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Baroreceptor-mediated reduction of jejunal mucosal perfusion, evaluated with endoluminal laser Doppler flowmetry in conscious humans
Journal of the Autonomic Nervous System 68 Ž1998. 157–163
Baroreceptor-mediated reduction of jejunal mucosal perfusion, evaluated with endoluminal laser Doppler flowmetry in conscious humans Anders Thoren ´ b
a,)
, Sven-Erik Ricksten a , Stefan Lundin a , Bertil Gazelius c , Mikael Elam
b
a Department of Anaesthesiology and IntensiÕe Care, Sahlgrenska UniÕersity Hospital, S-413 45 Goteborg, Sweden ¨ Institute of Clinical Neuroscience, Department of Clinical Neurophysiology, Sahlgrenska UniÕersity Hospital, Goteborg, Sweden ¨ c Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden
Received 3 February 1997; revised 18 September 1997; accepted 9 October 1997
Abstract Reduction of central blood volume elicits a peripheral vasoconstrictor reflex in various tissues including skin, skeletal muscle and the hepatomesenteric region. The aim of the present study was to investigate whether this reaction includes a decreased perfusion of the jejunal mucosa in man. Laser Doppler flowmetry ŽLDF. was used to monitor jejunal mucosal and skin perfusion simultaneously in eleven healthy volunteers. LDF recordings were performed during quiescent Žphase 1. periods of the migrating motor complex. Seven subjects demonstrated cycling changes of jejunal mucosal perfusion Žvasomotion.. The average minimum jejunal flux value was 72 " 6 perfusion units. The average intraindividual coefficient of variation was 18 " 2%. Lower body negative pressure ŽLBNP. was used to elicit controlled reductions of central blood volume. LBNP of 10 mm Hg induced a 12 " 4% Ž P - 0.05. decrease in jejunal perfusion and a 43 " 11% Ž P - 0.001. decrease in cutaneous perfusion. Corresponding responses to LBNP of 20 mm Hg were 17 " 5% Ž P - 0.01. and 37 " 10% Ž P - 0.01. reductions in jejunal mucosal and skin perfusion, respectively. Cardiac index was significantly reduced by the LBNP procedure, whereas heart rate remained unchanged and blood pressure changes were minor and inconsistent. These findings indicate that the reflex vasoconstriction induced by mild central hypovolemia includes a significant reduction of jejunal mucosal perfusion in supine resting humans. This reflex may provide one mechanism for the intestinal ischemia often occurring in critically ill patients. q 1998 Elsevier Science B.V. Keywords: Jejunal mucosal vasoconstriction; Laser Doppler flowmetry; Lower body negative pressure; Sympathetic reflex; Vasomotion
1. Introduction A decrease in central blood volume in humans elicits a baroreflex mediated peripheral vasoconstriction, mainly via unloading of cardiopulmonary Žlow pressure. receptors w49x. Experimental reduction of central blood volume by applying lower body negative pressure ŽLBNP. has been shown to elicit vasoconstriction of the vascular beds in both skin and muscle w24,45x. In microneurographic recordings, sympathetic vasoconstrictor fibres to the muscle vascular bed in both arm and leg have been found to respond to graded LBNP with an instantaneous and sustained increase in firing rate w36,40,47x. Several studies using indocyanine green clearance ŽICG. technique have indicated that the reflex vasoconstriction by LBNP-induced central hypovolemia also includes the )
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hepatomesenteric vascular bed w1,10,23x. However, this method does not allow a differentiation between intestinal and hepatic blood flow. Since intestinal ischemia is considered a risk factor in critically ill patients during hypovolemia and different shock states w31x, the evaluation of whether reductions in central blood volume may elicit intestinal vasoconstriction is of major clinical importance. Laser Doppler flowmetry is an established method for monitoring tissue perfusion w16,32x. It has been used so far mainly for evaluation of the cutaneous circulation. In recent years, however, the technique has also been used in other tissues, including the gastrointestinal tract. In man the method has been used for perfusion studies in the gastric, duodenal, jejunal, ileal and colonic intestinal wall, during laparatomy w3,4,21,27x or by the use of endoscopy w4,5,14,19,20,28,34,35 x. In a recent study in the duodenum w43x the LDF probe was positioned endoluminally using fluoroscopy.
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The specific aim of the present study was to elucidate whether an LBNP-induced reduction of central blood volume elicits a jejunal mucosal vasoconstriction in man. A general aim was to evaluate the feasibility of continuous monitoring of jejunal mucosal perfusion in awake subjects. Our results show that the vasoconstrictor response induced by central hypovolemia does involve jejunal mucosal perfusion.
