A new method for noninvasive bedside determination of pulmonary blood flow

A method is presented for determining the pulmonary blood flow from measurements of the time-averaged end-tidal pCO₂ and the CO₂ output. The novel technique is based on a formula that is derived from Fick's principle in such a way that it allows a direct calculation of the lung perfusion from simultaneously measured changes in end-tidal pCO₂ and CO₂ output. These changes are induced by altering the ventilation pattern of the patient for short (30s) periods of time. Different ways of doing this are discussed and it is shown that a bidirectional change in ventilation, involving hyper- and hypoventilation patterns, most adequately corresponds to the formula derived. The method has been validated by comparison with cardiac output data obtained by thermodilution. Forty-two measurements were performed during mechanical ventilation on five dogs and six patients with essentially healthy lungs. Lung perfusion was in the range 0·4–6·5l/min. We found that Q_{CO 2}=0·97 Q_thermo with a s.d.=18%. The reproducibility of individual measurements was better than 0·3l/min.     

Non-invasive assessment of cardiac output and stroke volume in patients during exercise

Summary A one-step CO₂ rebreathing method for the determination of cardiac output and stroke volume (SV) has been evaluated by comparison with the direct Fick technique during recumbent exercise (10–90 W) in 13 patients. In an initial analysis, the influence of different rebreathing times and of correction for haemoglobin concentration was studied. The best correlation with the direct Fick technique was obtained with the longest analysis time, i. e. 21 s, and correction for variations in haemoglobin concentration further improved the correlation. Consequently, an analysis time of 21 s and correction for haemoglobin have been used. At low cardiac outputs, the CO₂-rebreathing method overestimated the flow compared to the Fick technique. The correlation between the methods, however, was so good that a valid estimate of cardiac output could be obtained from the CO₂ rebreathing method with appropriate corrections (Cardiac output, CO₂ method=2.7+0.77. Cardiac output, Fick; r=0.91; Residual Standard deviation (SD res) =0.77 l · min⁻¹). Stroke volumes measured with the CO₂ rebreathing method did not differ significantly from those obtained with the direct Fick technique, although there was a tendency to overestimate stroke volume with the CO₂ rebreathing method (SV, CO₂ method=12+0.89 · SV, Fick; r=0.82; SD res=11 ml).     

Beeinflussung von Gasaustausch und Metabolismus durch unterschiedliche Hämodialyseverfahren

Summary We compared the effects of various dialysate composition on pulmonary and transdialyzer gas exchange in patients during hemodialysis. Under acetate hemodialysis there was a permanent loss of CO₂ (45–68 ml/min) into the dialysate resulting in a significant decrease of arterial pO₂, which can be explained by a reduced alveolar ventilation. The pulmonary oxygen uptake increased up to +20% during treatment, reflecting rising energy metabolism and possibly increased cardiopulmonary instability.Using different concentrates for bicarbonatehemodialysis we saw a moderate to clinical relevant uptake of CO₂ (40–60 ml/min) from the dialysate into the blood of the patients, cause the pCO₂ in the dialysate varied between 45 and 115 mmHg.Bicarbonate hemodialysis with high pCO₂-levels in the dialysate led to hyperventilation and markedly increased oxygen consumption. In critically ill hemodialysis patients the pathophysiologic effects on pulmonary gas exchange of either acetatehemodialysis and bicarbonatehemodialysis with high pCO₂ can explain the higher incidence of severe complications.

Herrn Professor Dr. F. Scheler zu seinem 65. Geburtstag gewidmet     

Ventilatory response to oscillating and non-oscillatingPa CO 2 in the anesthetized cat

Summary In 11 adult cats, lightly anesthetized with chloralose-urethane, blood from both common carotid arteries was led into a plastic chamber of 15–20 ml and returned to the carotids at a point 1.5 cm more cranial. By doing so arterial blood was assumed to pool within the chamber and lose itsP _{CO 2} oscillations which are normally known to exist as a result of the respiratory cycle. In control periods blood bypassed the chamber, thus maintaining respiratoryP _{CO 2} oscillations. Spontaneous ventilation was measured spirometrically. The animals were breathing pure O₂.Results. 1. When the sinus (carotid) nerves were intact or sectioned there was no significant difference in ventilation before or after switching from non-oscillating to oscillatingPa _{CO 2}. 2. When the vertebral arteries were ligated a drop in ventilation occurred after turning to oscillatingPa _{CO 2} which was followed by a slight rise above control values after 30–50 sec. This phenomenon was independent of sinus nerve integrity. Thus in hyperoxie condition the smallPa _{CO 2} oscillations known to occur in phase with respiration do not seem to provide a respiratory stimulus to resting ventilation above that generated by the mean level ofPa _{CO 2}. The ventilatory depression after vertebral artery ligation must at this time remain unexplained.     

