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Experimental Physiology 90.3 pp 349-355
DOI: 10.1113/expphysiol.2004.029512
© The Physiological Society 2005
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Laser Doppler flowmetry is valid for measurement of cerebral blood flow autoregulation lower limit in rats

Jan Tonnesen1, Anders Pryds1, Erik H. Larsen2, Olaf B. Paulson1, John Hauerberg1 and Gitte M. Knudsen1

1 Neurobiology Research Unit, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark2 August Krogh Institute, University of Copenhagen, Copenhagen, Denmark


   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Laser Doppler flowmetry (LDF) is a recent technique that is increasingly being used to monitor relative changes in cerebral blood flow whereas the intra-arterial 133xenon injection technique is a well-established method for repeated absolute measurements of cerebral blood flow. The aim of this study was to validate LDF for assessment of cerebral autoregulation and CO2 reactivity with the 133xenon injection technique as the gold standard. Simultaneous measurements of cerebral blood flow (CBF) were collected by LDF (CBFLDF) and the 133xenon method (CBFXe) while (1) cerebral autoregulation was challenged by controlled systemic haemorrhage, or (2) cerebral blood flow was varied by manipulating the arterial partial pressure of CO2 (Pa,CO2). LDF slightly overestimated CBF under conditions of haemorrhagic shock and haemodilution caused by controlled haemorrhage (paired t test, P < 0.05). However for pooled data, the autoregulation lower limit was similar when determined with the 133xenon and the LDF techniques: 65 ± 3.9 mmHg and 60 ± 5.6 mmHg, respectively. Linear regression analysis yielded CBFXe= (1.02 x CBFLDF) + 9.1 and r= 0.90. Even for substantial changes in Pa,CO2, the two methods resulted in similar results. We conclude that even though LDF overestimated CBF during haemorrhagic shock caused by controlled haemorrhage, the lower limit autoregulation was correctly identified. The laser Doppler technique provides a reliable method for detection of a wide range of cerebral blood flow changes under CO2 challenge. Haemodilution influences the two methods differently causing relative overestimation of blood flow by the laser Doppler technique compared to the 133xenon method.

(Received 24 November 2004; accepted after revision 5 January 2005; first published online 14 January 2005)
Corresponding author G. M. Knudsen: Neurobiology Research Unit, N9201, Rigshospitalet, Blegdamsvej 9, DK- 2100 Copenhagen, Denmark. Email: gitte{at}nru.dk


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Laser Doppler flowmetry (LDF) is a relatively new method for measuring tissue perfusion. The advantage of LDF in cerebral perfusion studies is its ability to measure non-lethally and continuously for up to several hours. Most other techniques for measuring cerebral blood flow (CBF) yield only few temporally discrete data and necessitate killing of the experimental animal immediately afterwards. On the other hand, LDF measures perfusion only in arbitrary units, enabling evaluation of relative changes in perfusion, but not in absolute values (Stern, 1975). Measurements of relative perfusion by LDF are particularly useful for assessment of cerebral autoregulation because continuous autoregulation curves can be obtained.

So far, among the techniques available for CBF measurements the 133xenon method allows for more repeated measurements. Usually more than 10 subsequent measurements can be made in a single animal. For that reason the 133xenon method has been extensively applied for haemorrhagic CBF autoregulation studies (Lassen & Hoedt-Rasmussen, 1966; Hertz et al. 1984; Rasmussen et al. 1992; Heimann et al. 1994; Hauerberg et al. 1995; Ma et al. 1999, 2000; Springborg et al. 2002; Pedersen et al. 2003, Bay-Hansen et al. 2003). LDF, on the other hand, yields continuous data. The method has previously been validated against various techniques for CBF measurements, including autoradiographic iodantipyrine (Eyre et al. 1988; Fabricius & Lauritzen, 1996), microspheres (Muller et al. 2002; Bishai et al. 2003), hydrogen clearance (Haberl et al. 1989; Fukuda et al. 1995; Kramer et al. 1996) and a thermal diffusion microprobe (Vajkoczy et al. 2000). In earlier validations, CBF has been challenged by various manipulations, including O2–CO2 reactivity (Haberl et al. 1989; Fukuda et al. 1995; Fabricius & Lauritzen, 1996; Vajkoczy et al. 2000; Muller et al. 2002; Bishai et al. 2003), haemorrhage (Skarphedinsson et al. 1988; Eyre et al. 1988; Vajkoczy et al. 2000) and middle cerebral or common carotid artery occlusion (Dirnagl et al. 1989; Kramer et al. 1996), and validations have generally shown that LDF correlates well with more established methods. By contrast, the performance of LDF to detect the lower limit autoregulation under conditions of hypotensive haemorrhage has never previously been validated, though the method has been widely applied for autoregulation studies. Vajkoczy et al. (2000) actually compared autoregulation lower limits measured by LDF and a thermal diffusion microprobe but they did not describe how the comparison was performed or present statistics.

