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NEUROSURGICAL ANESTHESIA

Noninvasive Estimation of Cerebral Perfusion Pressure and Zero Flow Pressure in Healthy Volunteers: The Effects of Changes in End-Tidal Carbon Dioxide

University Departments of Anaesthesia and Intensive Care, Queen’s Medical Centre and City Hospital NHS Trust, Nottingham, United Kingdom

Address correspondence and reprint requests to R. P. Mahajan, FRCA, DM, University Department of Anesthesia, Queen’s Medical Centre, Nottingham, NG7 2UH, UK. Address e-mail to ravi.mahajan{at}nottingham.ac.uk

	Abstract

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Zero flow pressure (ZFP) in the cerebral circulation is defined as the arterial pressure at which flow ceases. Noninvasive methods of estimating cerebral perfusion pressure (CPP) and ZFP using transcranial Doppler ultrasonography have been described. There is a paucity of normal physiological data related to changes in estimated CPP (eCPP) and ZFP induced by changes in carbon dioxide (CO₂). We studied the effects of CO₂ on eCPP and ZFP in 17 healthy volunteers. After baseline measurements of middle cerebral artery blood-flow velocity and blood pressure, subjects voluntarily hyperventilated to decrease their end-tidal CO₂ (PE'CO₂) by approximately 7.5 mm Hg, and then they increased their PE'CO₂ by approximately 7.5 mm Hg by breathing through a Mapleson D circuit. Blood-flow velocity and blood pressure were recorded at each stage. The eCPP and ZFP were calculated by using established formulas, and the results were analyzed with analysis of variance. With increasing PE'CO₂, eCPP increased from 50.67 mm Hg (8.33 mm Hg) (mean [SD]) to 60.87 mm Hg (9.28 mm Hg) (20% increase; P < 0.001), with a corresponding decrease in ZFP (P = 0.017); hypocapnia resulted in the opposite effects on eCPP and ZFP. These results indicate physiological changes in eCPP and ZFP that can be expected from changes in CO₂ in subjects without any neurological disorder.

IMPLICATIONS: Increasing end-tidal CO₂ increases the estimated cerebral perfusion pressure and vice versa. These results are opposite to those expected from the known effects of CO₂ on intracranial pressure. Thus, we support the suggestion that, in the absence of intracranial hypertension, vascular tone remains a major determinant of effective downstream pressure and cerebral perfusion.

	Introduction

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The maintenance of an adequate cerebral perfusion pressure (CPP) is of fundamental importance in managing patients under anesthesia and in critical care. This is usually calculated as the difference between mean arterial blood pressure (MAP) and intracranial pressure (ICP). Zero flow pressure (ZFP) in the cerebral circulation is defined as the arterial pressure at which the flow ceases (1,2); thus, it represents the effective downstream pressure, and the gradient between MAP and ZFP determines CPP. It is suggested that, in patients without increased ICP, ZFP is determined by arteriolar tone (1). Because ZFP cannot be measured directly, indirect methods of calculating ZFP from the instantaneous relationship between middle cerebral artery (MCA) blood-flow velocity (FV) and MAP during a cardiac cycle have been described. Of these, the method described by Belfort et al. (3) uses the values of mean and diastolic arterial blood pressure (BP) and FV. Because these measurements can be reliably obtained noninvasively in routine clinical practice, the method has potential for wider clinical and research applications.

Carbon dioxide (CO₂) is a known modulator of cerebral vascular tone (4,5). The effects of CO₂ on CPP or ZFP, as estimated by the method described by Belfort et al. (3), have not been well documented. As such, there is a paucity of data regarding CO₂-related changes in estimated CPP (eCPP) and ZFP, especially in subjects without any neurological disorder. Acquisition of this information is important as a point of reference while changes are assessed in eCPP and ZFP in patients with neurological disorders. We aimed to assess the effects of CO₂ on eCPP and ZFP, using the method described by Belfort et al. (3), in healthy volunteers.

	Methods

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After university ethics committee approval and informed consent, 17 healthy ASA status I volunteers aged 26–45 yr with no evidence of cerebrovascular disease were recruited. Those taking vasoactive medication or experiencing migraines or any other cerebrovascular disease were excluded.

The study was performed in a quiet room after the procedure was explained to each volunteer. All volunteers had a chance to rest and acclimatize to the surroundings. Each volunteer was studied in the supine position with the head resting on a pillow. Systolic and diastolic BP and MAP were measured continuously by using a Finapres (Ohmeda, Louisville, KY), and the MCA was insonated via the temporal window by using a 2-MHz transcranial Doppler (TCD) ultrasound probe (SciMed QVL 120; SciMed, Bristol, UK). The identity of the MCA was confirmed by using standard criteria (6,7), and the position of the probe was fixed with an elastic headband to maintain a constant angle of insonation. End-tidal CO₂ (PE'CO₂) was measured by using a face mask and a Capnomac Ultima monitor (Datex-Ohmeda, Helsinki, Finland).