Effect of prostaglandin B1 on the systemic and regional hemodynamics

The effect of prostaglandin B₁ (PGB₁) on the cardiovascular system was studied in experiments on anesthetized dogs. After intravenous injection of PGB₁ (40 g/kg in a single dose) arterial hypotension tachycardia, increased myocardial contractility, an increased cardiac output, and a rise of pressure in the pulmonary artery were observed. The total peripheral resistance and total pulmonary resistance were reduced. The work of the right and left ventricles was increased. The coronary blood flow was increased by 29%. The mean velocity of the volume blood flow in the renal and femoral arteries was appreciably increased after administration of PGB₁, but in the common carotid and superior mesenteric arteries the increase was not significant. Changes in the systemic and regional hemodynamics were of short duration.Department of Pharmacology, I. M. Sechenov First Moscow Medical Institute. Department of Anesthesiology, Institute of Clinical and Experimental Surgery, Ministry of Health of the USSR, Moscow. (Presented by Academician of the Academy of Medical Sciences of the USSR V. V. Zakusov.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 83, No. 2, pp. 131–133, February, 1977.     

Does the threshold of transcutaneous partial pressure of carbon dioxide represent the respiratory compensation point or anaerobic threshold?

On reaching the respiratory compensation point (RCP) during rapidly increasing incremental exercise, the ratio of minute ventilation (V_E) to CO₂ output (VCO₂) rises, which coincides with changes of arterial partial pressure of carbon dioxide (P _aCO₂). Since P _aCO₂ changes can be monitored by transcutaneous partial pressure of carbon dioxide (PCO_2,tc) RCP may be estimated by PCO_2,tc measurement. Few available studies, however, have dealt with comparisons between PCO_2,tc threshold (T _AT) and lactic, ventilatory or gas exchange threshold (V _AT), and the results have been conflicting. This study was designed to examine whether this threshold represents RCP rather than V _AT. A group of 11 male athletes performed incremental excercise (25 W · min^–1) on a cycle ergometer. The PCO_2,tc at (44°C) was continuously measured. Gas exchange was computed breath-by-breath, and hyperaemized capillary blood for lactate concentration ([la^–]_b) and P _aCO₂ measurements was sampled each 2 min. The T _AT was determined at the deflection point of PCO_2,tc curve where PCO_2,tc began to decrease continuously. The V _AT and RCP were evaluated with VCO₂ compared with oxygen uptake (VO₂) and V_E compared with the VCO₂ method, respectively. The PCO_2,tc correlated with P _aCO₂ and end-tidal PCO₂. At T _AT, power output [P, 294 (SD 40) W], VO₂ [4.18 (SD 0.57)l · min^–1] and [la^–] [4.40 (SD 0.64) mmol · l^–1] were significantly higher than those at V _AT[P 242 (SD 26) W, VO₂ 3.56 (SD 0.53) l · min^–1 and [la^–]_b 3.52 (SD 0.75), mmol · l^–1 respectively], but close to those at RCP [P 289 (SD 37) W; VO₂ 3.97 (SD 0.43) l · min^– and [la^–]_b 4.19 (SD 0.62) mmol · l^–1, respectively]. Accordingly, linear correlation and regression analyses showed that P, VO₂ and [la^–]_b at T _AT were closer to those at RCP than at V _AT. In conclusion, the T _AT reflected the RCP rather than V _AT during rapidly increasing incremental exercise.     

Serial observations of arterial and mixed-venous blood gases after step change in ventilation

Summary In 22 dogs, subjected to a step change in ventilation, serial changes in blood gas composition and lactate and pyruvate concentrations of arterial as well as mixed venous blood were studied. The change of was approximately 20 mm Hg both in hypo- and hyperventilation. During hypoventilation the difference in various forms of CO₂ between arterial and mixed venous blood showed first a downward shift and then gradually increased, whereas during hyperventilation they progressively increased and reached a constant level within 10–20 min. This difference was assumed to be mainly due to more efficient CO₂ elimination through lung ventilation in hyperventilation as compared with CO₂ accumulation from tissue metabolism in hypoventilation.In vivo buffer slopes for CO₂ during hypoventilation were about half those in vitro, whereas during hyperventilation both slopes were approximately the same. In vivo arterial buffer slope was higher during hypoventilation and lower during hyperventilation as compared to that of mixed venous blood in the respective state of ventilation.This word was supported in part by a research grant from the Ministry of Education of Japan (857025).     