The validity of LDF for autoregulation studies has actually been questioned, because the measuring area of the laser Doppler probe is very small (Jones et al. 2002). Previously used methods for assessment of CBF autoregulation detect both plasma and blood cell flow. Thus, changes in haematocrit as observed in haemorrhagic shock may potentially influence the assessment of the lower limit of autoregulation differently than with LDF measuring exclusively cell flow.

The aim of this study was to validate LDF for assessment of lower limit of autoregulation using the intra-arterial 133xenon method as the gold standard and lowering systemic blood pressure by controlled haemorrhaging. Simultaneous measurements by the two techniques were obtained during controlled systemic haemorrhage leading to profound reductions in the mean arterial blood pressure (MABP). As a control experiment, CBF was manipulated without changing haematocrit by varying the inspired CO2 concentration.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Animals

Male Sprague-Dawley rats (Charles River, Germany) weighing 250–350 g were used. The animals were housed in macrolon cages with food (Altromin 1314; Chr. Petersen, Ringsted, Denmark) and water available ad libitum. Lights were on from 07.00 h until 19.00 h.

All animal experiments were carried out in accordance with the European Communities Council Resolves of 24 November 1986 (86/609/EEC) and approved by the Danish State Research Inspectorate (J.No 1999-561-25).

Surgical procedures

Anaesthesia was induced with 5% isoflurane followed by 2.5% (Dräger, Lübeck, Germany) in 30% oxygen–70% nitrous oxide. After tracheostomy, rats were artificially ventilated by a small animals respirator (Harvard Apparatus Ltd, Kent, UK) and isoflurane was reduced to 1.5–1.7%. End tidal CO2 pressure was kept close to 40 mmHg by varying respiration depth. Rectal temperature was kept close to 37.5°C by a heating pad (Panlab, Barcelona, Spain). Both femoral arteries and veins were cannulated for blood sampling, haemorrhaging, blood pressure monitoring (equipment from Simonsen and Weel, Herlev, Denmark) and administration of donor blood and of drugs.

For 133xenon injections we used the procedure described by Hertz et al. (1984). In short, a pp25 catheter was placed in a retrograde direction in the right side of the external carotid with the tip just before the carotid bifurcation. Extra-cerebral branches, including the pterygopalatine artery, were ligated to avoid extra-cerebral distribution of 133xenon. After placement of the 133xenon catheter, the rat was positioned in a stereotactic frame (David Kopf Instruments, Germany) and the parietal bone was exposed. A burr hole sized 3 mm x 2 mm was drilled in the left side of the parietal bone exposing the parietal cortex but leaving the dura intact. The craniotomy was continuously superfused with saline. A single collimated (diameter, 3.9 mm) sodium iodine crystal was placed over the intact right side of the parietal bone for 133xenon clearance measurements.

Under an operating microscope, a micromanipulator was used to position the 1-mm diameter laser Doppler probe (wavelength, 780 nm; probe 407, Perimed, Stockholm, Sweden) just above the dura over the exposed left hemisphere. Care was taken to place the probe at a brain area with minimal vascularization. Following surgical procedures, the animal was left for 30–60 min to stabilize. The operation time from induction of anaesthesia to beginning of baseline measurements was ~1.5–2 h.

Data collection

All rats received 0.15 ml intravenous heparin (500 IU ml–1) to prevent blood coagulating in the catheters. Blood samples were replaced by equivalent amounts of freshly drawn blood from a donor rat of the same sex and strain, except for during haemorrhage.

Laser Doppler measurements were continued for 1–4 min after ending experiments by pentobarbital injection when CBF was zero to register the LDF ‘no-flow’ value, i.e. the laser Doppler value generated not by blood cell flux but by Brownian movements arising in the interstitial compartment (Kernick et al. 1999), external light sources and/or movements artefacts (own observations). Once a steady ‘no-flow’ value was obtained this was averaged over a 30-s period. The LDF data were corrected by subtracting the corresponding ‘no-flow’ value for each experiment.