After the baseline measurements of BP, PE'CO₂ breathing air, and MCA FV, subjects were asked to increase the rate and depth of their breathing to reduce their PE'CO₂ to approximately 7.5 mm Hg below baseline. At steady-state, repeat measurements of MCA FV and BP were recorded. PE'CO₂ was then allowed to normalize and MCA FV to return to baseline values. Subjects were then asked to breathe a mixture of air and oxygen at low flow through a Mapleson D breathing system to induce a degree of rebreathing and to increase the PE'CO₂ by approximately 7.5 mm Hg above baseline. Repeat measurements were again taken at steady-state. Steady-state was defined as <10% change in BP and MCA FV at the given level of PE'CO₂ (±2 mm Hg) over 60 s.

For the analysis, analog outputs of FV maximum, determined by using the upper envelope of the velocity power spectra, were taken. The TCD and Finapres were programmed to give results on the averages of six consecutive pulse waves (to cover at least one respiratory cycle). Time-averaged mean and diastolic FV (FV_mean and FV_diastolic) and simultaneously recorded MAP and diastolic BP (BP_mean and BP_diastolic) were taken to calculate eCPP and ZFP.

The following formulas were used: equation

equation

We calculated that approximately 17 subjects would be required to detect a total change of 15 mm Hg in eCPP over 3 different levels of PE'CO₂ with a 90% power at = 0.05, assuming a 10% coefficient of variation in eCPP values. The changes in MCA FV, BP, eCPP, and ZFP were analyzed with analysis of variance for repeated measures; P < 0.05 was considered significant.

	Results

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Twelve male and five female subjects participated in the study. All were successful in achieving an approximately 9 mm Hg increase and a similar decrease in PE'CO₂. Results are expressed as mean (SD).

There were no significant changes in BP_mean at each level of PE'CO₂ (Table 1). MCA FV increased during hypercapnia and decreased during hypocapnia (P < 0.001; Table 1; Fig. 1). During hypercapnia, eCPP increased with a corresponding decrease in ZFP; hypocapnia had the opposite effect (Figs. 2 and 3). The magnitude of change in eCPP was in the order of approximately 20% for each step change in PE'CO₂. The changes in eCPP and ZFP induced by changes in PE'CO₂ were significant (P < 0.05).

View larger version (16K): [in this window] [in a new window]   Figure 1. Mean middle cerebral artery flow velocity (FVmean) at different levels of end-tidal carbon dioxide (PECO2).

View larger version (16K): [in this window] [in a new window]   Figure 2. Estimated cerebral perfusion pressure (eCPP) at different levels of end-tidal carbon dioxide (PECO2).

View larger version (15K): [in this window] [in a new window]   Figure 3. Zero flow pressure (ZFP) at different levels of end-tidal carbon dioxide (PECO2).

	Discussion

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An editorial on CPP by Munis and Lozada (8) discusses various formulas in use for calculating CPP. They review the evidence for different factors responsible for effective downstream pressure in the cerebral circulation. These are mainly central venous pressure, ICP (assuming the existence of a Starling resistor or a vascular waterfall phenomenon at venous levels) (9), or vascular tone at the arteriolar level.

Burton (2) first introduced the concept of critical closing pressure. For vessels to remain in equilibrium, the law of Laplace must apply, where forces act on a cylindrical vessel in the relationship P = T/R, where P is the excess hydrostatic pressure of the interior of the vessel relative to the exterior, T is the tension in the wall, and R is the radius of the vessel. From this equation, the lower the pressure, the less will be the maximum tension that may develop before the vessel becomes unstable and closes. At a point R₀, which is the unstretched radius of the vessel, the active tension just balances the pressure. If tone remains constant, then slight reductions in pressure or radius will cause vessels to close. This is the critical closing pressure. Burton (2) proposed the origin of the tension in the wall to consist of a combination of elastic tension and active tension caused by contraction of smooth muscle fibers in the vessel wall, with this active tension being affected by vasomotor tone. This is the basis of the involvement of muscular arterioles in creating ZFP. Further work under conditions of hypoxia and hypercapnia and use of epinephrine infusions to vary vascular tone in animal models has been reported (10–13).