Erythrocyte volume in acifified venous blood from exercising limbs

Summary Fatiguing muscular exercise of short duration (7–9 min) with the arms produced large increments ofpCO₂ (>+30 mm Hg) and hydrogen ion concentration in venous blood from the working limbs. On the basis of these biochemical changes it might be expected to find a volumetric increase in the red cell of venous blood, since more osmotically active ions entered the erythrocytes through the chloride shift mechanism.However simultaneous measurements of mean corpuscular red cell volume (MVC) and mean corpuscular hemoglobin concentration (MCHC) failed to demonstrate a measurable change in the size of the erythrocyte in the acidified venous blood. The concomitantly determined significant elevation of the plasma osmolarity (+7.7%) suggests that in vivo the human red cells from venous blood in exercising limbs maintain a constant volume through counteracting osmotic forces in spite of large hematological changes.Supported by NASA Grant NGR 26-006-039     

CO2 responsivity in the mouse measured by rebreathing

We have modified the rebreathing method to study CO₂ responsivity in very small mammals. Tidal volume (V _T) and frequency (f) of pentobarbital-anesthetized mice were measured during rebreathing from a closed circuit, primed with 95% O₂, 5% CO₂, through which the gas was constantly circulated at 0.5 l·min^–1. The circuit consisted of T-tube from a plethysmograph, Tygon tubing with compliant element, CO₂ analyzer and pump, in series. CircuitPCO₂ (PctCO₂), which was recorded continuously during spontaneous breathing, rapidly equilibrated with end-tidalPCO₂. CO₂ response curves were constructed from extrapolated minute ventilation ( ),V _T,f and parameters of breath-to-breath timing, respectively, onPctCO₂. Analyses of slopes of the response curves, change from onset of rebreathing to peak response, andPctCO₂ at which the response peaked revealed that CO₂ stimulates by increasingf andV _T and that this is effected by facilitation of central inspiratory-expiratory phase switching and inspiratory drive mechanisms. However, the stimulatory effect of CO₂ on phase switching was not sustained, with maximal effect occurring before peak . The advantages and facility of the modified rebreathing method make it suitable for studies of other small mammals, including neonates.     

The influence of hyperventilation on the measurement of stroke volume using a CO2 rebreathing method

Summary The influence of different degrees of hyperventilation on stroke volume measured with a CO₂ rebreathing method was studied in seven normal subjects and seven patients with aortic regurgitation. Hyperventilation was initially performed with a rebreathing rate of 30 min^–1 and a tidal volume corresponding to 60% of the subject's vital capacity. The tidal volume was then randomly decreased or increased by 0.5 and 1.01 and the procedure was repeated with rebreathing rates of 25 and 35 min^–1. The possible influence of habituation to repeated measurements was tested in seven of the subjects. No significant differences in response to hyperventilation of stroke volume, cardiac output or heart rate were found between normal subjects and patients. When the tidal volume was increased, there was a significant increase in heart rate and also an increase in cardiac output, which was significant when comparing measurements performed with the lowest and highest tidal volumes. When comparing initial and final measurements, there was a significant decrease in heart rate and a tendency to decrease in cardiac output. Stroke volume was not affected by variations in rebreathing rate from 25 to 35 min^–1 or tidal volume changes of ±0.51 and was also unaffected by repeated measurements.     

Reliability of the cardiac output measurement with the indirect Fick-principle for CO2 during exercise

Cardiac output measurements were performed during 50 exercise tests in 16 normal subjects employing the indirect Fick principle for CO₂. During sub-maximal steady state exercise the plateau CO₂ tension ( ) was estimated with a rebreathing procedure. The mixed venous CO₂ tension ( ) was calculated by subtracting the alveolocapillary CO₂ tension difference from the . Compared with data from the literature the most valid calculation of the cardiac output was obtained by using the . Cardiac output values, calculated via the turned out to be too low.The reproducibility was tested by repitition of 18 exercise tests at least after 5 days. The relative standard error of a single observation was 4.1% for the cardiac output, which was found to be as good as that of invasive measurements.     

Exocrine ductalpCO2 in the rabbit pancreas

An improvedpCO₂ microelectrode has been evaluated and used to investigate whether a significant barrier to diffusion of CO₂ exists in the rabbit pancreas. The results of this study show the improved Carter and CaflischpCO₂ microelectrode to be an accurate and reliable tool for measuring pancreatic venous and ductalpCO₂. The similarities betweenpCO₂ values from the pancreatic ducts and small pancreatic veins suggest that there is no barrier to CO₂ diffusion between small veins and exocrine ducts in the rabbit pancreas, and that ductalpCO₂ is probably strongly influenced by the CO₂ tension of the small pancreatic blood vessels.     