Autoregulation

Cerebral autoregulation was challenged by constant systemic venous haemorrhage over 1–1.5 h thereby lowering MABP to ~30 mmHg. In four rats where baseline MABP was below 80 mmHg, noradrenaline (norepinephrine; 0.005–0.01 mg ml–1I.V.) was infused over a period of minutes to increase MABP by 10–15 mmHg before haemorrhaging to obtain a broader autoregulatory plateau. CBF was measured at intervals of approximately 10 mmHg during haemorrhage and MABP and LDF data were collected continuously (sampling rate 32 Hz) throughout the experiment. Xenon was injected as boluses of 0.05–0.08 ml 133xenon dissolved in saline (11–27 mCi ml–1) (Hertz et al. 1984). Corrections for background activity were applied on the basis of recordings obtained 30 s immediately before xenon injection. CBF was computed according to Pedersen et al. (2003) from the initial 30 s slope of the washout curve on a semilogarithmic plot considering background recordings (Olesen et al. 1971; Pedersen et al. 2003). The 30-s measuring periods yield mono-exponential clearance curves presumably representing predominantly grey matter (cortical) clearance (Olesen et al. 1971).

After each xenon clearance measurement arterial partial pressure of CO2 (Pa,CO2) and O2 (Pa,O2), and blood pH were determined from arterial blood samples (0.1 ml) by means of an ABL 605 blood gas analyser (Radiometer, Copenhagen, Denmark). Pa,CO2 was kept at 38–42 mmHg and Pa,O2 above 100 mmHg.

Typically 10 min passed between xenon measurements to allow previously injected xenon to clear via respiration. The autoregulation study was based on between 10 and 15 xenon measurements in each rat (n= 7; 90 data pairs).

CO2 reactivity

Hypocapnia was achieved through hyperventilation by increasing respiration depth. Hypercapnia was induced by adding up to 5% CO2 to inspired air at normal ventilation rate. Pa,O2 was kept above 100 mmHg as determined by arterial blood samples. Xenon clearance measurements, MABP and LDF measurements were performed as described above. The CBF CO2 reactivity was based on between six and 13 133xenon injections in each rat (n= 6; 66 data pairs).

Haematocrit

Rats (n= 3) were bled to produce a MABP of approximately 20 mmHg over ~1 h while 0.9-ml blood samples were drawn and analysed for haematocrit at regular intervals. Blood gas values and temperature were kept within the same limits as in the autoregulation lower limit study. Samples were centrifuged on a haematocrit centrifuge (BHG, Hermle) for 8 min, and volume fraction haematocrit was calculated.

Data analysis

LDF data from each of the 30-s periods over which 133xenon clearance was measured was averaged to allow pairwise comparisons of relative changes in CBF. Laser Doppler measurements (arbitrary units) were then indexed to the simultaneously collected absolute xenon baseline data (ml (100 g)–1 min–1).

Autoregulation curves (see Fig. 2) were analysed by plotting LDF or 133xenon data against simultaneously obtained MABP data. The lower limit of autoregulation was calculated by computer software as described earlier (Pedersen et al. 2003). In short, the lower limit was identified as the MABP corresponding to the intersection between two linear regression lines: one horizontal line above the lower limit (the plateau); and another oblique line below the lower limit. Regression lines were identified through least-squares routines. Autoregulation lower limits were determined on the basis of data pooled from all rats within a group. We also evaluated the outcome of estimates based on no plateau constraints on the autoregulation curve, thereby allowing the plateau to be sloped.



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  		Figure 2.  Autoregulation lower limit
The CBFXe and the simultaneously measured CBFLDF data plotted against the corresponding MABP values. In total 90 data pairs from seven rats. Statistically no significant difference could be demonstrated when assessing lower limit of cerebral autoregulation (two-tailed t test on intersections of regression lines). Lower limits using horizontal plateaux were 60 ± 5.6 (S.E.M.) and 65 ± 3.9 mmHg for CBFLDF and CBFXe, respectively, based on the pooled data. Allowing sloped plateaux yielded lower limits at 50 ± 42.1 mmHg (LDF) and 51 ± 13.1 mmHg (xenon). However when individually comparing the 90 CBF data pairs, a statistically significant difference was found (paired t test, P < 0.05). LDF values were indexed to xenon baseline measurements.

