Increased Cerebral Blood Flow And Cardiac Output Following Cerebral Arterial Air Embolism In Sheep

1. The effects of cerebral arterial gas embolism on cerebral blood flow and systemic cardiovascular parameters were assessed in anaesthetized sheep. 2. Six sheep received a 2.5 mL injection of air simultaneously into each common carotid artery over 5 s. Mean arterial blood pressure, heart rate, end-tidal carbon dioxide and an ultrasonic Doppler index of cerebral blood flow were monitored continuously. Cardiac output was determined by periodic thermodilution. 3. Intracarotid injection of air produced an immediate drop in mean cerebral blood flow. This drop was transient and mean cerebral blood flow subsequently increased to 151% before declining slowly to baseline. Coincident with the increased cerebral blood flow was a sustained increase in mean cardiac output to 161% of baseline. Mean arterial blood pressure, heart rate and end-tidal carbon dioxide were not significantly altered by the intracarotid injection of air. 4. The increased cardiac output is a pathological response to impact of arterial air bubbles on the brain, possibly the brainstem. The increased cerebral blood flow is probably the result of the increased cardiac output and dilation of cerebral resistance vessels caused by the passage of air bubbles.     

Methods in pharmacology: measurement of cardiac output

Many methods of cardiac output measurement have been developed, but the number of methods useful for human pharmacological studies is limited. The 'holy grail' for the measurement of cardiac output would be a method that is accurate, precise, operator independent, fast responding, non-invasive, continuous, easy to use, cheap and safe. This method does not exist today. In this review on cardiac output methods used in pharmacology, the Fick principle, indicator dilution techniques, arterial pulse contour analysis, ultrasound and bio-impedance are reviewed.     

Effects of tromethamine and sodium bicarbonate buffers during cardiac resuscitation

The effects on cardiac resuscitability of iso-osmolal solutions of tris-hydroxymethyl-aminomethane (tromethamine), sodium bicarbonate (NaHCO3) and sodium chloride placebo were compared in 30 domestic pigs using a well-established model of electrically induced cardiac arrest and resuscitation. We hypothesized that a carbon dioxide (CO2) consuming buffer like tromethamine would reduce and sodium bicarbonate would increase the respiratory acidosis of mixed venous blood, which had recently been demonstrated in our laboratory, Tromethamine did decrease and sodium bicarbonate did increase both arterial and mixed venous CO2 during cardiopulmonary resuscitation (CPR). Both concentrations of end-tidal CO2 and coronary venous PCO2 were significantly lower after tromethamine than after bicarbonate. However, tromethamine produced an unexpected vasodilator effect with reduction of mean aortic and coronary perfusion pressures to levels that are known to reduce resuscitability and survival independently of its buffer action. Neither resuscitability nor survival was altered by bicarbonate therapy in comparison with sodium chloride placebo.     

Ventilation and gas-dynamic work of breathing during CO2 stimulation in patients with airways obstruction prior to and following bronchodilation with reproterol (author's transl)

A new, non-invasive method for measuring chemo-sensitivity of the respiratory center is described, one that may sensibly be applied in patients with airways obstruction. It is used for measurement of ventilation and gas-dynamic work of breathing in body plethysmography during a modified unsteady state of CO2 rebreathing technique. In 9 patients suffering from chronic obstructive bronchitis, a linear correlation between the end-expiratory CO2 partial pressure and the respiratory work rate vs. the airways resistance was established while between the end-expiratory PCO2 and the respiratory minute volume as well as the respiratory minute volume and the respiratory work rate vs. airways resistance, a non-linear correlation exists. In tests with 7-(3[2-(3 5-dihydroxyphenyl)-2-hydroxy-ethyl-amino]-propyl)-theophylline (reproterol, Bronchospasmin), a beta-phenylethyl-amino alkylxanthine, with known bronchodilating effects and a preparation for which pharmacological considerations of central-analeptic effects cannot definitely be excluded, this method revealed in patients with airways obstruction no breathing stimulation. In contrast, however, specific airways resistance in patients afflicted with bronchitis was statistically significantly reduced.     