Recently, several studies have investigated the relationships among ZFP, ICP, and/or cerebrovascular tone (1,14–16) in humans. Weyland et al. (1) studied the effect of vascular tone on downstream pressure by using instantaneous pressure/FV plots in patients recovering from severe head injury and used linear regression analysis to calculate ZFP. They found that the effective downstream pressure increased with decreasing PaCO₂ while ICP decreased and that it exceeded ICP with increased cerebrovascular tone. This led them to postulate the existence of two Starling resistors in series; one at the arteriolar level and one at the level of collapsible cerebral veins. However, the results of this study were obtained from patients who were recovering from head injuries and in whom cerebral vascular reactivity and autoregulation were not assessed but could have been impaired. Therefore, it was not clear whether their data could be directly applied to patients without intracranial pathology. Panerai et al. (14) have shown that impaired cerebral autoregulation after breathing a mixture of 5% CO₂ is associated with a significant reduction in ZFP. Carey et al. (15) have shown that vasovagal syncope can be associated with an increase in ZFP induced by hypocapnia. Thees et al. (16) have shown that, in patients with neurotrauma, the actual "gold standard" of CPP determination (MAP-ICP) might overestimate the effective CPP of therapeutic significance (MAP-ZFP). From the results of these studies, it is clear that noninvasive estimation of CPP and ZFP is gaining importance in deciding therapeutic targets. However, noninvasive methods of assessing CPP and ZFP have not been extensively validated. Also, there is a lack of data with regard to the effects of normal physiological variables on noninvasive eCPP and ZFP in healthy subjects; these can serve as points of reference in assessing changes in disease. This study is a step in this direction, and our results in healthy volunteers support the findings of Weyland et al. (1) and Richards et al. (13), which point to the potentially deleterious effects of hyperventilation on CPP and ZFP.

Aaslid et al. (17) validated the method of estimating CPP by using TCD ultrasonography. They measured mean FV (V₀), the first harmonic of the velocity wave form (V₁), and the arterial blood pressure (ABP). The eCPP was then calculated as (V₀/V₁) x ABP (18). Here ABP/V₁ represents vascular resistance. On the basis of this method, Belfort et al. (3,18) modified the formula by using equation

to represent resistance in their estimation of CPP and, hence, ZFP: equation

Other groups have also used the same concept with slight variations in variables taken for calculating eCPP (13,14). Some groups have used regression lines of the relationship between simultaneously recorded instantaneous measurements of ABP and FV pulse waves to determine ZFP (1,19). There is no consensus on which method may be better. In this study, we used Belfort et al.’s method (3,18) because it is simpler, noninvasive, and clinically applicable in patients without invasive BP monitoring.

In theory, CO₂ can affect ZFP by its effects on either ICP or the arteriolar tone of the cerebral vasculature. In this study, we did not measure ICP directly because it would be too invasive and not feasible in volunteers. However, the expected changes in ICP, induced by changes in CO₂ in our subjects, would be small and, more importantly, opposite the observed changes in ZFP. As an example, hypocapnia would be expected to decrease ICP (and increase CPP), whereas we observed an increase in ZFP (and decreased CPP); similarly, hypercapnia would be expected to increase ICP, and we have observed a decrease in ZFP. Therefore, the effects of CO₂ on the arteriolar tone remain a reasonable explanation for the changes in CPP and ZFP in our study. The exact role of arteriolar tone in determining CPP and ZFP in patients with a neurological disorder (with or without increased ICP) remains to be evaluated. However, our results support the suggestion (1) that, in the absence of increased ICP, arteriolar tone is the major determinant of ZFP. In addition, our results may provide an explanation for the discrepancy between ICP and critical closing pressure (ZFP) in patients with neurotrauma, as reported by Thees et al. (16).

We used the Finapres in our study for noninvasive BP monitoring. This was used to ensure continuous monitoring of BP to establish steady-states during measurements. Another advantage of the Finapres for this study was its ability to capture the same pulse waves for BP measurements as for FV measurements. This was particularly important because the changes in PE'CO₂ (and related changes in FV) could not be sustained at a steady-state for a prolonged period of time. However, the Finapres may not be as accurate as other means of noninvasive BP measurements or, indeed, invasive BP readings, and therefore our calculated absolute values of eCPP and ZFP may have been different if we had used another method. However, the Finapres, despite being inaccurate for absolute values, has been shown to be sensitive and predictable in assessing changes in BP (20). Therefore, our results for the changes in eCPP and ZFP, which are based on relative changes in BP and FV during changes in PE'CO₂, are unlikely to have been significantly different if another method of assessing BP had been used.

We did not randomize the sequence of hypocapnia and hypercapnia. In our experience, hypercapnia can be unpleasant in some volunteers, who would then be less inclined to continue with the experiment. However, none of our volunteers experienced unpleasant effects. Also, all readings of MCA FV and BP were allowed to return to baseline from the effects of hypocapnia to prevent hysteresis before hypercapnia was induced.

In summary, our results show that, in subjects without any neurological disorder, varying PE'CO₂ produces significant changes in eCPP and ZFP. Hypocapnia decreases eCPP, and hypercapnia increases it; these effects are opposite to what would be expected from the known effects of CO₂ on ICP. The results of our study support the suggestion by Weyland et al. (1) that vascular tone is a major determinant of effective down stream pressure in the absence of intracranial hypertension. This may have implications in the manipulation of CO₂ during neuroanesthesia, neurotrauma, or both.

	References

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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999