Guidelines for the treatment of acidaemia with THAM.

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.

Contradictory effects of dopamine at 32 degrees C in pigs anesthetized with ketamine.

BACKGROUND: In critically ill patients who were surface cooled to 33 +/- 2 degrees C, we have observed that dopamine sometimes causes a substantial decrease in blood pressure. The present study was designed to compare the effects of dopamine in normothermia to those seen after surface cooling to 32 degrees C. METHODS: Seven pigs with a mean body weight of 21 kg were anesthetized with ketamine and muscle relaxation was induced with pancuronium. They were mechanically ventilated and given dopamine infusions (5 and 12 micrograms.kg-1.min-1)in normothermia and after surface cooling by cold water immersion to a central blood temperature of 32.0 degrees C (range 31.6-32.6 degrees C). RESULTS: In normothermia, dopamine at a dose of 5 micrograms.kg-1.min-1 increased mean arterial blood pressure (MAP) by 16% (P < 0.01) and cardiac output (CO) by 9% (P = 0.051); at 12 micrograms.kg-1.min-1 dopamine increased MAP by 26% (P < 0.01) and CO by 18% (P < 0.01). In hypothermia, MAP and CO did not change at an administration rate of 5 micrograms.kg-1.min-1; at 12 micrograms.kg-1.min-1 CO was unchanged but MAP was significantly reduced by 15% (P < 0.01). CONCLUSION: Dopamine increased CO and MAP in normothermia but not at 32 degrees C, where there was even a significant reduction of MAP in this porcine model.

Dynamics of carbon dioxide elimination following ventilator resetting.

BACKGROUND: Carbon dioxide elimination (VCO2) at steady state corresponds to the metabolic rate. A change in tidal ventilation will lead to a transient response in VCO2 if other determinants of VCO2 are constant. This principle may be applied in the critical care unit to reset ventilators. OBJECTIVE: To define and characterize the transient response of VCO2 to a well-defined change in ventilation. METHODS: Forty-four patients in stable condition receiving volume-controlled mechanical ventilation had trend recordings of ventilator pressures, flow, volumes, VCO2, and end-tidal CO2 (ETCO2) for 20 min. At time t0, the minute ventilation was either increased (n = 22) or decreased (n = 22) by 10% after which these parameters were monitored over 30 min. Blood gas values were measured 5 and 20 min after the change in ventilation and the dead space fractions were computed using the single breath-CO2 test. DATA ANALYSIS: The first ten breaths (till t1) after a change in ventilation were excluded. The time constant (tau) of the relative change in VCO2 (delta VCO2) was calculated by fitting exponential regressions to delta VCO2 for periods up to 20 min after t1. RESULTS: The delta VCO2 at t1 was proportional to the relative change in tidal volume (delta VT). The proportionality decreased gradually during 20 min. The proportionality of the relative change in ETCO2 (delta ETCO2) or PaCO2 (delta PaCO2) with delta VT was minimal at t1 and increased during the 20 min. tau increased progressively when calculated over longer periods (p < 0.001). tau was similar in the groups with increased and decreased ventilation up to 5 min, after which it was longer in the group with decreased ventilation (p < 0.05). The delta PaCO2 after 20 min correlated best with delta VCO2 at t1 (r = -0.8) and with delta ETCO2 at the end of 20 min (r = 0.8). CONCLUSIONS: Noninvasively monitored VCO2 provides an instantaneous indication of the change in alveolar ventilation in well-sedated, mechanically ventilated patients in stable condition without significant cardiopulmonary disease.

Effects of hypothermia with and without buffering in hypercapnia and hypercapnic hypoxemia.

