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.

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.

Clarification of the circulatory patho-physiology of anaesthesia - implications for high-risk surgical patients.

The paper examines the effects of anaesthesia on circulatory physiology and their implications regarding improvement in perioperative anaesthetic management. Changes to current anaesthetic practice, recommended recently, such as the use of flow monitoring in high risk patients, are already beginning to have an impact in reducing complications but not mortality [1]. Better understanding of the patho-physiology should help improve management even further. Analysis of selected individual clinical trials has been used to illustrate particular areas of patho-physiology and how changes in practice have improved outcome. There is physiological support for the importance of achieving an appropriate rate of oxygen delivery (DO2), particularly following induction of anaesthesia. It is suggested that ensuring adequate DO2 during anaesthesia will avoid development of oxygen debt and hence obviate the need to induce a high, compensatory, DO2 in the post-operative period. In contrast to the usual assumptions underlying strategies requiring a global increase in blood flow [1] by a stroke volume near maximization strategy, blood flow control actually resides entirely at the tissues not at the heart. This is important as the starting point for understanding failed circulatory control as indicated by 'volume dependency'. Local adjustments in blood flow at each individual organ - auto-regulation - normally ensure the appropriate local rate of oxygen supply, i.e. local DO2. Inadequate blood volume leads to impairment of the regulation of blood flow, particularly in the individual tissues with least capable auto-regulatory capability. As demonstrated by many studies, inadequate blood flow first occurs in the gut, brain and kidney. The inadequate blood volume which occurs with induction of anaesthesia is not due to blood volume loss, but probably results from redistribution due to veno-dilation. The increase in venous capacity renders the existing blood volume inadequate to maintain venous return and pre-load. Blood volume shifted to the veins will, necessarily, also reduce the arterial volume. As a result stroke volume and cardiac output fall below normal with little or no change in peripheral resistance. The resulting pre-load dependency is often successfully treated with colloid infusion and, in some studies, 'inotropic' agents, particularly in the immediate post-operative phase. Treatment during the earliest stage of anaesthesia can avoid the build up of oxygen debt and may be supplemented by drugs which maintain or restore venous tone, such as phenylephrine; an alternative to volume expansion. Interpretation of circulatory patho-physiology during anaesthesia confirms the need to sustain appropriate oxygen delivery. It also supports reduction or even elimination of supplementary crystalloid maintenance infusion, supposedly to replace the "mythical" third space loss. As a rational evidence base for future research it should allow for further improvements in anaesthetic management.

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.

Normal cardiac output, oxygen delivery and oxygen extraction.

The total amount of blood flow circulating through the heart, lungs and all the tissues of the body represents the cardiac output. Most individual tissues determine their own flow in proportion to their metabolic rate. The skin is a notable exception where the priority is thermal rather than metabolic. Renal blood flow and metabolic rate are related but plasma flow determines metabolic rate rather than metabolic rate determining blood flow. Brain, heart, skeletal muscle and the splanchnic area all vary their blood flows according to local tissue metabolic rate. Summation of peripheral blood flows constitutes venous return and hence cardiac output. Cardiac output is therefore, largely, determined by the metabolic rate of the peripheral tissues; the heart 'from a flow standpoint, plays a "permissive" role and does not regulate its own output'. This peripheral tissue, largely metabolic, determination of cardiac output has been known for many years. Evidence will be presented that blood flow is scaled according to a tissue specific ratio of oxygen delivery (DO2) to oxygen consumption (VO2). For the brain DO2 is approximately three times VO2, for heart muscle DO2 is 1.5 to 1.6 times VO2 and is very similar for skeletal muscle for moderate exercise. Brain, heart and skeletal muscle have the ability to sustain appropriate blood flow in the face of varying blood pressure within limits--the phenomenon known as 'autoregulation'. "Autoregulation, in regard to arterial blood pressure, has been observed" also "in the kidney" and "modest autoregulation" was observed "in the intestines and liver but not in skin". Guyton et al. have suggested that the term 'auto-regulation' should also include variation of blood flow in proportion to metabolic rate and the compensatory changes in blood flow which occur in the face of varying arterial oxygen content (CaO2). This article gives examples of the very precise compensation for CaO2 change in the form of sustained tissue specific DO2:VO2 ratios (corresponding with tissue specific oxygen extraction, E = VO2/DO2). The adequacy of this adjustment for brain, exercising skeletal muscle and heart is particularly striking; skeletal muscle will, for example when CaO2 is reduced, steal blood supply from nonexercising tissues sustaining its own oxygen delivery at normal levels.