 
Statistics

Comparison between the relative CBF measured by LDF (CBFLDF) and the absolute CBF measured by 133xenon (CBFXe) data pairs and comparison between lower limits measured by the two methods were made by paired two-tailed t test (normality test passed). Lower limits were compared by two-tailed t test on regression line intersections. Level of significance was set at P= 0.05.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
LDF as measured in arbitrary units varied considerably between different probe sites within and between animals. Arbitrary LDF baseline values were in the order of 150–500 laser Doppler units (1 unit = 10 mV).

Autoregulation

Linear regression analysis between the indexed CBFLDF and the 133xenon data yielded the relation CBFLDF= 1.02CBFXe+ 9.1, r= 0.90 (Fig. 1). When pairwise comparisons of the 90 samples were conducted, LDF overestimated CBF significantly (P < 0.05). However, pooling data from all animals resulted in similar values of the lower limit of autoregulation. When limited to a horizontal plateau, the lower limit was identified at 65 ± 3.9 mmHg (mean ±S.E.M.) by the 133xenon method and at 60 ± 5.6 mmHg with LDF (two-tailed t test on intersection of two regression lines, P > 0.05). When a sloped plateau was allowed, lower limits were 50 ± 42.1 mmHg and 51 ± 13.1 mmHg for LDF and xenon, respectively (Fig. 2).



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  		Figure 1.  Haemorrhage group
Relationship between relative changes in CBF measured simultaneously by the LDF (CBFLDF) and the 133xenon (CBFXe) methods during lowering of MABP by controlled haemorrhage. Arbitrary LDF units were normalized to absolute CBFXe baseline measurements to enable a direct comparison. LDF baseline values were calculated relative to xenon baseline measurements to allow direct comparison.

 
CO2 reactivity

As Pa,CO2 values ranged between 25 and 70 mmHg, CBFXe varied between 40 and 302 ml (100 g)–1 min–1. MABP was above the lower limit of autoregulation for all measurements (> 70 mmHg). Comparison of CBFLDF and CBFXe data pairs showed that these did not differ significantly. Linear regression analysis yielded CBFLDF= 0.996CBFXe+ 0.3, r= 0.96. (Fig. 3). The CO2 reactivity was not calculated because exact Pa,CO2 values corresponding to each CBF value were not obtained for all CBF measurements.



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  		Figure 3.  CO2 reactivity group
The correlation between CBFXe and CBFLDF was found to be strong when varying Pa,CO2 between 25 and 70 mmHg. No significant difference could be demonstrated between the two groups (paired t test, P > 0.05). In total 66 data pairs were obtained from six rats. LDF values were given relative to xenon baeline measurements.

 
Haematocrit

Three rats were bled from 107 ± 14.4 (mean ±S.D.) to 20 ± 3.5 mmHg MABP. Haematocrit decreased from 47 to 30%. Hemorrhaging time was approximately 1 h. The MABP and haematocrit relationship was well described by a linear function (haematocrit = 0.15MABP + 29.4, r= 0.94; Fig. 4).



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  		Figure 4.  Haematocrit
Haematocrit decreased linearly with MABP during controlled haemorrhage. MABP was decreased from 107 ± 14.4 to 20 ± 3.5 mmHg. Haematocrit decreased linearly with MABP. The relationship between MABP and haematocrit was well described by a positive linear correlation.

 

   Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
This is the first time that a pairwise comparison of simultaneously obtained CBF data reveals that relative CBF is overestimated by LDF as compared to the 133xenon method during controlled systemic haemorrhage. By contrast, manipulating CBF without changing haematocrit yielded an almost perfect correlation. In spite of the overestimation, we found that LDF reliably assessed the lower limit of cerebral autoregulation as compared to the intra-arterial 133xenon method as the gold standard.

In an earlier validation study, LDF and thermal diffusion microprobe measurements were successfully compared by Vajkoczy et al. (2000) who found that the lower limit was around 65 mmHg with either method; however, no statistical analysis was performed.

The reasons for the observed discrepancy between the two methods under hypovolaemic hypotension and haemodilution are not straightforward. As LDF measures the flow of blood cells whereas the 133xenon method measures whole blood flow, haemodilution is expected to lead to an underestimation of LDF-determined CBF, yet we observed the opposite.

