Clinical validation of a capnodynamic method for measuring end-expiratory lung volume in critically ill patients.

RATIONALE: End-expiratory lung volume (EELV) is reduced in mechanically ventilated patients, especially in pathologic conditions. The resulting heterogeneous distribution of ventilation increases the risk for ventilation induced lung injury. Clinical measurement of EELV however, remains difficult. OBJECTIVE: Validation of a novel continuous capnodynamic method based on expired carbon dioxide (CO2) kinetics for measuring EELV in mechanically ventilated critically-ill patients. METHODS: Prospective study of mechanically ventilated patients scheduled for a diagnostic computed tomography exploration. Comparisons were made between absolute and corrected EELVCO2 values, the latter accounting for the amount of CO2 dissolved in lung tissue, with the reference EELV measured by computed tomography (EELVCT). Uncorrected and corrected EELVCO2 was compared with total CT volume (density compartments between - 1000 and 0 Hounsfield units (HU) and functional CT volume, including density compartments of - 1000 to - 200HU eliminating regions of increased shunt. We used comparative statistics including correlations and measurement of accuracy and precision by the Bland Altman method. MEASUREMENTS AND MAIN RESULTS: Of the 46 patients included in the final analysis, 25 had a diagnosis of ARDS (24 of which COVID-19). Both EELVCT and EELVCO2 were significantly reduced (39 and 40% respectively) when compared with theoretical values of functional residual capacity (p < 0.0001). Uncorrected EELVCO2 tended to overestimate EELVCT with a correlation r2 0.58; Bias - 285 and limits of agreement (LoA) (+ 513 to - 1083; 95% CI) ml. Agreement improved for the corrected EELVCO2 to a Bias of - 23 and LoA of (+ 763 to - 716; 95% CI) ml. The best agreement of the method was obtained by comparison of corrected EELVCO2 with functional EELVCT with a r2 of 0.59; Bias - 2.75 (+ 755 to - 761; 95% CI) ml. We did not observe major differences in the performance of the method between ARDS (most of them COVID related) and non-ARDS patients. CONCLUSION: In this first validation in critically ill patients, the capnodynamic method provided good estimates of both total and functional EELV. Bias improved after correcting EELVCO2 for extra-alveolar CO2 content when compared with CT estimated volume. If confirmed in further validations EELVCO2 may become an attractive monitoring option for continuously monitor EELV in critically ill mechanically ventilated patients. TRIAL REGISTRATION: clinicaltrials.gov (NCT04045262).

Capnodynamic monitoring of lung volume and pulmonary blood flow during alveolar recruitment: a prospective observational study in postoperative cardiac patients.

Alveolar recruitment manoeuvres may mitigate ventilation and perfusion mismatch after cardiac surgery. Monitoring the efficacy of recruitment manoeuvres should provide concurrent information on pulmonary and cardiac changes. This study in postoperative cardiac patients applied capnodynamic monitoring of changes in end-expiratory lung volume and effective pulmonary blood flow. Alveolar recruitment was performed by incremental increases in positive end-expiratory pressure (PEEP) to a maximum of 15 cmH2O from a baseline of 5 cmH2O over 30 min. The change in systemic oxygen delivery index after the recruitment manoeuvre was used to identify responders (> 10% increase) with all other changes (≤ 10%) denoting non-responders. Mixed factor ANOVA using Bonferroni correction for multiple comparisons was used to denote significant changes (p < 0.05) reported as mean differences and 95% CI. Changes in end-expiratory lung volume and effective pulmonary blood flow were correlated using Pearson's regression. Twenty-seven (42%) of 64 patients were responders increasing oxygen delivery index by 172 (95% CI 61-2984) mL min-1 m-2 (p < 0.001). End-expiratory lung volume increased by 549 (95% CI 220-1116) mL (p = 0.042) in responders associated with an increase in effective pulmonary blood flow of 1140 (95% CI 435-2146) mL min-1 (p = 0.012) compared to non-responders. A positive correlation (r = 0.79, 95% CI 0.5-0.90, p < 0.001) between increased end-expiratory lung volume and effective pulmonary blood flow was only observed in responders. Changes in oxygen delivery index after lung recruitment were correlated to changes in end-expiratory lung volume (r = 0.39, 95% CI 0.16-0.59, p = 0.002) and effective pulmonary blood flow (r = 0.60, 95% CI 0.41-0.74, p < 0.001). Capnodynamic monitoring of end-expiratory lung volume and effective pulmonary blood flow early in postoperative cardiac patients identified a characteristic parallel increase in both lung volume and perfusion after the recruitment manoeuvre in patients with a significant increase in oxygen delivery.Trial registration This study was registered on ClinicalTrials.gov (NCT05082168, 18th of October 2021).

