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THAM ampoules, glistening seductively

This has only come up once in the exam. Question 27 from  the first paper of 2009 asked the candidates to compare and contrast the pharmacology of carbicarb, sodium bicarbonate and THAM. The unusual feature was of course the fact that carbicarb is not available in Australia, and THAM is so rarely used that our local supply consists of imported ampoules with labels exclusively in German.

The answer to Question 27 works best as a table; it is reproduced below to simplify revision. As far as literature references go, the majority are from the 1980s and 90s (back when buffer therapy was still considered a viable option in cardiac arrest, for example). One potentially relevant article is a 1998 paper by Bar-Joseph et al, which compared THAM, Carbicarb and sodium bicarbonate in a canine cardiac arrest model.

Exogenous Buffers used in Intensive Care

 Sodium bicarbonateCarbicarbTHAM
Properties

An 8.4% (1mol/L) solution of NaHCO3 which offers 1000mmol/L of HCO3- and Na+ions.

 

An equimolar (300mmol/L) solution of Na2CO3 and NaHCO3which offers 666mmol/L of HCO3- ions, and 1000mmol/L of Na+ ions

An organic amine buffer, otherwise known as tris-hydroxymethyl-aminomethane, or tromethamine.

 

Administration

Ideally IV, but can be given orally

IV only

IV only

Pharmacokinetics

Eliminated renally, as well as being converted to CO2 and exhaled (in process of buffering reactions). These two substances differ mainly in the amount of bicarbonate anion they add.

Rapidly eliminated by the kidney; 75% is excreted in the urine after 8 hours.

Adverse effects
  • Hypokalemia
  • Fluid overload
  • Hypercapnoea
  • Phlebitis
  • Hypokalemia
  • Fluid overload
  • Phlebitis
  • Fluid overload
  • Hypoglycaemia
  • Hyperkalemia
  • Phlebitis
  • Respiratory depression
  • Osmotic diuresis
Rationale for use

Sodium bicarbonate contributes HCO3which is a natural buffer, thus replenishing the buffer systems of the body in a state of acidosis.

 

The sodium carbonate component is supposed to act as a bicarbonae precursor, regenerating HCO3buffers without increasing the PaCO2.

 

THAM is a "third buffer" to complement the buffering capacity of endogenous HCO3and body protein.

At pH of 7.40, 30% of THAM is not ionized and therefore may penetrate cells and act as an intracellular buffer.

Indications
  • Metabolic acidosis with pH <7.10 and hemodynamic instability
  • Normal anion gap metabolic acidosis (esp. RTA)
  • Alkalinisation of urine to enhance the elimination of acidic drugs

 

  • Metabolic acidosis with hypercapnea
  • Viewed as an alternative to sodium bicarbonate for the treatment of metabolic acidosis

Contraindications

(or, situations in which it is known to be useless)

  • Hypokalemia
  • lactic aciosis
  • DKA
  • Hypokalemia
  • lactic aciosis
  • DKA
  • Uremia
  • Anuric renal failure

 

In neonates it is 
also contraindicated in chronic respiratory acidosis and salicylate intoxication.

Critical appraisal of non-bicarbonate buffers

It is not inconcievable that at some stage, the college may ask candidates to critically evaluate the use of THAM in intensive care. The likelihood of a carbicarb question cropping up is fairly limited, as it is only interesting by virtue of its sodium carbonate contents (Na2CO3). These days, this stuff is only found in antacids and alkaline baths. Pfizer make a oral preparation (Tanasid) and Lafedar have put it in ear drops (Otocerol), but as far as I can tell from looking through Micromedex, the intravenous formulation is no longer available anywhere.

