Christopher B. Wolff

Cardiovascular and respiratory adjustments at altitude sustain cerebral oxygen delivery — Severinghaus revisited

Analysis of a paper by Severinghaus et al. (see text) has already shown that sea level oxygen delivery (D(a)O(2)) is sustained 8 h after ascent to 3810 m, despite low arterial oxygen content (C(a)O(2)), largely as a result of increased cerebral blood flow (CBF). The present study extends the analysis to show that D(a)O(2) is also sustained after 3 and 5 days at altitude, despite a progressively falling CBF. It is shown that this later compensation is a result of the improvement in C(a)O(2), which accompanies acclimatisation. Since less than 3% rise in haemoglobin occurred, the rise in C(a)O(2) was predominantly respiratory. It has been shown elsewhere that as acclimatisation occurs, the fall in arterial PCO(2) (P(a)CO(2)) results in increased arterial PO(2) (P(a)O(2)) until they are related according to P(a)CO(2)=0.25 P(a)O(2)+/-15 mmHg. The results from Severinghaus et al. at 3 and 5 days fall close to this line. We also report arterialised capillary blood gases from 18 normal subjects, acclimatised at 5300 m. The values fall in a group centred on the same line. In summary, soon after arrival at altitude (8 h), cerebral oxygen delivery is largely sustained by an increase in CBF. The present study shows that, although CBF declines during the 3-5 day period, D(a)O(2) is sustained as a result of the improvement in C(a)O(2), which is mainly due to respiratory acclimatisation.

Partitioning of Arterial and Venous Volumes in the Brain under Hypoxic Conditions

Cerebral oxygen delivery is sustained in the face of, at least moderate, hypoxia.1 The measurements required to show this have, in the past, been especially invasive, with a requirement for jugular venous bulb sampling and carotid arterial administration of a marker to allow measurement of flow by dye dilution.2 With the advent of middle cerebral arterial blood velocity measurement (Doppler) and arterial oxygen saturation measurement (pulse oximetry) the procedure is greatly simplified, at least on a relative basis: SaO2 multiplied by middle cerebral artery velocity will, arguably, give individual changes in oxygen delivery for, at least, the distribution supplied by the middle cerebral artery. This will, for normal subjects, usually change in proportion to global changes.

Extravascular lung water volume measurement by a novel lithium-thermal indicator dilution method: comparison of three techniques to post-mortem gravimetry

ObjectiveTo compare the lithium-thermal double indicator dilution (Li-thermal), indocyanine green-thermal double indicator dilution (ICG-thermal), single thermal indicator dilution (single-thermal) and gravimetric techniques of extravascular lung water volume (EVLW) measurement in porcine models of acute lung injury.DesignTwo animal models designed to invoke a systemic inflammatory response.SettingLaboratory study.SubjectsA total of 12 immature Deutsches Landschwein pigs.InterventionsExtravascular lung water volume was measured at four time points using Li-thermal, ICG-thermal and single-thermal techniques. Measurements were performed using existing technology according to manufacturer’s instructions. Post-mortem gravimetric EVLW measurements were performed by measuring wet and dry mass of lung tissue. Measurements were compared using the Bland–Altman method. Data are presented as mean (SD).Measurements and main resultsData were collected in 12 animals and comparison between all 4 techniques was possible in 10 animals. EVLW measured by gravimetry was 9.2 (±3.0)ml kg−1. When compared to gravimetry, both Li-thermal and ICG-thermal techniques showed minimal bias but wide limits of agreement (LOA) [Li-thermal: bias −1.8 ml kg−1 (LOA ± 13.1); ICG-thermal bias −1.0 ml kg−1 (LOA ± 6.6)]. Comparison between the single-thermal and gravimetric methods identified both considerable bias and wide LOA [+8.5 ml kg−1 (LOA ± 14.5)].ConclusionClinically significant differences between EVLW measurements obtained with the gravimetric method and three in vivo indicator dilution techniques were identified. While none of the techniques could be considered ideal, the ICG-thermal method appeared more reliable than either the Li-thermal or single thermal techniques. Further research is required to determine whether the accuracy of the prototype Li-thermal technique can be improved.

Comparison of three methods of extravascular lung water volume measurement in patients after cardiac surgery.

