Infusion Of Tris Hydroxymethyl Aminomethane Research Articles

THAM reduces CO2-associated increase in pulmonary vascular resistance - an experimental study in lung-injured piglets.

IntroductionLow tidal volume (VT) ventilation is recommended in patients with acute respiratory distress syndrome (ARDS). This may increase arterial carbon dioxide tension (PaCO2), decrease pH, and augment pulmonary vascular resistance (PVR). We hypothesized that Tris(hydroxymethyl)aminomethane (THAM), a pure proton acceptor, would dampen these effects, preventing the increase in PVR.MethodsA one-hit injury ARDS model was established by repeated lung lavages in 18 piglets. After ventilation with VT of 6 ml/kg to maintain normocapnia, VT was reduced to 3 ml/kg to induce hypercapnia. Six animals received THAM for 1 h, six for 3 h, and six serving as controls received no THAM. In all, the experiment continued for 6 h. The THAM dosage was calculated to normalize pH and exhibit a lasting effect. Gas exchange, pulmonary, and systemic hemodynamics were tracked. Inflammatory markers were obtained at the end of the experiment.ResultsIn the controls, the decrease in VT from 6 to 3 ml/kg increased PaCO2 from 6.0±0.5 to 13.8±1.5 kPa and lowered pH from 7.40±0.01 to 7.12±0.06, whereas base excess (BE) remained stable at 2.7±2.3 mEq/L to 3.4±3.2 mEq/L. In the THAM groups, PaCO2 decreased and pH increased above 7.4 during the infusions. After discontinuing the infusions, PaCO2 increased above the corresponding level of the controls (15.2±1.7 kPa and 22.6±3.3 kPa for 1-h and 3-h THAM infusions, respectively). Despite a marked increase in BE (13.8±3.5 and 31.2±2.2 for 1-h and 3-h THAM infusions, respectively), pH became similar to the corresponding levels of the controls. PVR was lower in the THAM groups (at 6 h, 329±77 dyn∙s/m5 and 255±43 dyn∙s/m5 in the 1-h and 3-h groups, respectively, compared with 450±141 dyn∙s/m5 in the controls), as were pulmonary arterial pressures.ConclusionsThe pH in the THAM groups was similar to pH in the controls at 6 h, despite a marked increase in BE. This was due to an increase in PaCO2 after stopping the THAM infusion, possibly by intracellular release of CO2. Pulmonary arterial pressure and PVR were lower in the THAM-treated animals, indicating that THAM may be an option to reduce PVR in acute hypercapnia.

Buffer capacity of 4% succinylated gelatin does not provide any advantages over acidic 6% hydroxyethyl starch 130/0.4 for acid-base balance during experimental mixed acidaemia in a porcine model

Four percent gelatine is an alkaline compound due to NH2 groups, whereas 6% hydroxyethyl starch 130/0.4 (HES130) has acidic features. We investigated whether these solutions lead to differences in acid-base balance in pigs during acidaemia and correction of pH. Anaesthetized pigs were randomized to HES130 or gelatine infusion (n = 5 per group). Animals received acid infusion (0.4 M solution of lactic acid and HCl diluted in normal saline) and low tidal volume ventilation (6-7 mL kg(-1), PaCO2 of 80-85 mmHg, pH 7.19-7.24). Measurements were made before and after induction of acidaemia, before and after correction of pH with haemofiltration (continuous venovenous haemofiltration) and tris-hydroxymethylaminomethane infusion. We measured parameters describing acid-base balance according to Stewart's approach, ketone body formation, oxygen delivery, haemodynamics, diuresis and urinary pH. Acid-base balance did not differ significantly between the groups. In HES130-treated pigs, the haemodilution-based drop of haemoglobin (1.4 +/- 1.0 g dL(-1), median +/- SD) was paralleled by an increase in the cardiac output (0.5 +/- 0.4 L min(-1). Lacking increases in cardiac output, gelatine-treated pigs demonstrated a reduction in oxygen delivery (149.4 +/- 106.0 mL min(-1)). Tris-hydroxymethylaminomethane volumes required for pH titration to desired values were significantly higher in the gelatine group (0.7 +/- 0.1 mL kg(-1) h(-1) vs. HES130: 0.5 +/- 0.2 mL kg(-1) h(-1)). The buffer capacity of gelatine did not lead to favourable differences in acid-base balance in comparison to HES130.