Cardiac output of Indian men by a non-invasive method the Indirect Fick Principle

The cardiac-output (Q) of seven young healthy Indians with common physical characteristics at rest and after a single bout of exercise of 600 kpm for 10 min on a bicycle ergometer was ascertained by the Indirect Fick Principle. The end tidal alveolar Co2 pressure was obtained at the end of a normal expiration and PvCo2 was obtained by the help of the exponential rise (Defares method) in Co2 concentration during rebreathing from an initially low Co2 in O2 mixture (3-4%). The standard Co2 dissociation curve of oxygenated blood was used to find out the corresponding arterial and venous Co2 content, assuming the Hb content of these individuals to be normal. The mean value of the Cardiac-Output so obtained during rest is 4.21 liters/min when Co2 rebreathing time does not exceed 10 secs, and 17.33 litres/min., 2 to 3 breaths after exercise, when rebreathing time did not exceed 5 to 7 secs. Repeated studies and better training of the subjects will perhaps improve the resting values, while after exercise and during recovery our values are better reproducible.     

Acute effects of propranolol on the circulation and on oxygen uptake in conscious rats.

1 The acute effect of orally administered propranolol (100 mg/kg) on blood pressure, heart rate, cardiac output, venous pressure, haemoglobin concentration and oxygen uptake was studied in conscious rats. 2 Oxygen uptake was measured in a closed circuit respirometer and cardiac output determined by the direct Fick method. Other variables were measured by means of chronically implanted cannulae. 3 Significant falls occurred in heart rate (8.9%), cardiac output (30.5%), derived stroke volume (21.3%) and oxygen uptake (12.2%). 4 There were significant rises in arterial blood pressure (12.9%), derived arterial resistance (69%), arterio-venous oxygen difference (31.5%) and arterial haemoglobin concentration (6.3%). 5 A rise in venous pressure occurred in lightly anaesthetized rats but was only of borderline significance. 6 Correlations between the different variables revealed only one significant relationship, between heart rate and oxygen uptake. 7 It is concluded that only one primary site of action of propranolol has to be postulated to account for these findings, that of the well known negative inotropic and chronotropic effect on the heart.     

HAEMODYNAMIC AND HORMONAL EFFECTS OF N-NITRO-l-ARGININE, AN INHIBITOR OF NITRIC OXIDE BIOSYNTHESIS, IN SHEEP

1. The haemodynamic and hormonal responses to N-nitro-l-arginine (NOLA), a potent inhibitor of nitric oxide biosynthesis in endothelial cells, were investigated in conscious sheep. 2. Mean arterial blood pressure (MAP), heart rate (HR) and cardiac output by thermodilution (CO) were measured in four oophrectomized ewes. Two other ewes were surgically implanted with aortic electromagnetic flow probes and an indwelling carotid arterial line for monitoring CO and MAP over 40 h. 3. After a control period, NOLA (10 mg/kg) was injected intravenously and MAP, HR and CO monitored and blood samples taken at intervals over the following 24 h. 4. NOLA increased blood pressure within minutes, from 76 ± 4 to a maximum of 99 ± 4 mmHg (P<0.001) at 6 h after injection. It remained elevated 24 h after injection. CO and HR fell but these falls were not sustained longer than 6 h. Calculated total peripheral resistance increased to a maximum of 2 h, but had returned to control levels 24 h after injection. There were no significant changes in plasma concentrations of renin, atrial natriuretic factor, vasopressin, noradrenaline or endothelin during the first hour. 5. NOLA may be a useful tool in understanding the role of the endothelium and nitric oxide in the control of blood pressure.     

A comparison between thermodilution, electromagnetic and Doppler methods for cardiac output measurement in the rabbit

SUMMARY 1. Electromagnetic and Doppler flowmeter methods were compared with the thermodilution technique for the measurement of cardiac output in unanaesthetized rabbits. Cardiac output was varied by haemorrhage and transfusion.
2. All three methods give a satisfactory estimate of cardiac output over a wide range of flows. The electromagnetic method is probably the most accurate; errors due to transducer instability, the use of end-diastolic flow as an index of zero flow, and the failure to detect coronary flow appear negligible.
3. The Doppler flowmeter gives a systematic 3–4% overestimate of cardiac output; the error is most probably due to registration of backflow in the aortic root as forward flow.
4. The thermodilution technique gives a good estimate of cardiac output at low and normal resting cardiac outputs, but is subject to a small but increasing error as cardiac output rises; the error at high flows is of the order of 10%.     