CO2 inhibition of the generation of reactive oxygen species in cells of internal organs and its biological importance

Carbon dioxide is shown to inhibit the generation of superoxide anion radical in bioptates both directly exposed to CO₂ and after preliminary exposure of the whole organism to CO₂. A similar effect is noted for gas mixtures similar in composition to arterial and venous blood. The results substantiate the important evolutionary role of CO₂ for the maintenance of life on Earth with the appearance of potentially toxic oxygen. Translated from Byulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 121, No. 4, pp. 407–410, April, 1996 Presented by F. I. Komarov, Member of the Russian Academy of Medical Sciences     

Ventilatory CO2 response in endurance-trained rats

Summary A CO₂ rebreathing technique was used to assess possible changes in the ventilatory response to CO₂ in rats following a 14-week swim training program. Over the final 9 weeks, the rats swam 1 h per day with a weight of 2.5% of the body weight attached to the tail. Ventilation was measured by a barometric method in awake, restrained rats in a total body plethysmograph at CO₂ concentrations of 0, 2, 4, 6, and 8%, with an initial O₂ concentration of approximately 100%. Ventilation increased in the trained rats with increasing CO₂ from 775 ml·min^–1·kg^–1 at 0% CO₂ to 1,387 ml·min^–1·kg^–1 at 8% CO₂. This increase was a consequence of a 34% increase in tidal volume and a 32% increase in breathing frequency. In comparison with a group of sedentary control rats, there was a significantly higher ventilation and tidal volume at 0% CO₂; however, this difference disappeared with increasing levels of CO₂. A significantly lower resting heart rate was observed in the exercised (296±44 beats·min^–1, mean±SD) compared to the sedentary control rats (380±42). It was concluded that, while the normal training response of resting bradycardia was observed following this duration and intensity of training, endurance swimming had no significant effect on the ventilatory response to CO₂ in the rat.This research was funded in part by grants from the University of Waterloo Research Foundation, the Ontario Heart Foundation, and the Medical Research Council of Canada     

Carbon dioxide sensitivity of the central chemosensitive mechanisms

Summary In urethane-anaesthetised adult albino rats ventral surface of the brainstem was stimulated chemically by increasing the local CO₂ concentration and electrically. Two areas were demarcated on the ventral surface of the brainstem, one which showed an increase in pulmonary ventilation on chemical and electrical stimulation, and another which showed a decrease in pulmonary ventilation and sometimes even respiratory arrest. EEG activity recorded from the area from where increased pulmonary ventilation was obtained showed a synchronous slow wave activity during chemical stimulation and inhalation of a CO₂-air mixture. This area is situated 0.5–1 mm lateral to the mid-line extending up to the rootlets of the VIIth to IXth cranial nerves. The response increased proportionately on increasing the strength of the chemical stimulus, till it reached a plateau. In carotid body denervated and chronic hypoxic animals, the magnitude of the responses was shown to be increased, probably due to increased sensitivity of the central chemosensitive mechanisms.     

CO2 Pressure in mixed venous blood measured incruently

Summary In a subject rebreathing in a small bag, the rate of increase of Paco₂ is, within a circulation time, linear function of PA_{co 2} itself; by graphical extrapolation of this function, experimentally obtained using a rapid CO₂ meter, the CO₂ pressure of mixed venous blood may be obtained; the values of PacO₂ VO ₂ R being determined, the values of A-V difference and therefore of cardiac output can be obtained.The detailed experimental procedure is described.     

An evaluation of exercise cardiac output using the CO2 rebreathing extrapolation technique

We investigated the reproducibility of the carbon dioxide (CO₂) rebreathing extrapolation technique of Defares to determine the mixed venous partial pressure of CO₂ (P _vCO₂) using a direct, rather than the commonly used indirect, extrapolation method. The P _vCO₂ determinations were made five times a day on four subjects who exercised for 4?h daily on a bicycle ergometer over a period of 13?days. The concentration of CO₂ in the rebreathing bag was monitored continuously using a rapid-response infrared capnograph. The mean standard deviation was 1.56?mmHg (0.21 kPa) for a mean P _vCO₂ of 47.6?mmHg (6.3?kPa), giving a mean coefficient of variation of 3.3%. This level of reproducibility agrees favourably with the reliability of direct measurements of pulmonary arterial partial pressure of CO₂. We conclude that the CO₂ rebreathing extrapolation technique can give reproducible P _vCO₂ values when a direct method of extrapolation is used.     

