Faculty Bibliography

A sensitive high performance liquid chromatographic (HPLC) assay was developed to quantitate the organic amine proton-acceptor, tris(hydroxymethyl)aminomethane (THAM) in human plasma, erythrocytes, and whole blood. An aliquot of the sample was heat evaporated (200 degrees C for 2 h), derivatized, extracted, and then injected onto a symmetry Cs column. The UV absorbance of the effluent was monitored at 237 mn. 2-Amino-2-methyl-1,3-propanediol was found to be an appropriate internal standard. The method has been applied to quantitate the samples from patients undergoing orthotopic liver transplantation. The assay has also been employed to assess the in vitro time of THAM-uptake into the erythrocytes from blood samples incubated at 37 degrees C

THAM (trometamol; tris-hydroxymethyl aminomethane) is a biologically inert amino alcohol of low toxicity, which buffers carbon dioxide and acids in vitro and in vivo. At 37 degrees C, the pK (the pH at which the weak conjugate acid or base in the solution is 50% ionised) of THAM is 7.8, making it a more effective buffer than bicarbonate in the physiological range of blood pH. THAM is a proton acceptor with a stoichiometric equivalence of titrating 1 proton per molecule. In vivo, THAM supplements the buffering capacity of the blood bicarbonate system, accepting a proton, generating bicarbonate and decreasing the partial pressure of carbon dioxide in arterial blood (paCO2). It rapidly distributes through the extracellular space and slowly penetrates the intracellular space, except for erythrocytes and hepatocytes, and it is excreted by the kidney in its protonated form at a rate that slightly exceeds creatinine clearance. Unlike bicarbonate, which requires an open system for carbon dioxide elimination in order to exert its buffering effect, THAM is effective in a closed or semiclosed system, and maintains its buffering power in the presence of hypothermia. THAM rapidly restores pH and acid-base regulation in acidaemia caused by carbon dioxide retention or metabolic acid accumulation, which have the potential to impair organ function. Tissue irritation and venous thrombosis at the site of administration occurs with THAM base (pH 10.4) administered through a peripheral or umbilical vein: THAM acetate 0.3 mol/L (pH 8.6) is well tolerated, does not cause tissue or venous irritation and is the only formulation available in the US. In large doses, THAM may induce respiratory depression and hypoglycaemia, which will require ventilatory assistance and glucose administration. 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 body-weight (kg) x base deficit (mmol/L). The maximum daily dose is 15 mmol/kg for an adult (3.5L of a 0.3 mol/L solution in a 70kg patient). When disturbances result in severe hypercapnic or metabolic acidaemia, which overwhelms the capacity of normal pH homeostatic mechanisms (pH < or = 7.20), the use of THAM within a 'therapeutic window' is an effective therapy. It may restore the pH of the internal milieu, thus permitting the homeostatic mechanisms of acid-base regulation to assume their normal function. In the treatment of respiratory failure, THAM has been used in conjunction with hypothermia and controlled hypercapnia. Other indications are diabetic or renal acidosis, salicylate or barbiturate intoxication, and increased intracranial pressure associated with cerebral trauma. THAM is also used in cardioplegic solutions, during liver transplantation and for chemolysis of renal calculi. THAM administration must follow established guidelines, along with concurrent monitoring of acid-base status (blood gas analysis), ventilation, and plasma electrolytes and glucose

BACKGROUND: Acute changes in cerebral function after elective coronary bypass surgery is a difficult clinical problem. We carried out a multicenter study to determine the incidence and predictors of -- and the use of resources associated with -- perioperative adverse neurologic events, including cerebral injury. METHODS: In a prospective study, we evaluated 2108 patients from 24 U.S. institutions for two general categories of neurologic outcome: type I (focal injury, or stupor or coma at discharge) and type II (deterioration in intellectual function, memory deficit, or seizures). RESULTS: Adverse cerebral outcomes occurred in 129 patients (6.1 percent). A total of 3.1 percent had type I neurologic outcomes (8 died of cerebral injury, 55 had nonfatal strokes, 2 had transient ischemic attacks, and 1 had stupor), and 3.0 percent had type II outcomes (55 had deterioration of intellectual function and 8 had seizures). Patients with adverse cerebral outcomes had higher in-hospital mortality (21 percent of patients with type I outcomes died, vs. 10 percent of those with type II and 2 percent of those with no adverse cerebral outcome; P<0.001 for all comparisons), longer hospitalization (25 days with type I outcomes, 21 days with type II, and 10 days with no adverse outcome; P<0.001), and a higher rate of discharge to facilities for intermediate- or long-term care (69 percent, 39 percent, and 10 percent ; P<0.001). Predictors of type I outcomes were proximal aortic atherosclerosis, a history of neurologic disease, and older age; predictors of type II outcomes were older age, systolic hypertension on admission, pulmonary disease, and excessive consumption of alcohol. CONCLUSIONS: Adverse cerebral outcomes after coronary bypass surgery are relatively common and serious; they are associated with substantial increases in mortality, length of hospitalization, and use of intermediate- or long-term care facilities. New diagnostic and therapeutic strategies must be developed to lessen such injury

BACKGROUND: The paradox of present cardiac surgery is that the more elderly and debilitated patients benefit most from cardiac surgery compared with medical therapy, yet they sustain greater overall risk for morbidity and mortality after cardiac surgery. The goal of the present study was to develop a preoperative index predicting major perioperative neurological events in patients undergoing coronary artery bypass graft surgery. METHODS AND RESULTS: As part of a prospective, multicenter, observational study (McSPI Research Group), we enrolled 2417 patients at 24 academic medical centers in the United States. Patients who died intraoperatively or had concomitant open-heart procedures were excluded from analysis, resulting in a total of 2107 for analysis. Sixty-eight patients (3.2%) developed adverse neurological events, defined as cerebrovascular accident, transient ischemic attack (TIA), or persistent coma. Bivariate analysis was applied to determine associations between preoperative variables and neurological events. Significant bivariate predictors were identified then logically grouped, and for each cluster, a score was calculated based on principal components. Key predictor variables were age, history of previous neurological disease, diabetes, history of vascular disease, previous coronary artery surgery, unstable angina, and history of pulmonary disease, the coefficients for which were used to develop a preoperative stroke risk index that was validated by bootstrap (c-index = 0.778). Stroke risk could then be determined for each patient, calculating a patient's risk for stroke within 95% confidence intervals. CONCLUSIONS: With the McSPI stroke risk index developed in this study, neurological risk can be estimated, and the most appropriate group for perioperative therapy can be identified. Further refinement and validation of this index, however, are necessary and are under way in current studies