Capnodynamic determination of cardiac output in hypoxia-induced pulmonary hypertension in pigs.

BACKGROUND: Effective pulmonary blood flow (COEPBF) has recently been validated for its ability to measure cardiac output (CO) in children and animals. This study compared COEPBF with the Fick method (COFick) and CO measurements using an invasive pulmonary artery flow probe (COTS). The aim of the study was to validate COEPBF against these reference methods in a porcine model of hypoxia-induced selective pulmonary hypertension. METHODS: Ten anaesthetised mechanically ventilated piglets (median weight 23.9 kg) were exposed to a hypoxic gas mixture inducing selective pulmonary hypertension. Pulmonary hypertension was subsequently reversed with inhaled nitric oxide. Simultaneous recordings of COEPBF, COFick, and COTS were performed throughout the protocol and examined for agreement and trending ability. RESULTS: Overall bias (Bland-Altman) between COEPBF and COTS was 0.2 L min-1 (limits of agreement -0.5 and +0.9 L min-1) with a mean percentage error of 25%. Overall bias between COEPBF and COFick was -0.1 L min-1 (limits of agreement -0.9 and +0.6 L min-1) and a mean percentage error of 25%. The concordance rate was 86% for COEPBF when compared with COTS using a 10% exclusion zone. CONCLUSIONS: Estimation of CO with COEPBF results in values very close to the gold standard reference methods COFick and COTS. COEPBF appears to be an accurate tool for monitoring absolute values and changes in CO during hypoxia-induced pulmonary hypertension and inhaled nitric oxide treatment.

Validation of capnodynamic determination of cardiac output by measuring effective pulmonary blood flow: a study in anaesthetised children and piglets.

BACKGROUND: Effective pulmonary blood flow (COEPBF) has recently been validated as a technique for determining cardiac output (CO) in animals of varying sizes. The primary aim of our study was to investigate this new technique in paediatric surgical patients, compared with suprasternal two-dimensional Doppler (COSSD). METHODS: A total of 15 children undergoing cleft lip/palate surgery were investigated. Before the start of surgery, manoeuvres that were anticipated to reduce (increase in PEEP from 3 to 10 cm H2O) and increase (atropine) CO were undertaken. A study in mechanically ventilated piglets was also undertaken under general anaesthesia, measuring COEPBF and pulmonary artery (COTS) flow by ultrasonic probe as the comparator. Bias (Bland-Altman plots) and limits of agreement were assessed for effective pulmonary blood flow and COSSD or COTS. RESULTS: In paediatric patients (median age 8.5 months), overall bias was -8.1 (limits of agreement -82 to +66) ml kg-1 min-1, with a mean percentage error of 48% and a concordance rate of 64%. In the piglet model, overall bias was -1 (-36 to +38) ml kg-1 min-1, with a mean percentage error of 31% and a concordance rate of 95%. CONCLUSIONS: Under controlled experimental conditions, COEPBF is associated with excellent agreement and good trending ability when compared with the gold standard COTS. In the paediatric clinical setting, COEPBF performs well; by contrast, COSSD, an operator- and anatomy-dependent technology, appears less reliable than COEPBF.

A novel continuous capnodynamic method for cardiac output assessment in a porcine model of lung lavage.