Anesthetized, paralyzed and mechanically ventilated pigs were hypoventilated to extreme hypercapnia (PaCO2 approximately 20 kPa) at FiO2 0.5, and allotted to receive hypothermia (approximately 31.5 degrees C) and buffer infusion, (HB-group, n = 6) or to a hypothermic control group (H-group, n = 6). The HB-group had higher arterial pH (7.34 vs 7.09, P < 0.01) and plasma bicarbonate (58.8 vs 35.4 mmol.l-1, P < 0.01) than the controls, but lower mean pulmonary arterial pressure (MPAP), (16 vs 23 mmHg (2.1 vs 3.1 kPa), P < 0.01) and pulmonary vascular resistance (PVR), (512 vs 699 dyn.s.cm-5 (5120 vs 6990 microN.s.cm-5), P < 0.05). Mixed venous PO2 (PVO2) was lower in the HB-group (5.1 vs 6.8 kPa, P < 0.01), as well as serum potassium (2.8 vs 3.7 mmol.l-1, P < 0.01) and ionized calcium (1.01 vs 1.29 mmol.l-1, P < 0.01). Subsequently, the inspired oxygen fraction (FiO2) was decreased stepwise (0.3, 0.25, 0.21, 0.15, 0.10) at 30 min intervals. At FiO2 0.3, the HB-group had lower PVO2 (6.6 vs 7.8 kPa, P < 0.01), O2 half saturation tension (3.6 vs 4.2 kPa, P < 0.01), MPAP (17 vs 25 mmHg (2.3 vs 3.3 kPa, P < 0.01) and PVR (598 vs 793 dyn.s.cm-5 (5980 vs 7930 microN.s.cm-5, P < 0.05) compared with the controls, but higher arterial O2 saturation (95.3 vs. 88.6%, P < 0.01) and O2 content (17.7 vs 15.7 ml.100 ml-1, P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of buffering in hypercapnia and hypercapnic hypoxemia.

Anesthetized, paralyzed and mechanically ventilated pigs were exposed to extreme hypercapnia (PaCO2 approximately 20 kPa) at FiO2 0.4 for 480 min, with (n = 6) or without (n = 6) continuous infusion of isotonic buffers (bicarbonate and trometamol). Arterial pH was higher in buffered animals than controls, 7.21 +/- 0.01 vs 7.01 +/- 0.01 (mean +/- s.e.mean, P < 0.01). Serum osmolality and PaCO2 did not differ between groups throughout the experiment. The hemodynamic response to hypercapnia was attenuated in the buffered group, who had lower heart rate, 133 +/- 6 vs 189 +/- 12 min-1 (P < 0.01), mean arterial pressure (MAP) 109 +/- 4 vs 124 +/- 4 mmHg (14.5 +/- 0.5 vs 16.5 +/- 0.5 kPa) (P < 0.05), mean pulmonary arterial pressure 16 +/- 1 vs 23 +/- 1 mmHg (2.1 +/- 0.1 vs 3.1 +/- 0.1 kPa) (P < 0.01), and pulmonary vascular resistance (PVR) 249 +/- 21 vs 343 +/- 20 dyn s.cm-5 (2490 +/- 210 vs 3430 +/- 200 microN.s.cm-5) (P < 0.01), compared with the control group. Subsequently, both groups were exposed to hypercapnic hypoxemia by stepwise increases in FiO2 (0.15, 0.10, 0.05) at 30-min intervals, while FiCO2 was kept at 0.2. PVR increased in both groups (P < 0.05) but, except for heart rate, all hemodynamic differences between the groups disappeared during hypoxia. At FiO2 0.15, buffered animals had higher arterial oxygen saturation (73 +/- 5%) than the controls (55 +/- 5%), (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of hypothermia in hypercapnia and hypercapnic hypoxemia.