Estimation of cardiac output in a pharmacological trial using a simple method based on arterial blood pressure signal waveform: a comparison with pulmonary thermodilution and echocardiographic methods

Objective Cardiac output (CO) has traditionally been measured using invasive techniques, which involve an element of risk. Thus, a reliable less-invasive method for determining CO would be very valuable for research use. We tested whether simple analysis of the arterial pulse waveform, not requiring large-vessel catheterisation or expensive equipment, could provide an estimate of CO that is accurate enough for pharmacological studies.Methods We measured CO in 11 healthy male subjects who received low and high doses of dexmedetomidine (α₂-adrenoceptor agonist), using pulse contour analysis, echocardiography and pulmonary thermodilution techniques.Results At baseline, these methods gave the following mean (SD) values of CO: 6.18 (1.59), 5.22 (1.35) and 7.03 (1.54) l/min, respectively. High-dose dexmedetomidine reduced CO to 4.50 (0.68), 3.65 (0.65) and 4.80 (0.89) l/min, corresponding to −25 (14) %, −28 (12) % and −30 (14) % reductions from baseline, respectively. The pulse contour method described these dexmedetomidine-induced changes in CO very similarly to the thermodilution and echocardiographic methods. The limits of agreement [bias (2SD)] were 0.55 (2.55) and −0.10 (2.04) l/min, respectively.Conclusion The minimally invasive pulse contour analysis technique might be suitable for pharmacological studies for the detection of major drug-induced reductions in CO.     

A sex difference in the effects of oral codeine and promethazine on the ventilatory response to carbon dioxide in human volunteers.

1 Interactions between codeine and promethazine have been studied in male and female volunteers, measuring ventilation, end tidal PCO2, ventilatory response to CO2, pulse and blood pressure. 2 The effects of codeine on the above measurements have been compared in subjects who habitually smoke cigarettes and non smoking subjects. 3 Codeine displaced the ventilatory response to CO2 to the right and increased end tidal PCO2 in female subjects but not in males. 4 Promethazine plus codeine displaced the ventilatory response to CO2 to the right in male subjects but tended to reduce the response to codeine in females. 5 The slope of the ventilatory response to CO2 was significantly steeper in smokers and codeine caused significant reductions in slope in these subjects.     

The effects of long-term infusions of angiotensin II into the pregnant ewe on uterine blood flow and on the fetus

The effects of intravenous (i.v.) infusions of 62.5 microg/h of angiotensin II (Ang II) on maternal arterial pressure (MMAP), cardiac output (CO), and uteroplacental blood flow (UPF) were studied in 11 chronically catheterized pregnant ewes and their fetuses. Over the first 4 h of infusion, MMAP (p < 0.01) increased and CO decreased (p < 0.05). UPF and fetal PO2, PCO2, and pH were unchanged. After 16-24 h, MMAP increased further (p < 0.05-p < 0.005); UPF decreased (p < 0.05), and vascular resistance increased (p < 0.05). Fetal arterial PO2 decreased and PCO2 increased (p < 0.001; p < 0.05). There were correlations between fetal arterial PO2 and UPF (r = 0.6; p < 0.00005; n = 81), pH and UPF (r = 0.39; p < 0.0003; n = 81) and a negative correlation between PCO2 and UPF (r = -0.5; p < 0.00005; n = 81). Infusions of 33 microg/h of noradrenaline initially caused a decrease in UPF. In the longer term, UPF was unchanged, as was UVR. There were no changes in fetal blood gases or pH, but there was a correlation between fetal arterial PO2 and UPF (r = 0.48; p < 0.01; n = 27). The short-term effects of Ang II and noradrenaline on UPF and UVR are similar to effects reported previously. The finding that long-term infusions of Ang II caused a reduction in UPF and compromised fetal gas exchange was unexpected. Thus the protective effect of reduced vascular reactivity of the uteroplacental circulation to Ang II is only a transient phenomenon.     

Effects of rac-albuterol on arterial blood gases in patients with stable hypercapnic chronic obstructive pulmonary disease

AIMS: Many patients with chronic obstructive pulmonary disease (COPD) are treated with high dose beta(2)-adrenoceptor agonists, which can increase ventilation/perfusion mismatching, and tremor and cardiac output, thereby increasing oxygen uptake and carbon dioxide output (VCO(2)). Patients with severe COPD and hypercapnia may be unable to increase ventilation in response to increased VCO(2), in which case arterial carbon dioxide tension (P(a)CO(2)) may rise. Our aim was to determine whether high dose nebulized rac-albuterol could increase P(a)CO(2) in patients with COPD, limited bronchodilator reversibilty and hypercapnia. METHODS:We compared 10 mg and 400 microg rac-albuterol, given in two doses 1 h apart on nonconsecutive days, in a double-blind randomized crossover study in 14 patients with severe COPD. P(a)CO(2), arterial oxygen tension (P(a)O(2)) and heart rate were measured over 120 min and change from baseline was plotted against time to obtain an area under the curve. RESULTS: Mean P(a)CO(2) fell slightly over 120 min, with no difference between treatments (0.03 kPa h(-1) (95% confidence interval 0.02, 0.04)) and only three subjects had an increase in P(a)CO(2) after high dose rac-albuterol. High dose rac-albuterol caused a greater fall in P(a)O(2)[0.1 kPa h(-1) (95% confidence interval 0, 0.2)] and increase in heart rate than the low dose, although the differences were small. CONCLUSIONS: Under stable conditions most subjects with severe COPD and hypercapnia will have a fall in P(a)CO(2) and P(a)O(2) following 10 mg rac-albuterol, suggesting that they maintain capacity to respond to any increase in VCO(2) and prevent a rise in P(a)CO(2).     