Now, being a fluid with a thousand (contested) uses, sodium bicarbonate already enjoys a reasonable amount of coverage on Deranged Physiology:

Somehow, the sodium bicarbonate pages all ended up somewhere related to either acid-base disorders or in the "core topics", whereas THAM has ended up in this lectrolyte and fluid section, according to some sort of arbitrary whim of the author. Without wasting time by questioning this weirdness any further, let us apply a "critically evaluate" template to THAM. If the reader is for some reason not satisfied with the (already arubaly excessive) level of detail here, they are referred to the excellent and all-encompassing homage by Nahas et al (1998) whose work is the main source for the information offered below.

Rationale for the use of buffer therapies, and specifically of THAM

  • Acidaemia is a harmful physiological state, which has multiple adverse consequences for the critically ill patient.
  • Specific issues associated with acidaemia include poor metabolic enzyme function, decreased cardiac contractility, and decreased smooth muscle tone. Acidaemia impairs the association of receptors and ligands (eg. resulting in a diminished response to catecholamines) and changes the protein binding oI drugs and ions (eg. calcium) which has undesirable physiological and pharmacokinetic effects.
  • The correction of acidaemia is therefore of theoretical benefit, as it restores enzyme function and protein bindings to its optimal level
  • The correction of acidaemia may be carried out with sodium bicarbonate, but this has a series of undesirable effects, which include the generation of excess CO2, the administration of a hyperosmolar solute which expands the circulating volume, a potentially undesirable dose of sodium ions (which might not be helpful if the patient is hypernatremic) and the (unproven) possibility that intracellular acidosis may be produced. Sodium bicarbonate is usually available only as 1 molar solution and it will give rise to thrombophlebitis if given peripherally, requiring a cenral venous catheter.
  • THAM is an alternative buffer which may be used instead of (or alongside with) sodium bicarbonate, and which does not have the limitations o sodium bicarbonate.

Biochemistry of THAM

  • THAM is a biologically inert amino alcohol with the formula (HOCH2)3CNH.
  • It has a pKa of 8.07 at 25 °C, which is how it is normally used (as a buffer for cytology purposes, usually applied to living cell suspensions in the lab and at room teperature).
  • At 37° C, THAM has a pKa  of 7.8, which makes it a more effective buffer than bicarbonate. Bicarbonate has a pKa of 6.1,  and should only be used in an open system which allows carbon dioxide to be eliminated.
  • THAM buffers protons 1:1; i.e. one mole of THAM will accept 1 mole of protons.

Pharmacokinetics of THAM

  • THAM is highly soluble in water, and has low lipid solubility.
  • It rapidly distributes to all extracellular fluid, and also gradually mirates into intracellular fluid (more rapidly into red blood cells and hepatocytes)
  • The protonated form of THAM is rapidly excreted in the kidneys.
  • It undergoes no metabolism. You don't have a mechanism to metabolise it.
  • Its renal clearance is rapid: healthy volunteers cleared 25% of the IV bolus dose within 30 minutes.

Practial guide to the use of THAM (a THAM protocol, if you will)

  • One may make an attempt to calculate the correction dose on the basis of the patient's weight and base deficit, but this may lead to unnecessary wankery. Instead, it is possible to use a series of standard doses, and titrate to effect. In case one wishes to do the calculations anyway, the dose of 0.3mol/L solution is offered here, mainly for my own reference. Locally, the THAM protocol seems to have been Google-translated from German, and is therefore inaccessible.
    • THAM dose in ml of 0.3 molar solution = (lean weight in kg × base deficit in mmol/L)
    • Thus, for a 60kg person with a -10 SBE, dose  = (60 × 10) = 600ml
    • Thus, for 3 mol/L solution, that dose is 60ml or 3 × 20ml ampoules.
  • Alternatively, one can give an empirical dose.
    Of the 3 mol/L solution, one uses two 20ml ampoules (a total of 120 mmol).
  • The 120 mmol dose of THAM is diluted in 500ml of 5% dextrose
  • This infusion may be given over 2 hours, checking BSL every 30 minutes.
  • The maximum daily dose is 15 mmol/kg, which means a normal 70kg adult male may safely receive 1050 mmol every 24 hours. That would be about seventeen ampoules of the 3mol/L solution, or roughly twice the amount of THAM currently kept as ward stock on E3A at Westmead.