Evaluation of tris-hydroxymethylaminomethane on reversing coagulation abnormalities caused by acidosis in pigs*

To investigate the effect of tris-hydroxymethylaminomethane (THAM) pH neutralization on reversing coagulation abnormalities caused by acidosis. Random and controlled study. Animal research facility and laboratory. Yorkshire swine (n = 18). Acidosis was induced in 12 pigs by infusing 0.2 M hydrochloric acid (HCl). When the target pH of 7.1 was achieved, the pigs were infused with either 0.3 M THAM to achieve pH of 7.4 (intervention group) or an equal volume of lactated Ringer's solution (acid control group). Blood samples were taken at baseline, 15 mins after reaching pH of 7.1, and 15 mins after THAM pH neutralization. Coagulation function was assessed by thrombin generation, prothrombin time, activated partial thromboplastin time, activated clotting time, and thromboelastography (maximum clot formation time [R+K], clotting rapidity [alpha], and clot strength [maximum amplitude]). An additional six pigs (sham group) were infused with THAM, and an equal volume of fluid as the 12 coagulopathic pigs was given to assess effects of THAM and hemodilution. Comparisons were made using a mixed model analysis of variance. No change in any indexes of coagulation was observed in sham pigs. Compared with baseline, acidosis of pH 7.1 decreased base excess from 6.6 +/- 0.5 mM to -12.4 +/- 0.5 mM; reduced fibrinogen levels to 72% +/- 2%, platelet counts to 53% +/- 3%, thrombin generation to 58% +/- 4%, alpha to 84% +/- 2%, and maximum amplitude to 75% +/- 3%; and prolonged prothrombin time to 113% +/- 2%, partial thromboplastin time to 122% +/- 4%, activated clotting time to 124% +/- 3%, and R + K to 119% +/- 3% (all p < .05). THAM infusion corrected pH to 7.40 +/- 0.02 and base excess to 2.6 +/- 0.9 mM (p < .05). However, there were no differences in thrombin generation, prothrombin time, partial thromboplastin time, activated clotting time, R+K, alpha, or maximum amplitude between the groups with or without pH correction. Acidosis impaired coagulation by depleting clotting factors, inhibiting thrombin generation, and affecting clot strength and stability. THAM corrected acid-base deficit but did not acutely reverse the coagulation abnormalities in the model.

Effect of tris-(hydroxymethyl)-aminomethane on experimental focal cerebral ischemia.

Systemic and focal cerebral acidosis is considered deleterious to cell metabolism and neuronal recovery. We investigated the immediate effect of tris-(hydroxymethyl)-aminomethane (THAM), an alkalizing agent, on focal cerebral ischemia produced by occlusion of the left middle cerebral artery (MCA) in cats with systemic acidosis. Occlusion of MCA resulted in prompt decreases in local cerebral blood flow of the ipsilateral marginal and ectosylvian gyri from 47.7 ml/100 g per minute in control to 32.3 ml/100 g per minute and 8.3 ml/100 g per minute, respectively. In the control group, physiological saline was infused continuously and the treated group received 0.3 M THAM to normalize systemic and focal cerebral acidosis. There were no significant changes in the systemic arterial pressure, arterial PO2 and PCO2 throughout the experiments in the two groups. Arterial pH decreased from 7.42 to 7.30 in the control, while it remained normal during THAM treatment. Extracellular pH of the marginal gyrus (peri-infarct zone) decreased from 7.39 to 6.87 with 6 h ischemia in the control group. In THAM infusion, extracellular pH was kept between 7.26 and 7.29, which was significantly higher than the control group. THAM significantly decreased infarct volume and lactate and water contents of the gray matter in the marginal gyrus at 6 h after occlusion. It is concluded that THAM infusion immediately after ischemia onset is considered effective in improving acidosis at the site of ischemic penumbra and consequently reduces lactate production, brain edema, and infarct volume.

Effects of a continuous infusion of tris(hydroxymethyl)aminomethane on acidosis, oxygen affinity, and serum osmolality.

The effects of a continuous infusion of tris(hydroxymethyl)aminomethane (THAM) on pH, base excess, p50, serum osmolality, and plasma drug concentration during respiratory acidosis were studied in newborn piglets. Measurements were made during three experimental periods: (1) control period with normal blood gases; (2) hypercapnia period, and (3) hypercapnia plus THAM period (THAM infusion: 1.65 mmol/kg/h). pH decreased and paCO2 increased between control period (7.40 +/- 0.05 and 45 +/- 3 mm Hg) and hypercapnia period (7.24 +/- 0.06 and 59 +/- 2 mm Hg; p < 0.001; mean +/- SD). pH returned to baseline (7.37 +/- 0.04) during the hypercapnia plus THAM period, while paCO2 remained elevated (63 +/- 4 mm Hg). p50 increased from 30.7 +/- 5.9 to 38.3 +/- 4.7 (p < 0.05) during hypercapnia and decreased with hypercapnia plus THAM. THAM concentration and base excess increased with time and were linearly related. Serum osmolality was unchanged during the THAM infusion. We conclude that continuous infusion of THAM is effective in normalizing pH during respiratory acidosis in the piglet.