THE CARDIOVASCULAR EFFECTS OF INTRA VERTEBRAL ANGIOTENSIN II BEFORE AND AFTER TREATMENT WITH CLONIDINE

1. In anaesthetized mongrel dogs it was shown that intravertebral infusions of angiotensin II (2–4 ng/kg per min) increased mean arterial pressure by causing an increase in cardiac output, while infusions of 10 ng/kg per min increased mean arterial pressure through an effect on peripheral resistance. After intravenous clonidine, intravertebral angiotensin no longer had any stimulatory effect on cardiac output, but arterial pressure still increased to the same extent. 2. It is concluded that intravertebral angiotensin can increase arterial pressure by increasing either cardiac output or peripheral resistance. The effects of intravertebral angiotensin on cardiac output can be reduced by concomitant stimulation of baroreflex pathways but its effects on peripheral resistance are not so readily antagonized.     

Haemodynamic dose-response effects of intravenous nisoldipine in coronary artery disease.

The circulatory consequences of slow-calcium channel blockade with a new dihydropyridine nisoldipine were evaluated at rest and during exercise-induced angina in 16 patients with angiographically proven coronary artery disease. In 10 patients resting cardiac stroke output (thermodilution) and pulmonary artery occluded pressure were determined following four intravenous nisoldipine injections (cumulative dosage of 1, 2, 4 and 8 micrograms kg-1). The exercise effects of nisoldipine were evaluated by comparing the effects of the 8 micrograms kg-1 cumulative dosage with a control exercise period at the same workload. At rest nisoldipine reduced systemic vascular resistance and mean arterial pressure, and increased heart rate, cardiac and stroke volume indices. During 4 min supine-bicycle exercise nisoldipine reduced systemic mean arterial pressure and vascular resistance; this resulted in augmented cardiac and stroke volume indices at an unchanged pulmonary artery occluded pressure. In six additional patients rest and exercise ejection fractions were measured using a nonimaging nuclear probe. Nisoldipine (4 micrograms kg-1) resulted in a small trend to increase left ventricular rest and exercise ejection fraction. These data demonstrated improved rest and exercise cardiac performance following nisoldipine in patients with severe coronary artery disease.     

COMPARATIVE HAEMODYNAMIC EFFECTS OF VERAPAMIL, FLECAINIDE, AMIODARONE AND SOTALOL IN THE CONSCIOUS RABBIT

1. The effect of intravenous boluses of verapamil (0.15 mg/kg), flecainide (2 mg/kg), amiodarone (5 mg/kg), and sotalol (l.5 mg/kg) on mean arterial pressure, heart rate (HR), cardiac output (CO), total peripheral resistance (TPR), and peak rate of change of left ventricular pressure (LV dP/dt) were assessed in the conscious rabbit. 2. All four drugs had negative inotropic effects: verapamil reduced peak LV dP/dt by 19±4% (mean±s.e.m.; P<0.01), flecainide by 27 ± 9% (P<0.001), amiodarone by 11 ± 2% (P<0.01) and sotalol by 13 ± 3% (P<0.01). 3. The drugs had different effects on CO as a result of differences in their actions on peripheral blood vessels: verapamil and amiodarone produced, respectively, a 12 ± 4% (P<0.03) and 16 ± 6% (P<0.01) increase in CO associated with a substantial vasodilatory effect (TPR reduced 15 ± 7%[P<0.05] and 20 ± 5% [P<0.01], respectively). Flecainide caused only a small (6 ± 1%; P<0.01) increase in CO and sotalol had no effect on either CO or TPR. 4. Bolus intravenous injections of verapamil, flecainide and amiodarone produced an increase in HR, while sotalol reduced HR by 10 ± 2% (P<0.01). The increase in HR and cardiac output seen with verapamil, flecainide and amiodarone was in part secondary to reflex increase in sympathetic tone and these changes were abolished after total cardiac autonomic blockade. 5. The modest reduction in cardiac performance associated with sotalol was abolished by cardiac autonomic blockade, suggesting that the predominant effect of sotalol on contractility was mediated through its β-adrenoceptor blocking effect.     