Our data are at odds with a previous study where concordance between LDF and radionuclide-labelled microsphere measurements were described under haemorrhagic conditions (Eyre et al. 1988). However, in that study only three measurements in each of five rabbits were performed and minor discrepancies between the methods may have been difficult to demonstrate. In cats lowering of systemic haematocrit by 25% through hypervolaemic haemodilution lead to a significant underestimation of CBF by LDF as compared to hydrogen clearance (Kramer et al. 1996), also discordant with our data. Hypervolaemic haemodilution is, however, not anticipated to elicit the same microcirculatory response as hypovolaemic haemodilution due to haemorrhagic shock.

Because the 133xenon technique measures regional distribution and clearance of 133xenon in whole blood, whereas LDF primarily depends on highly localized red blood cell flow, four different explanations for the observed discrepancy are considered: (1) the cerebral capillary red blood cell concentration increases during hypotensive bleeding; (2) a decrease of the blood–brain grey matter partition coefficient ({lambda}) for xenon occurs during hypotensive bleeding; (3) plasma velocity through cerebrocortical capillaries decreases relatively more than red blood cell velocity during hypotensive bleeding; and (4) the two methods measure different tissue beds and these respond differently to haemorrhagic hypotension.

As a linear positive relationship was found between MABP and systemic haematocrit, explanation (1) seems unlikely. Assuming that the decreasing haematocrit is also reflected in the cerebral microcirculation (Knudsen et al. 1992), a correction of {lambda} for haematocrit can be applied (Harrigan et al. 2000) and the introduction of such a correction will change the calculated CBF inversely to haematocrit values. By using the identified relationship between haematocrit and MABP (Fig. 4), a maximal increase of 0.049 in the {lambda}-corrected as compared to uncorrected CBF values is found. However, even with this correction a significant difference was still present (P < 0.05). Regarding explanation (3), a relatively larger decrease in plasma velocity than in red blood cell velocity during haemorrhage may actually happen. Under isovolaemic haemodilution in the rat, with systemic arterial haematocrit decreasing from 44 to 15%, cerebral capillary red blood cell velocity and supply rate were found to increase in parallel using videomicroscopy. However, lineal cell density, an index of capillary haematocrit, remained constant suggesting that cerebral capillary haematocrit is more independent of arterial haematocrit (Hudetz et al. 1999). This finding is at odds with the observation that when systemic haematocrit decreased as a consequence of isovolaemic haemodilution, the plasma velocity increased in rat cerebral microvessels while red blood cell velocity remained constant (Lin et al. 1995). There are no published data available where the cerebral capillary response to haemorrhagic shock has been described, and for that reason we cannot exclude the possibility that relative changes in plasma versus red blood cell velocity may play a role.

Regarding explanation (4), cortical blood flow to superficial and deeper vascular beds is possibly separated (Harper & Bohlen, 1984), and perhaps a rearrangement of blood flow during hypotension, prioritizing the superficial layer, could account for the apparent overestimation of relative CBF by LDF, assuming the 133xenon method measures deeper tissues than LDF.

The perfect correlation during capnic challenges is in agreement with earlier studies. This applies for hydrogen clearance methods in rats (Fukuda et al. 1995) and microsphere techniques in fetal sheep (Kimme et al. 2002). Further, measurements obtained simultaneously in rabbits while administering noradrenaline or trimetaphan camsilate to either increase or decrease MABP, respectively, or during hypo- and hypercapnia, showed excellent correlation between LDF and the hydrogen clearance method (Fukuda et al. 1995).

When the autoregulatory plateau was allowed to be sloped, lower limits were estimated at 50 ± 42.1 mmHg and 51 ± 13.1 mmHg for LDF the 133xenon method, respectively. As expected, the sloped plateau approach yielded relatively lower estimates of the autoregulation lower limit, than did the traditional (horizontal plateau) approach, but at the same time the variability of the estimates increased dramatically. The sloped plateau may turn out to be feasible in future studies where an impaired, but not completely abolished autoregulation is expected.

In conclusion, LDF is a valuable tool for continuously measuring relative changes in CBF. Under conditions of hypovolaemic haemodilution and haemorrhagic shock caused by controlled haemorrhage, the LDF method yields significantly higher relative CBF values than the 133xenon injection technique. This discrepancy does not, however, influence the assessment of the lower limit of autoregulation significantly.


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 Discussion
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   Acknowledgements
 
We thank the Simon Fougner Family Foundation for financial support.




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expphysiol.2004.029512v1
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