Anesthetized, paralyzed and mechanically ventilated pigs were hypoventilated to extreme hypercapnia (PaCO2 approximately 20 kPa) at FiO2 0.5, and allotted to a hypothermic group (31.5 +/- 0.1 degrees C, n = 6) or a control group (39.6 +/- 0.2 degrees C, n = 6). Compared with the controls, the hypothermic animals had higher PaO2 (19.2 vs 15.6 kPa, P < 0.05), SaO2 (97.2 vs 89.3%), SvO2 (78.7 vs 68.2%), end-tidal O2 (34.5 vs 24.8 kPa) and arterial pH (7.01 vs 6.91), (P < 0.01), but lower PvO2 (7.0 vs 10.2 kPa) and PaCO2 (13.2 vs 23.5 kPa), (P < 0.01). Hypothermia reduced O2 delivery (DO2), O2 consumption (VO2) and CO2 production by 40-45% (P < 0.05), but O2 extraction ratio, i.e. VO2.DO(2)-1 x 100(%), did not differ between groups. Hypothermic animals had lower heart rate (127 vs 223 beats.min-1, P < 0.05) and cardiac output (2.5 vs 3.9 l.min-1, P < 0.01). Subsequently, the inspired oxygen fraction (FiO2) was decreased stepwise (0.3, 0.25, 0.21, 0.15, 0.10) at 30-min intervals. At FiO2 0.3, the hypothermic group had higher PaO2 (10.0 vs 5.7 kPa), SaO2 (91.3 vs 28.5%), PvO2 (5.8 vs 3.4 kPa), SvO2 (70.7 vs 10.3%), end-tidal O2 (16.7 vs 8.5 kPa), O2 delivery (344 vs 155 ml.min-1), arterial pH (7.02 vs 6.94) and systemic vascular resistance (3850 vs 1652 dyn.s.cm-5 (38,500 vs 16,520 microN.s.cm-5)) compared with the controls (P < 0.01), while PaCO2 was lower (12.4 vs 22.7 kPa), as well as O2 extraction ratio (23 vs 63%) and O2 half saturation tension (4.3 vs 8.0 kPa) (P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Combined use of hypothermia and buffering in the treatment of critical respiratory failure.

A 20-year-old male, recovering from post-traumatic ARDS, subsequently developed pneumonia with extreme hypercapnia (PaCO2 max 19.4 kPa) and hypoxemia (PaO2 min 5.1 kPa), in spite of maximal mechanical ventilation. Hypothermia was induced by surface cooling, reducing the body temperature from 40 degrees C to a mean of 33.3 degrees C. Buffer infusion (1375 mmol) during the first 2 days increased base excess from 3 to 22 mmol/l and pH from 7.16 to a median value of 7.30. Active cooling was discontinued on day 11. Weaning from the ventilator was possible 9 days later and the patient subsequently recovered fully. Combined use of hypothermia and buffering might offer an alternative to extracorporeal lung assist (ECLA) and facilitate a reduction of barotrauma and oxygen toxicity during mechanical ventilation.

Pulmonary sequelae of prolonged total venoarterial bypass: evaluation with a new experimental model.

Total normothermic venoarterial bypass was established in 6 healthy pigs over a period of 18 hours. A heparin-coated closed extracorporeal system was used and no heparin was administered systemically. During the bypass period the main pulmonary artery was occluded and the heart was maintained in a beating state. All the animals maintained stable hemodynamics and normal blood gases during the entire period of bypass. In the postbypass period, the central hemodynamics continued to be stable while the arterial oxygen tension (inspired oxygen fraction = 0.21) decreased significantly (p less than or equal to 0.05). The total body oxygen uptake, on the other hand, remained unaltered. All the animals died within 4 hours after weaning off the venoarterial bypass circuit on account of pulmonary edema in 2 and cardiac arrest in 4. Death was preceded by progressive pulmonary hypertension and lactacidosis in all the animals. Histological examination of the lungs showed pulmonary parenchymal damage ranging from interstitial edema to intraalveolar hemorrhage and parenchymal necrosis involving more than 80% of the pulmonary parenchyma. A normothermic total venoarterial bypass of 18 hours duration or more produces pulmonary edema of varying severity, pulmonary hypertension, pulmonary parenchymal necrosis, and lactacidosis in healthy juvenile pigs, resulting uniformly in their death. Despite these sequelae the systemic arterial hypoxemia may only be mild to moderate.

Veno-right ventricular bypass as total extracorporeal lung assistance. An experimental study.