量压法和酶法测定血清二氧化碳的方法学比较

目的：对量压法和酶法检测血清二氧化碳的方法学进行比较,分析两种方法测定血清二氧化碳有无显著性差异。方法依据美国国家临床实验室标准委员会（NCCLS）制定的有关文件,用量压法与酶法分别测定血清二氧化碳100例,运用两种方法检测血清二氧化碳的浓度,计算相关系数r和线性回归方程,并验证两种方法的可比性、精密度和线性关系。结果量压法和酶法相关性比较的回归方程为Y=0.8149X＋4.7625,相关系数r=0.9133,差异有统计学意义（P〈0.001）;量压法测定血清中的二氧化碳浓度为（22.68±2.03） mmol/L,酶法为（23.24±1.81） mmol/L,说明量压法与酶法测定血清CO2浓度的差异无统计学意义（P〉0.001）;两种方法的批内和批间精密度均〈5%。结论量压法与酶法测定血清中CO2的相关性、线性和精密度均较好,测定结果具有可比性,可以为临床所接受。     

Cardiocirculatory responses to AII and AVP in conscious rats.

Cardiac and peripheral circulatory responses to changes in afterload with angiotensin II (AII) and vasopressin (AVP) were investigated in ganglion-blocked (hexamethonium) conscious rats. Cardiac output (CO) was measured by thermodilution. Both hormones were infused at a dose adjusted to increase mean arterial pressure 70% above baseline. AVP (11.4 +/- 2.2 ng/kg/min, n = 6) decreased CO from 43.4 +/- 2.3 to 34.1 +/- 2.9 ml/min/100 g (p less than 0.001), whereas AII (33.4 +/- 7.4 ng/kg/min, n = 7) increased CO from 38.7 +/- 2.6 to 44.9 +/- 3.4 ml/min/100 g (p less than 0.01). Heart rate did not change with the increase in afterload with either vasoconstrictor. To study whether the different effects of AII and AVP on CO may be explained by their different actions on the venous system, changes in venous tone were evaluated by measuring mean circulatory filling pressure (MCFP) and determining the pressure gradient for venous return (PGVR). AVP changed neither MCFP nor PGVR, whereas AII increased both these parameters, 20.7 +/- 2.8% (p less than 0.01) and 20.3 +/- 6.4% (p less than 0.01), respectively, above control. We also examined the effects of AII and AVP on ventricular dynamics: left ventricular systolic pressure and left ventricular dP/dtmax increased as aortic pressure was increased in a similar manner with both vasoconstrictors. However, AVP induced a greater increase in left ventricular end diastolic pressure than AII. Our results indicate that AII induces an increase in preload by its effect on venous tone, which is adequate to increase cardiac output. The decrease in cardiac output induced by increasing afterload with AVP can be explained by two mechanisms: an inadequate venous return and a failure of the left ventricle to overcome the increased afterload.     

THE EFFECTS OF AN HISTAMINE H2-RECEPTOR AGONIST, IMPROMIDINE (SK & F 92676), ON THE GENERAL AND CARDIAC HAEMODYNAMICS OF THE INTACT DOG

The effects of impromidine (16 nmol/kg intravenously) were studied in the general and coronary circulations of the intact anaesthetized dog. The drug caused tachycardia, increased cardiac output and coronary sinus flow, and induced minor changes in systemic and pulmonary arterial pressures. It increased left and right ventricular work, and decreased calculated resistance values in the greater and lesser circulations. Coronary vascular resistance fell, cardiac O₂ extraction increased. These changes were substantially prevented by treatment with cimetidine. The action of an H₂-receptor agonist then is associated with a general and coronary vasodilator response, with maintenance of calculated cardiac efficiency.     

HAEMODYNAMIC EFFECTS OF LONG-TERM ENDOTHELIN INFUSION IN CONSCIOUS SHEEP

1. Synthetic human endothelin-1 was infused intravenously at 15 micrograms/h for 24 h to examine its cardiovascular actions in five conscious sheep. 2. Endothelin produced a maximum increase in mean arterial pressure (MAP) of +8 mmHg at 8 h, with an increase in calculated total peripheral resistance (CTPR) of +2.6 mmHg/L per min, whilst cardiac output (CO) was unchanged. At 24 h MAP was not significantly elevated, however CTPR had increased by +2.8 mmHg/L per min and CO had decreased by 0.9 L/min. 3. This study shows that long-term administration of endothelin produces sustained arterial vasoconstriction in sheep.