Effect of alteration of peripheral blood flow on the central circulation in man during supine cycling in different ambient temperatures

Summary Whether the alteration of peripheral circulation caused by changing ambient temperature (T_a) affects central circulatory changes in man during supine cycling was investigated in four well-trained men, who exercised at two levels (117.7 or 176.6 W). Exercise metabolic rate (VO₂) in cold (0 C or 10 C) was the same as it was at 20 C, whereas the cardiac output (CO; CO₂ rebreathing technique) and heart rate were significantly lower (e.g., 176.6 W at 0 C, both p<0.01). In heat (30 C or 40 C), the VO₂ reduced with falling CO and mean arterial blood pressure from those at 20 C (e.g., 176.6 W at 40 C, all cases p<0.01), whereas the peak post-exercise calf blood flow (CBF_p) increased (p<0.01). The VO₂ and stroke volume (SV) were inversely proportional to the ratio of CBF_p to CO/kg body weight (CBF_p/CO) (r>–0.78, p<0.001). Total peripheral resistance (TPR) was related to arteriovenous oxygen difference (A-VO₂ difference) (r>0.78, p<0.001). The TPR and A-VO₂ difference decreased as T_a rose, while CBF_p/CO was almost the same. As CBF_p/CO had exceeded 50 and further progressed, however, the two parameters elevated until the same level as that at 0 C. The present results suggest that during moderately prolonged (16–60 min) supine cycling in different T_a's the central circulatory changes are mainly affected by the altered peripheral blood flow in competing between skin and muscle for blood flow.     

The involvement of expiratory termination in the vagally mediated facilitation of ventilatory CO2 responsiveness during hyperoxia

In anaesthetized rabbits the influence of differential vagal cold blockade on the ventilatory response to inhaled CO₂ during hyperoxia was investigated.Following total inactivation, the relationship between ventilation ( ) and arterialPCO₂ (P _aCO₂) was shifted to the left and steepened slightly over a range of modest hypercapnia, but was progressively flattened as hypercapnia intensified. The latter effect, suggestive of a vagally mediated facilitation of ventilatory CO₂ responsiveness, was studied further.Differential vagal cold blockade to a temperature (5–11°C) which abolished the Breuer-Hering inflation reflex (end-inspiratory tracheal occlusion no longer eliciting a prolongation of expiratory duration,T _E) had no effect on either during normocapnia or at a substantial level of hypercapnia. Only with further vagal cooling to 0°C did the ventilatory depression during hypercapnia emerge, largely becauseT _E failed to shorten in response to the hypercapnic stimulus.It is concluded that the integrity of expiratory-terminating mechanisms is crucial for the manifestation of the vagally mediated facilitation of and its CO₂ responsiveness which is evident during hyperoxic hypercapnia. A possible role is suggested for lung epithelial irritant receptors or for the tonic late-expiratory activity from pulmonary stretch receptors.Supported by the Deutsche Forschungsgemeinschaft, SFB 114Preliminary reports of this work have been presented in Pflügers Arch 355: (Suppl) R47 (1975); 377: (Suppl) R54 (1978) and in Proc. XXVIII. Int. Congr. of Physiol. Sciences, Budapest, Vol VIV, 515 (1980)     

Sensation and control of breathing: A dynamic model

A dynamic model of the CO₂ respiratory control system is proposed, which can provide a qualitative basis for predicting breathing sensations. The discomfort index, which represents breathing sensations, is assumed to be composed of two sources: the arterial CO₂ level and the respiratory motor command. The respiratory controller receives inhibitory neuromechanical and excitatory CO₂ signals from the plant. The CO₂ signal is enhanced by exercise stimuli. This dynamic multiplicative-type controller is used in simulations of key experiments: exercise and CO₂ rebreathing with and without resistive loading. The dynamics of the discomfor index, the respiratory motor command, ventilation, and arterial CO₂ concentration conform to the experimental data. The perceptual sensitivity to CO₂ relative to respiratory effort is significantly correlated with the slope of hypercapnic ventilatory response. This result shows a clear linkage between ventilatory response and breathing sensations. Although it is shown that the automatic controller effectively minimizes the discomfort index for perturbations about an operating point under certain conditions, the discomfort index itself does not seem to be an underlying control principle of the proposed automatic controller model. Rather, breathing sensations may influence ventilatory responses by modifying the output of the automatic controller.