Efficacy of veno-right ventricular bypass as a total extracorporeal lung assistance was studied for a period of 24 hours in six healthy pigs with a mean weight of 60 kg. A covalently bonded heparin-coated extracorporeal membrane oxygenation system and a roller pump were used for the bypass. No local or systemic heparin was administered. The bypass was established with an open chest with two 28F venous cannulas and one 24F arterial cannula. The arterial cannula was placed in the right ventricle across the tricuspid valve. With the lung function totally disabled, this extracorporeal lung assistance maintained normal systemic arterial and mixed venous blood gases during the entire 24-hour period in all the animals. No significant tricuspid insufficiency was observed, and the animals maintained normal central hemodynamics. There was no hemolysis, and the platelet counts remained essentially unaltered. Multiple foci of clot formation were observed in all the oxygenators, but no macroscopic thrombosis or embolization was seen either in the heart or in the lungs. A veno-right ventricular bypass offers total extracorporeal lung assistance in 60 kg juvenile pigs for a period of 24 hours. Tricuspid valve competence is an important prerequisite for the success of this procedure.

Total extracorporeal lung assist--a new clinical approach.

Total extracorporeal lung assist (ECLA) requires a bypass flow approaching cardiac output. Recirculation of venous blood through the oxygenator is minimized with a veno-right ventricular cannulation technique which separates venous drainage from returned oxygenated blood. A case of posttraumatic ARDS was treated with surface-heparinized veno-right ventricular ECLA for 35 days. Cardiac output was stabilized by means of sedation, hypothermia (35 degrees C) and beta blockers (pulse rate less than 90) in order to match the maximal venous drainage achieved (5.5 l/min). A bypass flow around 85% of cardiac output resulted in mean arterial PO2 values between 9-13.6 kPa without any contribution from the lungs. Low platelet counts and a marked bleeding tendency complicated treatment, even though no heparin was used during the last 24 days of ECLA. Weaning from the ventilator was accomplished 2 months after ECLA. Lung function tests show constant improvement.

Veno-venous extracorporeal membrane oxygenation with a heparin-coated system in adult respiratory distress syndrome.

Three patients with adult respiratory distress syndrome were treated with veno-venous extracorporeal membrane oxygenation, ECMO, using a heparin-coated system for 8, 12 and 34 days, respectively. Despite extracorporeal blood flow of 4-5 l/min, the patients were ventilator-dependent in the initial period of ECMO. Two of the three patients showed bleeding diatheses despite only slightly elevated activated partial thromboplastin time (APTT). Blood platelet count followed a variable course and serum fibrinogen was normal. Acute pulmonary hypertensive crises, fatal systemic infection, recurrent pneumothorax and plasma leakage from the oxygenators were other main complications during ECMO. Two of the three patients survived, and follow-up showed that severely damaged lungs, if supported in the acute phase, can recover sufficiently to permit normal living.

Acute lung injury monitored with radiolabeled transferrin and lung volume measurements.

Anesthetized pigs (n = 12) were given oleic acid (OA) to induce acute lung injury. Three additional pigs were used as uninjured controls. Six of the animals were pretreated with terbutaline before OA infusion. 113mIn-labeled transferrin and 99mTc-labeled erythrocytes were used for tracing of extravascular plasma leakage. A computerized gamma camera supplied image analysis of the radioactivities over the heart and lungs. A lung transferrin index (LTI), which describes the net accumulation of plasma equivalents in the lung, was calculated. OA caused an immediate increase in LTI and concurrent, correlated decreases in functional residual capacity, lung thorax compliance and arterial PO2. LTI was also correlated to the content of plasma equivalents in lung tissue samples and also to the wet weight/dry weight-ratios of the same tissue samples. Finally, LTI was correlated to the calculated plasma loss from the circulation. Changes in all these parameters were correlated to the dose of OA. We conclude that this noninvasive double radioisotope technique can detect plasma protein leakage in lung injury of different degrees. We found no significant anti-edema effect of terbutaline.