BACKGROUND: We have evaluated a new method for continuous monitoring of effective pulmonary blood flow (COEPBF ), i.e. cardiac output (CO) minus intra-pulmonary shunt, during mechanical ventilation. The method has shown good trending ability during severe hemodynamic challenges in a porcine model with intact lungs. In this study, we further evaluate the COEPBF method in a model of lung lavage. METHODS: COEPBF was compared to a reference method for CO during hemodynamic and PEEP alterations, 5 and 12 cmH2 O, before and after repeated lung lavages in 10 anaesthetised pigs. Bland-Altman, four-quadrant and polar plot methodologies were used to determine agreement and trending ability. RESULTS: After lung lavage at PEEP 5 cmH2 O, the ratio of arterial oxygen partial pressure related to inspired fraction of oxygen significantly decreased. The mean difference (limits of agreement) between methods changed from 0.2 (-1.1 to 1.5) to -0.9 (-3.6 to 1.9) l/min and percentage error increased from 34% to 70%. Trending ability remained good according to the four-quadrant plot (concordance rate 94%), whereas mean angular bias increased from 4° to -16° when using the polar plot methodology. CONCLUSION: Both agreement and precision of COEPBF were impaired in relation to CO when the shunt fraction was increased after lavage at PEEP 5 cmH2 O. However, trending ability remained good as assessed by the four-quadrant plot, whereas the mean polar angle, calculated by the polar plot, was wide.

Novel continuous capnodynamic method for cardiac output assessment during mechanical ventilation.

BACKGROUND: It is important to be able to accurately monitor cardiac output (CO) during high-risk surgery and in critically ill patients. The invasiveness of the pulmonary artery catheter (PAC) limits its use, and therefore, new minimally invasive methods for CO monitoring are needed. A potential method is estimation of CO from endogenous carbon dioxide measurements, using a differentiated Fick's principle to determine effective pulmonary blood flow (EPBF). In this study, we aimed to validate a novel capnodynamic method (COEPBF) in a wide range of clinically relevant haemodynamic conditions. METHODS: COEPBF was studied in 10 pigs during changes in preload, afterload, CO increase, and bleeding. An ultrasonic flow probe around the pulmonary artery was used as reference method of CO determination. CO was also measured using a PAC thermodilution technique (COPAC). CO and other haemodynamic data were recorded before and during each intervention. Accuracy and precision and also the ability to track changes in CO were determined using Bland-Altman, four-quadrant plot and polar plot analysis. RESULTS: COEPBF and COPAC showed equally good agreement, with a tendency to overestimate CO (bias 0.2 and 0.3 litre min(-1), respectively). The overall percentage error was 47% for COEPBF and 49% for COPAC. The concordance for tracking CO changes was 97 and 95% for COEPBF and COPAC, respectively, with an exclusion zone of 15% and radial limits of ±30°. CONCLUSIONS: COEPBF showed reliable trending abilities, equivalent to COPAC. COEPBF and COPAC also showed low bias but high percentage errors. Further studies in animal models of lung injury and in high-risk surgery patients are warranted.

Cardiovascular reactivity and design in rats with experimental "neurogenic hypertension".

The arterial barorecptors were denervated in 20 normotensive Wistar rats. 2 1/2 months after the operation their cardiovascular responses to "mental stress" were compared to those of matched control rats (NCR). At the time of investigation the blood pressure of the baroreceptor denervated rats (BDR) was increased some 15 per cent above that of the control group. There was, however, no difference in response to "mental stress" between groups, if anything the BDR reponded with less pronounced tachycardia. Two months subsequent to the stress-test the men blood pressure of the BDR was still significantly above normal levels, but the BDR did not exhibit structural cardiovascular adaptation, which has been documented in most types of stable hypertension as a response to the increased mean blood pressure. The results imply that hypertension induced by baroreceptor denervation is not of a stable and persistent type in which case structural changes in the cardiovascular system would have developed within the observation period (approximately 4 months). Emotional stimuli, however, do not seem to contribute to periodic blood pressure increase at the time of measurement, as earlier suggested.