Metabolic CO2Removal by Dialysis: THAM vs NaOH Infusion

New methods of respiratory support are needed to reduce the high mortality rate of acute respiratory failure. To simplify the procedures of extracorporeal CO2 elimination under apneic oxygenation, one approach is to replace the membrane lung by a hemodialyzer and to administer an alkali, since hemodialysis requires a lower blood flow rate than blood-gas exchange. This study compared the effectiveness of trishydroxymethyl aminomethane (THAM) and NaOH in this procedure. Twelve male Anglo-Poitevin dogs (25 to 33 kg) were anesthetized, curarized and mechanically hypoventilated (VE = 41% of the control value). After not less than 15 min, a venovenous shunt was used for dialysis with blood flow of 7-10 ml. min.-1kg-1 for at least 8 hours. The dialysate contained no acetate, bicarbonate or lactate, but was alkalinized to a pH of 8-9 by the addition of NaOH. A solution of THAM (0.5 N) was infused into the right heart at the rate of 0.30 ml.min.-1kg-1 in six animals, and NaOH (0.15 N) was infused in the other six at the rate of 0.80 ml.min-1kg-1. The injected volumes were compensated for by an equivalent amount of ultrafiltration. Elimination of CO2 (mean TCO2 = 2.3 ml.min.-1kg-1) was the same with both methods and the difference for the electrolytes and acid-base equilibrium was only very small. However, hemolysis was six times greater with NaOH than with THAM. Despite ultrafiltration, a similar marked weight gain was observed from the second hour of the experiment in the NaOH series, but only after 7 hours with THAM. It thus appears that hemodialysis combined with alkalinisation is still too complex a procedure to be safely applied in acute or chronic pulmonary failure.

THAM and metabolic rate in the newborn guinea pig

The metabolic effects of tris-hydroxymethylaminomethane (THAM) in the newborn were investigated in neonatal guinea pigs. In 32 healthy piglets administration of THAM at pH 7.4 intraperitoneally in a dose of 1,200 mg. per kilogram did not affect oxygen consumption or the ability to maintain body temperature during exposure to cold. Furthermore the same dose of neutral THAM administered by slow intra-arterial infusion had no effect on the oxygen consumption of 12 anesthetized piglets. On the other hand, slow intra-arterial infusion of alkaline THAM or sodium bicarbonate at pH 8.6 led to a temporary increase in oxygen consumption. Rapid intra-arterial infusion of the alkaline solutions resulted in a profound though transient depression of respiration and oxygen consumption. It is concluded that THAM in the dose employed in these experiments does not appear to interfere with metabolic rate in the healthy neonatal guinea pig. The temporary alterations in ventilation and oxygen consumption observed following intravascular administration are due to pH of the infusate rather than to specific interference with metabolic processes.

EFFECTS OF CHANGES IN CORONARY BLOOD PH ON THE HEART.

The effects of localized acidosis and alkalosis on coronary blood flow, myocardial contractile force, and heart rate were studied in anesthetized, open-chest dogs. Acidosis of the coronary vascular bed was induced by infusion of 5,5-dimethyl-2, 4-oxazolidinedion (DMO) into the total coronary artery inflow, and alkalosis by infusion of tris hydroxymethyl aminomethane (THAM), Na 2 CO 3 or NaHCO 3 . DMO infusion caused an initial slight increase of coronary blood flow, followed by a decrease. The decrease was accompanied by and attributed to a moderate to marked decrease of myocardial contractile force and bradycardia. THAM and Na 2 CO 3 infusion caused a marked increase of coronary blood flow, associated with a decrease of coronary oxygen A-V difference, indicating coronary vasodilation. A slight to moderate increase of myocardial contractile force but little or no change in heart rate was noted. NaHCO 3 infusion caused changes similar to those induced by DMO but of smaller magnitude. It was suggested that the direct effects of DMO and NaHCO 3 are attributable to intracellular acidosis, whereas those of THAM and Na 2 CO 3 are attributable to intracellular alkalosis.

The effect of Tris (hydroxymethyl) aminomethane on glucose utilization of skeletal muscle

The effect of Tris (hydroxymethyl) aminomethane (THAM) on the glucose metabolism of the isolated rat diaphragm was studied in vitro. The addition of THAM (pH 7.45) to the incubation medium significantly stimulated the uptake of glucose, lactic acid production and the oxidation of glucose to CO 2, but significantly decreased the glycogen content of the tissues. The stimulatory effect of THAM on glycolysis was independent of the bicarbonate or CO 2 concentration in the medium. THAM-chloride (0.05 M) increased glycolysis significantly when added to the balanced salt solution or when substituted for equimolar concentrations of NaCl in the medium; however, the former effect was significantly greater. The effect of insulin and THAM on glucose uptake and lactic acid production was additive, while the effect of the 2 agents on glycogen synthesis was opposite. Insulin stimulated the membrane transport of d-xylose into the intact rat diaphragm preparation, while THAM had no effect. THAM did not affect the incorporation of C 14 from leucine into proteins. 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. These findings could explain the hypoglycemia observed in human subjects and animals following the infusion of THAM.