.5 to 1 mmol/kg is given over 30 minutes. Treatment may be continued with: (a) continuous infusion at a rate not to exceed 0.3 to 0.6 mmol/kg/h; or (b) intermittent short term infusions given when necessary to correct elevated ICP, at a dose equal to the initial administration. Plasma glucose levels must be monitored and 5% dextrose should be available for concurrent administration. The dosage of THAM should not exceed 15 mmol/kg/day.[DRUGS paper]
Intracellular Alkalinizing
Theoretically THAM will have effects to raise intracellular pH while NaBicarb will lower it. So potentially we are looking at the wrong numbers when we look at plasma pH.
Adverse Effects
Hypoglyemia
? osmotic effect???
In healthy volunteers, a fall in blood glucose level, associated with a fall in plasma phosphate level, was significant when doses in excess of THAM 500 mg/kg (4 mmol/kg) were administered over 1 hour.[110,111] In experimental studies, the hypoglycaemic activity of THAM was related to its nonprotonated fraction (R-NH2), which penetrates into intracellular compartments. The hypoglycaemic effect of THAM results from increased insulin release[112-114] and activity. [Drugs Paper]
In a rat study, it is suggested that THAM stimulates the utilization of glucose by skeletal muscle directly, by a mechanism which is different from that of insulin, but insulin has a permissive role. [10.1016/0026-0495(64)90061-7]
Hyperkalemia
This was a rabbit hole! I can't find anything regarding the mechanism
Hypercapnic acidosis increases plasma catecholamine concentration and blood pressure.[133] Correction of hypercapnic acidosis with THAM rapidly restores plasma catecholamines to normal levels is what the [DRUGS paper] posits as an etiology.
Apnea
If given too rapidly in a patient without acidosis, solely from a rapid lowering of PaCO2
In Renal Failure
THAM is primarily eliminated from the plasma by renal filtration of its protonated form.[78] THAM can accumulate in patients with renal insufficiency, and produce an ‘osmolar gap’ with pseudohyponatraemia. Meaning that just like glucose, eventually the sodium will be driven down if THAM+ stays in the blood? [Drugs Paper]
Clinical Uses
Sepsis
A solution of THAM acetate 0.3 mol/L (pH 8.4) was administered, with a loading loading dose of 2 to 4 mmol THAM/kg bodyweight over 20 minutes, followed by a constant infusion of 0.5 to 1 mmol/kg/h for 4 to 10 hours
[DRUGS and Crit Care Med 1985; 13: 818] As a result, increases in arterial pH of 0.05 to 0.15 were observed without increases in paCO2, and there was a brisk diuresis.
Cardiac Arrest
Arterial Blood Gas first?
shooting for a pH of at least 7.2
Hypercarbia in ALI or Asthma
ALI Study [10.1164/ajrccm.161.4.9906031]
Interesting Studies
Operative Study
- Head to head bicarb vs. THAM, with ventilation changed to keep CO2 constant. Equally effective. No adverse effects with either med. THAM increased the bicarb and decreased SIG and increased SIDe.
- THAM to set up CO2 Dialysis [2513278]
- Head to Head in the ICU, but only with mild acidosis and the ability to breathe off CO2 [16013019]
Combo Therapy?
One study, unfortunately on isolated heart model, used a combo of sodium bicarbonate and THAM with excellent buffering [ 10.1164/ajrccm.155.3.9117032 ]
Key References
- Nahas et al. Guidelines for the Treatment of Acidaemia with THAM. Drugs 1998;55:191–224 [10.2165/00003495-199855020-00003]
- Nahas et al. The Clinical Pharmacology of THAM [10.1002/cpt196346784]
- Cosby et al. Respiratory Effects of THAM
- Package Insert
- Radosevich, Wieruszewski et al. Tris-Hydroxymethyl Aminomethane in Critically Ill Adults: A Systematic Review [10.1213/ANE.0000000000006485]
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Professor
Nassau University Medical Center
No conflicts of interest (coi).
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Amazing stuff as usual. Just wanted to say that I’m Sweden (and probably other places too), Fresenius is selling a combination of bicarb, THAM, and acetate under the brand name “Tribonat”.
100 ml contains 15 mmol HCO3, 20 mmol acetate, and 30mmol THAM.
It’s used as a buffer for metabolic acidosis, much in the same way as bicarb.
After listening to this episode I think I will start using it more.
Thanks again.
Yes!! Saw this in some of the papers. It seems ideal.
Would you consider this to combat transient hypercapnea you may not want when transitioning to APRV?
now that APRV allows release frequency of down to 1.5 seconds, undesired hypercapnea is not really an issue anymore, but sure
For folks who have access to this, but aren’t compounding it themselves, who/where are you getting it from? I was talking with my OR pharmacist yesterday and was told that they haven’t been able to find it since Pfizer stopped making it.
Pfizer started making it again I believe