2. Methods
2.2. Simulated hypoÕolemia The lower part of the body, up to the iliac crest, was placed in the LBNP box. To prevent air leakage a flexible broad rubber band was taped to the skin of the lower abdomen and trunk. The LBNP box was closed and a vacuum cleaner was used to apply repeated suction of 10 and 20 mm Hg. The pressure inside the box was monitored by a pressure transducer calibrated against a mercury column. A stable level of 10 or 20 mm Hg suction was reached within 10 s. 2.3. Study design
Experiments were performed on 13 healthy volunteers Ž6 male, 7 female; mean age 32.7 years, range 24–48. after an over-night fast. Informed consent was given by all subjects and the investigation was approved by the Human Ethics Committee at the University of Goteborg. ¨ 2.1. Laser Doppler flowmetry Tissue perfusion was monitored with laser Doppler flowmeters ŽLDF; Periflux PF 4001 for jejunal and PF 2b for skin perfusion, Perimed AB, Jarfalla ¨ ¨ .. Intestinal perfusion was monitored with a custom build probe developed for the study. Two sets of three fiberoptic channels were incorporated in a catheter with an outer diameter of 5 mm. The fibres have a diameter of 150 m m and the fibre center separation within the sets of three fibres is 200 m m. Light with the wavelength of 780 nm is guided in one fibre of each set, ending 23 mm Ždistal. and 123 mm Žproximal., respectively, from the tip of the catheter. Two fibres of each set receive the Doppler-broadened and backscattered light from the tissue and transmit it to the photodetectors, allowing the monitoring of perfusion in two separate intestinal positions. The catheter was placed endoluminally under fluoroscopic guidance, using the nasogastric route, with the two sets of LDF fibres positioned approximately 10–40 cm distal to the ligament of Treitz. Skin perfusion was simultaneously monitored, with a conventional probe placed on the volar aspect of a finger tip Ždig II or III.. For all flux measurements, a time constant of 0.2 s and a band width of 12 kHz was used and calibration was performed as recommended by the manufacturer. The output signal of the flowmeter yields no absolute blood flow value, but shows relative changes in the flux of blood cells Žfor technical details and evaluation of the flowmeter see Refs. w14,30x.. Heart rate was recorded continuously during the experiments. Cardiac output and blood pressure responses to LBNP were recorded in a separate session Žcf. below.; cardiac output was measured non-invasively in all subjects with the transthoracic electrical impedance technique ŽBiomed NCCOM3-R7. and blood pressure oscillometrically every 25 s ŽCardiocap II-2S, Datex..
LDF recordings of intestinal perfusion were only analyzed in periods with stable pulse-synchronous flux waves ŽFig. 1., without movement artefacts or intestinal peristalsis. Such quiescent periods in fasting humans are called phase 1, and constitute the initial part of ‘the migrating motor complex’ ŽMMC.. It is followed by a period of irregular contractions Žphase 2. and subsequently a period of intense regular contractions Žphase 3.. These three phases form the MMC and migrate from the duodenum towards the colon w43,46x. All perfusion values presented in this study are calculated from phase 1 periods starting one minute after phase 3 activity and ending with the onset of phase 2. The obtained LDF flux values from the proximal and distal fibres were averaged.
Fig. 1. Laser Doppler records of jejunal perfusion Župper two traces. and radial arterial pressure Žlower trace. recorded simultaneously, illustrating the pulse-synchronous nature of jejunal flux waves.
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to reach adequate suction level excluded from analysis. LBNP analysis included three minutes following the termination of LBNP. The number of LBNP trials were determined by the amount of phase 1 activity exhibited by the subjects and ranged from 0–3 trials for 10 and 20 mm Hg of LBNP, respectively. Repeated trials were averaged for each subject before the statistical analysis. LBNP epochs where sharp increases in the perfusion signal, indicating motor activity or optical discoupling, occurred during the provocation were excluded from analysis. At least 20 min of recovery was allowed between LBNP maneuvers. The parallel monitoring of skin perfusion during LBNP maneuvers was performed as an ‘internal control’, to ensure that the procedure elicited reflex skin vasoconstriction. Due to the limited number of phase 1 periods suitable for LDF recordings during LBNP Žcf. Section 3., the changes in cardiac index and blood pressure during LBNP were established in a separate recording session on the same individuals and responses to three 1 min periods of 10 and 20 mm Hg LBNP, respectively, were recorded. Separate measurements of LBNP-induced cardiac output changes were considered justified, given a very limited intra- and interindividual variability of these changes Žcf. Fig. 4, lower panel.. 2.4. Analysis All values are presented as mean " SEM. Statistical comparisons were made between control period Ž1 min. and LBNP period Ž1 min. and also between LBNP periods Ž10 and 20 mm Hg.. Two way ANOVA for repeated measures was used for the evaluation of perfusion and
Fig. 2. Records of jejunal perfusion during MMC phase 1 in Ža. a subject exhibiting pronounced vasomotion Ž2.7–3.3 cycles miny1 . and Žb. a subject without apparent mucosal vasomotion. Skin perfusion lacks obvious vasomotion in both subjects. Note also the marked difference in resting skin perfusion between subjects.