Haemodynamic changes during tilt after autonomic blockade in spontaneously hypertensive rats.

The haemodynamic shifts during head up and head down tilt were investigated in adult spontaneously hypertensive rats (SHR) and matched normotensive control rats (NCR) under nembutal anaesthesia and autonomic blockage. During head up tilt a greater fall in blood pressure and stroke volume was observed in SHR than in NCR, while the reverse was true when tilted in the opposite direction. This altered cardiac response to venous filling, also observed in patients with essential hypertension, is suggested to be caused by an altered Frank-Starling relationship of the hypertrophied heart in hypertensive individuals.

Dependence on external calcium for the noradrenaline contractility of the resistance vessels in spontaneously hypertensive and renal hypertensive rats, as compared with normotensive controls.

Isolated hindquarters of rats were perfused at constant flow with a plasma substitute so that pressor responses to various concentrations of noradrenaline (NA) could be measured in consective sections of the vascular bed with normal (greater than 1.5 mM) or low (0.2 mM) Ca2+ in the perfusate. The animals used were 6-week-old spontaneously hypertensive rats of the Okamoto strin (SHRy), normotensive controls of the same age NCRy); 6--7-month-old SHR (SHRA) and NCR (NCRA); and rats made hypertensive by clipping of one renal artery (RHR) plus matched normotensive controls (NCRR). Concentration-response curves to NA showed that constrictor responses to NA become more dependent on external calcium as one proceeds peripherally in the vascular system in both SHRA and NCRA, with responses in proximal vessels being least and small pre- and postcapillary vessels being most dependent in both cases. In low calcium SHRA retained their responses better than NCRA, whereas RHR retained their responses to NA poorer than did NCRR. No significant differences in responses in low calcium were observed in SHRY compared to NCRY though a trend in the same direction as in SHRA could be traced. It is concluded that there is no evidence that altered handling of calcium initiates vascular hyperreactivity in SHR, but that the handling of vascular calcium in SHR differs from RHR and both differ from NCR.

Oxygen consumption and contractile force during vibrations of cat soleus muscle.

The influence of longitudinal vibrations (50 Hz, 0.4 mm) on isometric twitch force development (4 Hz), blood flow and oxygen consumption was studied in the acutely denervated soleus muscle of the anesthetized cat. It was found that the sinusoidal vibrations reduced the twitch amplitude by 60 per cent whereas oxygen consumption and blood flow were lowered by 15 per cent only. Similar reduction in twitch force was also obtained by lowering the nerve stimulation intensity (4 Hz). This was associated with a diminution in oxygen consumption, the degree of which was linearly related to the attenuation of active force, i.e. the number of activated motor units. The results are in agreement with previous observations as to the mechanical effect of vibrations on active force in smooth and striated muscle. They demonstrate that vibrations prevent the contractile response with maintained high oxygen consumption which adds further support to the hypothesis forwarded by Joyce et al. (1969) that vibrations cause increased rate of detachment of actin-myosin cross-links. In addition it appears possible that vibrations to some extent prevent formation of such cross-links.

Mechanisms of spontaneous hypertension in rats.

Studies on the Kyoto (SHR) and the New Zealand (GHR) strains of genetically predisposed hypertensive rats have shown that in the SHR neurogenic influences, primarily of higher central origin, play an important role in the initiation of hypertension. Studies on human essential hypertension indicate that this may also be true for man, although it is far from being the sole explanation. Brookhaven hypertension-prone rats illustrate the interaction between genetic and exogenous factors since they require an overload of salt for the development of high blood pressure. The Milan hypertensive rats (MHS), on the other hand, illustrate a genetic deviation of renal function with imbalance between glomerular filtration and tubular resorption of sodium and water, which may simulate at least some variants of the relatively mild forms of low renin hypertension in man. Structural adaptive vascular changes have been demonstrated in SHR and GHR and in nongenetic renal hypertension in rats, and there are several indications of their presence in MHS. Thus, regardless of the nature of the initiating factors, these secondary but rapidly established changes occur and greatly contribute to the maintenance and acceleration of the hypertensive state. The vascular changes can even be regarded as a common denominator for chronic hypertension and serve as an element which, in fact, reinforces the initiating mechanisms. The progress of the vascular changes can be interfered with by reducing the pressure load. Lowering the blood pressure by pharmacologic treatment is most effective when the treatment is initiated as such an early age when the cardiovascular structural adaptation is still minimal. Treatment in later phases is less successful since the adaptive increases in cardiac and vessel wall thickness can then no longer be fully normalized by pressure reduction because of increased amounts of collagen and other connective tissue elements in the vessel wall, which regress poorly. An increased wall thickness of the resistance vessels implies a vascular hyperreactivity to constricting influences which, in turn, rapidly brings the blood pressure back to supranormal levels as soon as therapy is stopped.