IntroductionMeasurement of extravascular lung water (EVLW) by using the lithium-thermal (Li-thermal) and single-thermal indicator dilution methods was compared with the indocyanine green-thermal (ICG-thermal) method in humans.MethodsSingle-center observational study involving patients undergoing cardiac surgery with cardiopulmonary bypass. Paired measurements were taken 1, 2, 4, and 6 hours after surgery. Bland-Altman analysis was used to calculate bias and limits of agreement. Data are presented as mean (SD) or median (IQR).ResultsSeventeen patients were recruited (age, 69 years (54 to 87 years); Parsonnet score 10 (0 to 29)). Sixteen ICG-thermal measurements were excluded after blinded assessment because of poor-quality indicator dilution curves. EVLW volume as measured by the ICG-thermal technique was 4.6 (1.9) ml/kg, compared with 5.3 (1.4) ml/kg for the single-thermal method. Measurements taken with the Li-thermal method were clearly erroneous (-7.6 (7.4) ml/kg). In comparison with simultaneous measurements with the ICG-thermal method, single-thermal measurements had an acceptable degree of bias, but limits of agreement were poor (bias, -0.3 ml/kg (2.3)). Li-thermal measurements compared poorly with the ICG-thermal reference method (bias, 13.2 ml/kg (14.4)).ConclusionsThe principal finding of this study was that the prototype Li-thermal method did not provide reliable measurements of EVLW volume when compared with the ICG-thermal reference technique. Although minimal bias was associated with the single-thermal method, limits of agreement were approximately 45% of the normal value of EVLW volume. The Li-thermal method performed very poorly because of the overestimation of mean indicator transit time by using an external lithium ion electrode. These findings suggest that the assessment of lung water content by lithium-indicator dilution is not sufficiently reliable for clinical use in individual patients.

Near infra-red spectroscopy and arterial oxygen extraction at altitude.

The ratio of oxygenated to total haemoglobin (Hb), or rSO2, obtained by near infrared spectroscopy (NIRS), includes both arterial and venous blood of the region examined. The relationship of arterial oxygen extraction, E, and saturation, SaO2, to rSO2 can be expressed, for normally functioning tissue, as E = 1.39 (1 - rSO2/SaO2). Cerebral E, at rest, is constant at lower altitudes but is reduced at 5000 m. This corresponds to constant values of E for SaO2 values above 90% (approximately). E declines linearly for lower SaO2 values, either including measurement at high altitude or at sea level with a reduced inspiratory oxygen concentration. In addition to measurements of brain NIRS resting oxygen extraction of liver, muscle and kidney have also been calculated from NIRS measurements made, on normal inspired air, at sea level and after acute ascent to 2400 m and 5050 m. At 5050 m E was reduced for all four regions but at 2400 m was the same as at sea level for brain, liver and muscle; for the kidney E was elevated at 2400 m. Cerebral oxygen extraction was calculated for rest and the full range of exercise. It was constant at sea level for the lower levels of exercise and, if the calculated extraction value assumptions still hold at lower SaO2 values, reduced for the higher work rates at intermediate altitudes. The present study confirms constancy of oxygen extraction and hence the ratio of oxygen delivery to oxygen consumption (1/E), within physiological limits, and appears to show where those limits lay and, to some extent, show how matters change beyond ordinary physiological limits.

Oxygen Delivery: The Principal Role of the Circulation

Autoregulation of blood flow to most individual organs is well known. The balance of oxygen supply relative to the rate of oxygen consumption ensures normal function. There is less reserve as regards oxygen supply than for any other necessary metabolite or waste product so oxygen supply is flow dependent. Reduced rate of supply compromises tissue oxygenation long before any other substance. The present report reiterates evidence from earlier studies demonstrating that the rate of oxygen delivery (DO2), for most individual tissues, is well sustained at a value bearing a ratio to oxygen consumption (VO2) which is specific for the organ concerned. For the brain DO2 is sustained at approximately three times the rate of oxygen consumption and for exercising skeletal muscle (below the anaerobic threshold), a ratio close to 1.5. The tissue-specific ratios are sustained in the face of alterations in local VO2 and lowered arterial oxygen content (CaO2). Tolerance varies between different organs. Hence, the role of the circulation is predominantly one of ensuring an adequate supply of oxygen. The precise values of the individual tissue DO2:VO2 ratios apply within physiological ranges which require further investigation.

A Simple Volume Related Model of Arterial Blood Pressure Generation

A single compartment model of the arterial circulation was used to generate an arterial blood pressure waveform from pre-determined stroke volume (SV) and arterial resistance (R). With fixed stroke volume and varying resistances blood pressure waveforms showed mean values proportional to resistance but amplitude lessening with higher pressure; the amplitude of the hypothetical volume waveform of the arterial system was the same for all resistance values. Where SV varied and R changed reciprocally, the waveform when analysed with the PulseCO algorithm gave estimates slightly higher than the input stroke volumes (r 0.9998; y = 0.99x + 5.28 ml). Where SV varied with fixed R mean blood pressure varied with stroke volume; SV estimates were, again, slightly higher than the input stroke volumes (r 0.9994; y = 0.986x + 6.04 ml). Estimates of SV and R from Valsalva manoeuvre BP were used in the model to generate arterial blood pressure. SV estimates closely resembled the original model values (r 0.988; y = 1.0802x - 3.9251). The model appears capable of generating BP waveforms compatible with real BP waveforms since stroke volume estimates closely resemble the original stroke volumes used in the model.