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 at sea level and altitude (after slow ascent to 5000 meters), at rest and in mild exercise.

Oxygen delivery (DO2) calculated from cardiac output, haematocrit (Hct) and arterial oxygen saturation (SaO2), has been obtained on six subjects at sea level (London) and after slow ascent to 5000 meters (Chamlang base camp) at rest and during mild exercise (25 watts and 50 watts). Haematocrit was increased in all six subjects at 5000 m and expressed as haemoglobin (Hb) rose from a mean (+/- standard error; SEM) of 13.8 +/- 0.1 g (100 ml)(-1) to 15.8 +/-0.3 g (100 ml)(-1) (t = 6.3, p = 0.0014). SaO2 was almost constant with exercise at sea level (rest 98.5%, 25 w 98.3% and 50 w 98.3%) but declined more steeply with exercise at 5000 m (rest 88.8 +/-0.6%, 25 w 85.4 +/-0.4% and 50 w 84.4 +/- 0.5%). Arterial oxygen content (CaO2) was very similar for 25 watts exercise at altitude (5000 m, 18.1 ml per decilitre--dl) as at sea level (London, CaO2 18.2 ml dl(-1)). At rest CaO2 was higher at altitude (18.8 +/-0.2 ml dl(-1)) than at sea level (18.3 +/- 0.4 ml dl(-1)) and at 50 w CaO2 was lower at altitude (17.9 +/- 0.4 ml dl(-1)) than at sea level (18.2 +/- 0.2 ml dl(-1)). Hence, similar cardiac output values at rest (sea level, 5.0 +/- 0.4 litres min(-1) l min(-1); altitude, 5.6 +/- 0.31 min(-1)-) and at 25 w exercise (sea level, 8.2 +/-0.7 1 min(-1); altitude, 8.3 +/-0 .9 1 min'(-1) resulted in similar values for DO2 at rest (sea level, 0.9 +/-0.1 l min(-1) altitude, 1.0 +/-0.1 l min(-1) and 25 w exercise (sea level, 1.5 +/-0.1 l min(-1) altitude, 1.5 +/- 0.2 l min(-1). For 50 w exercise cardiac output and oxygen delivery were greater at altitude in one subject but were significantly reduced for the remaining five (cardiac output mean difference 3.0 +/- 0.91 min(-1), p = 0.015; DO2 mean difference, 0.56 +/- 0.21 l min(-1) p = 0.028). Acclimatization was therefore adequate to sustain a normal value for oxygen delivery for rest and 25 watts exercise (via compensatory erythropoiesis) but insufficient for 50-watt exercise in five of the six subjects.

Cardiac output, oxygen consumption and muscle oxygen delivery in submaximal exercise. Normal and low O2 states.

Cardiac output (Q) changes linearly with oxygen consumption (VO2) in normal subjects undertaking submaximal exercise (Q = A + B x VO2 where A is the y intercept and B the slope). If (hypothesis 1) the increase in cardiac output above the resting state represents the blood flow to exercising muscle (qm) and the increase in VO2 represents the oxygen consumption of exercising muscle (VO2m) then, where CaO2 is the arterial oxygen content, oxygen extraction, Em = 1/(B x CaO2). Secondly, exercising muscle venous oxygen content, CvO2m = CaO2 - 1/B. Limiting the hypothesis just to the calculation of VO2m (hypothesis 2) allows calculation of qm if CaO2 and CvO2m are available. From Koskolov et al. (Am. J. Physiol.: Heart and Circ. Physiol. 273, H1787-H1793, 1997), exercising muscle blood flow (qm) is equal to the increment in cardiac output when CaO2 is normal but exceeds it when CaO2 is low. Muscle Oxygen extraction (Em) is found to be 68% in submaximal exercise. Hence, muscle oxygen delivery (DaO2m) for a given metabolic rate is sustained in low O2 states (at 1.48 ml DaO2m per ml VO2m), confirmed by analysis of Roach et al. (Am. J. Physiol.: Heart and Circ. Physiol. 276, H438-H445, 1999).

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.