Contractile responses to noradrenaline: varying dependence on external calcium of consecutive vascular segments of perfused rat hindquarters.

To study the dependency of vascular smooth muscle contractions, produced by noradrenaline, on the concentration of extracellular calcium, experiments were performed on adult male Wistar rats. The hemodynamic characteristics of the isolated, perfused hindquarters were investigated from maximal dilatation up to maximal, noradrenaline-induced constriction under constant flow conditions. Pressor responses to noradrenaline in the consecutive segments of the vascular bed ("proximal" and "distal" precapillary resistance vessels and postcapillary resistance vessels) were determined at low (0.2mM) and at normal (1.5-2.0 mM) Ca++ concentrations in the perfusate. Dependence on external calcium is much greater peripherally. The smallest pre- and postcapillary resistance vessels are the most dependent while the larger, "proximal" resistance vessels are the least dependent on the availability of external calcium. The results illustrate the considerable differentiation of smooth muscle, depending on its location along the vascular circuit. They further indicate that it is likely that the hemodynamically so important microvessels are highly dependent on extrinsic Ca++ sources not only concerning their involvement of remote adrenergic control, but also in their maintenance of normally pronounced "myogenic" tone.

Cardiovascular control in the Milan strain of spontaneously hypertensive rat (MHS) at "rest" and during acute mental "stress".

The cardiovascular responses to acute mental "stress" were compared in the Milan strain of spontaneously hypertensive rats (MHS) and in normotensive control rats (NR). Blood pressure and heart rate were followed in pairs of awake MHS and NR, while defence reactions were provoked by alerting stimuli (noise, vibration). No differences were noted between the two groups in response to "stress" although resting heart rate in MHS was lower than in NR. Administration of atropine or propranolol to MHS and NR showed the MHS to have a higher resting vagal tone and lower sympathetic tone than the NR. Subsequent (at least two weeks later) hemodynamic investigation, under nembutal anesthesia, showed no difference in cardiac output between MHS and NR but a higher stroke volume, presumably related to the lower heart rate in MHS. Thus, total peripheral resistance was increased in MHS as was the ratio left ventricular weight/body weight, and in good proportion to the blood pressure rise. Thus MHS differ substantially in both their responses to "stress" and also hemodynamically from the Okamoto strain of spontaneously hypertensive rat (SHR), being the so far most studied and best known model of essential hypertension in man. In MHS the hypertension is more of a systolic type and is of primarily renal origin. As such, MHS provide another model for investigating the polygenic nature of hypertension in man.

Effects of noradrenaline on consecutive vascular segments at low or normal calcium concentrations in control and spontaneously hypertensive rats.

1. An 'isogravimetric' technique, plus measurement of pressure in a small artery, was used to investigate the responses of upstream and downstream precapillary and postcapillary resistance vessels in the hindquarters of spontaneously hypertensive rats (SHR) and normal control rats perfused at constant flow. 2. Dose-response curves to noradrenaline were constructed under conditions of low or normal calcium. 3. In both control rats and SHR the dependence on external calcium during contraction increased peripherally, with the smaller pre- and post-capillary resistance vessels being most dependent and larger arteries least dependent. 4. There may be differences between SHR and control rats in regard to the handling of calcium, particularly in the small pre- and post-capillary resistance vessels.