A Discussion on the Regulation of Blood Flow and Pressure

This paper discusses two kinds of regulation essential to the circulatory system: namely the regulation of blood flow and that of (systemic) arterial blood pressure. It is pointed out that blood flow requirements sub-serve the nutritional needs of the tissues, adequately catered for by keeping blood flow sufficient for the individual oxygen needs. Individual tissue oxygen requirements vary between tissue types, while highly specific for a given individual tissue. Hence, blood flows are distributed between multiple tissues, each with a specific optimum relationship between the rate of oxygen delivery (DO2) and oxygen consumption (VO2). Previous work has illustrated that the individual tissue blood flows are adjusted proportionately, where there are variations in metabolic rate and where arterial oxygen content (CaO2) varies. While arterial blood pressure is essential for the provision of a sufficient pressure gradient to drive blood flow, it is applicable throughout the arterial system at any one time. Furthermore, It is regulated independently of the input resistance to individual tissues (local arterioles), since they are regulated locally, that being the means by which the highly specific adequate local requirement for DO2 is ensured. Since total blood flow is the summation of all the individually regulated tissue blood flows cardiac inflow (venous return) amounts to total tissue blood flow and as the heart puts out what it receives cardiac output is therefore determined at the tissues. Hence, regulation of arterial blood pressure is independent of the distributed independent regulation of individual tissues. It is proposed here that mechanical features of arterial blood pressure regulation will depend rather on the balance between blood volume and venous wall tension, determinants of venous pressure. The potential for this explanation is treated in some detail.

Oxygen delivery deficit in exercise with rapid ascent to high altitude.

This study of high altitude physiology was undertaken during an 11-day expedition to the Himalaya with ascent to Annapurna base camp (4,130 m) reaching it on the sixth day. Fourteen male UK residents (13 aged 16-17 years; 1 adult) measured arterial oxygen saturation (SaO(2)) and heart rate (HR) at rest and at 2 min exercise (30 cm step), daily, after arrival at each altitude. Precision was limited by availability of only one oximeter (CMS50-DLP model, Contec Medical Systems, Qinhuangdao, P.R. China). Mean HR correlated (negatively) with SaO(2) both for rest (HR = -1.7974 × SaO(2)% + 236.33, r = 0.841, p = 0.001) and exercise (HR = -0.8834 × SaO(2)% + 226.14, r = 0.711 p < 0.02). Four subjects individually showed significant HR/SaO(2) correlations at rest (nos. 10, 11, 12 and 13) and one, subject 11, in exercise. SaO2 in exercise was lower than at rest (SaO(2), exercise = 1.5835 × SaO(2), rest - 59.177, r = 0.987, p < 0.001). The product, HR × SaO(2), calculated as a surrogate for oxygen delivery (DO(2), Brierley et al., Adv Exp Med Biol 737:207-212, 2012), from mean values was approximately constant for rest, suggesting good cardiac output (CO) compensation for de-saturation. The HR × SaO(2) for exercise, however, showed a dramatic fall at the highest altitude. Since this deficit occurred at the highest altitude, following 2 days of rapid ascent, there was probably impairment of adequate oxygen delivery (DO(2)) at this point. Correlation, HR versus SaO(2) for exercise, was highly significant, with greater significance (HR = -1.798 × SaO(2) + 281.83, r = 0.769, p = 0.01) on omission of the values for the highest ascent point (4,130 m), where the reduced HR × SaO(2) occurred. In conclusion, oxygen delivery is sustained well here except where there are the extra stresses of rapid ascent and exercise.

Attenuation of Splanchnic Autotransfusion Following Noninvasive Ultrasound Renal Denervation: A Novel Marker of Procedural Success

Background Renal denervation has no validated marker of procedural success. We hypothesized that successful renal denervation would reduce renal sympathetic nerve signaling demonstrated by attenuation of α‐1‐adrenoceptor‐mediated autotransfusion during the Valsalva maneuver. Methods and Results In this substudy of the Wave IV Study: Phase II Randomized Sham Controlled Study of Renal Denervation for Subjects With Uncontrolled Hypertension, we enrolled 23 subjects with resistant hypertension. They were randomized either to bilateral renal denervation using therapeutic levels of ultrasound energy (n=12) or sham application of diagnostic ultrasound (n=11). Within‐group changes in autonomic parameters, office and ambulatory blood pressure were compared between baseline and 6 months in a double‐blind manner. There was significant office blood pressure reduction in both treatment (16.1±27.3 mm Hg, P<0.05) and sham groups (27.9±15.0 mm Hg, P<0.01) because of which the study was discontinued prematurely. However, during the late phase II (Iii) of Valsalva maneuver, renal denervation resulted in substantial and significant reduction in mean arterial pressure (21.8±25.2 mm Hg, P<0.05) with no significant changes in the sham group. Moreover, there were significant reductions in heart rate in the actively treated group at rest (6.0±11.5 beats per minute, P<0.05) and during postural changes (supine 7.2±8.4 beats per minute, P<0.05, sit up 12.7±16.7 beats per minute, P<0.05), which were not observed in the sham group. Conclusions Blood pressure reduction per se is not necessarily a marker of successful renal nerve ablation. Reduction in splanchnic autotransfusion following renal denervation has not been previously demonstrated and denotes attenuation of (renal) sympathetic efferent activity and could serve as a marker of procedural success. Clinical Trial Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT02029885.