Advantages of using THAM

  • The buffering power is unrelated to temperature (it works at all sorts of temperatures)
  • An open system is not required: THAM may be used in a closed system, and it will still exert its buffering effect. When a bottle of bicarbonate is given, ti will generate up to 1000ml of CO2; whereas THAM will not. Rather, in the presence of an elevated CO2, THAM will generate bicarbonate (by acting as a proton acceptor).
  • By generating bicarbonate from dissolved CO2, THAM can be viewd as a means of renally clearing accumulated CO2 in patients who cannot be ventilated in the conventional sense (i.e. patients with very severe respiratory acidosis).
  • Unlike with sodium bicarbonate, serum potassium levels remain constant when THAM is used.
  • In the absence of working kidneys, THAM will stil exert a buffering effect.
  • The administration of THAM seems to rapidly reverse the increase in intracranial pressure which is associated with respiratory acidosis. THAm rapidly decreased intracranial pressure, likely by reducing brain extracellular CO2, and its effect is therefore analgous to hyperventilation.

Disadvantages and adverse effects of using THAM

  • Unlike sodium bicarbonate, it must be given intravenously. It will still aklainise body fluids if given orally, but it is "unpalatable" and produces diarrhoea.
  • The main adverse effect is respiratory depression and hypoglycaemia. The hypoglycaemic effect is actualy due to increased insulin release and increased insulin sensitivity, which is an efect of the non-protinated form of THAM.
  • Vomiting and nausea coompany large bolus doses in conscious patients
  • THAM is cleared renally and requires either working kidneys or a commitment to dialysis; however the patient destined for dialysis already has a solution for their acid-base problems, which begs the question of whether the THAM is really necessary in such a situation.
  • It also has an osmotic diretic effect, with sodium and chloride loss.

Accepted indications for THAM

  • Severe hypercapneic respiratory acidosis with no ventilator solution (eg. the patient with an absurdly high CO2 who does not qualify for ECMO)- examples include status asthmaticus, apnoeic oxygenation for bronchoscopy, and ARDS
  • Diabetic ketoacidosis
  • Salicylate or barbiturate intoxication
  • Increased intracranial pressure associated with cerebral trauma responds to THAM (it is at least as effective as 20% mannitol). However, the effect - apart for lowering CSF CO2 - is likely the same as for mannitol, i.e. osmotic diuresis.
  • THAM is also used in cardioplegic solutions, as it seems
  • THAM used during liver transplantation helps to correct the acidaemia associated with the inevitable lactic acidosis during the anhepatic phase.
  • THAM has been used for chemolysis of renal calculi.

 

 

References

Bar-Joseph, Gad, et al. "Comparison of sodium bicarbonate, Carbicarb, and THAM during cardiopulmonary resuscitation in dogs." Critical care medicine 26.8 (1998): 1397-1408.

Nahas, Gabriel G., et al. "Guidelines for the treatment of acidaemia with THAM." Drugs 55.2 (1998): 191-224.

The HOSPIRA booklet for THAM

Rhee, K. H., et al. "Carbicarb, sodium bicarbonate, and sodium chloride in hypoxic lactic acidosis. Effect on arterial blood gases, lactate concentrations, hemodynamic variables, and myocardial intracellular pH." CHEST Journal 104.3 (1993): 913-918.

Schmidt, G. A. "Treatment of Acidosis: Sodium Bicarbonate and Other Drugs."Anaesthesia, Pain, Intensive Care and Emergency Medicine—APICE. Springer Milan, 2002. 681-693.

Filley, G. F., and N. B. Kindig. "Carbicarb, an alkalinizing ion-generating agent of possible clinical usefulness." Transactions of the American Clinical and Climatological Association 96 (1985): 141.