A ten minute long period of phase 1 was required to establish a ‘minimum jejunal mucosal flux value’. When subjects exhibited longer or several phase 1 periods, the period with the lowest mean flux value was chosen. An intraindividual coefficient of variation was also calculated during this period. LBNP trials during phase 1 were preceded by a 70 s control period, with the last 10 s excluded to avoid influence of arousal reactions during announcing of the LBNP. LBNP was performed for 70 s, with the first 10 s needed
Fig. 3. Parallel jejunal mucosal Župper two traces. and skin Žlower trace. vasoconstriction during an LBNP of 10 mm Hg, all three records returning to control perfusion level after termination of the stimulation.
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hemodynamic changes during LBNP. P - 0.05 was considered statistically significant.
3. Results Two subjects were excluded from analysis due to extensive intestinal peristalsis, resulting in a lack of sufficiently long phase 1 Žquiescent. periods to calculate a minimum flux value or to perform LBNP maneuvers. The remaining eleven subjects had an average minimum jejunal mucosal flux value of 72 " 6 perfusion units ŽPU.. The average coefficient of variation was 18 " 2%. The intraindividual variation was in part due to cyclic changes in mucosal flux values during phase 1, exhibited by seven subjects Ž64%, Fig. 2a,b..
3.1. Perfusion during LBNP Flux values in the control period before LBNP were higher than the minimum flux value mentioned above, averaging 92 " 8 PU. LBNP of 10 mm Hg was performed on nine subjects and LBNP of 20 mm Hg was performed on 8 subjects. During LBNP of 10 mm Hg perfusion decreased in eight subjects and increased in one, yielding an average perfusion decrease of 12 " 4% Ž P - 0.05. ŽFigs. 3 and 4.. During LBNP of 20 mm Hg, perfusion decreased in six subjects, increased in one and remained unchanged in one, resulting in an average reduction of 17 " 5% Ž P - 0.01. ŽFig. 4.. The difference in reduction of perfusion between the two LBNP levels was not significant. A similar decrease in skin perfusion was found at both LBNP levels, the average reduction being 43 " 11% Ž P 0.001. and 37 " 10% Ž P - 0.01. ŽFigs. 3 and 4., during LBNP 10 and 20 mm Hg, respectively. 3.2. LBNP effects on hemodynamics Resting heart rate averaged 57 " 2 in the study group, and remained unaffected during LBNP. Cardiac index decreased ŽFig. 4. with 6 " 3% Ž P - 0.05. and 17 " 2% Ž P - 0.001. during LBNP 10 and 20 mm Hg, respectively Ž P - 0.05 between LBNP levels.. Pulse pressure only tended to decrease during LBNP 10 mm Hg Ždown 2.0 " 2.3 mm Hg, ns., but decreased 4.3 " 2.0 mm Hg during LBNP 20 mm Hg Ž P - 0.001.. Mean arterial blood pressure was reduced during LBNP 10 mm Hg Ž3.9 " 3.5 mm Hg, P - 0.01., but not significantly reduced during LBNP 20 mm Hg Ž2.7 " 4.4 mm Hg, ns.. 3.3. RecoÕery Jejunal mucosal perfusion reached control level within 2–3 min after the termination of LBNP, skin perfusion within 1 min and hemodynamic variables within 2 min.
4. Discussion
Fig. 4. Mean perfusion reductions recorded from the jejunal mucosa Župper panel. and skin Žmiddle panel. during LBNP of 10 ŽB. and 20 Žv . mm Hg, respectively. Both jejunal mucosal and skin vasoconstrictor responses were significant, and similar at both LBNP levels. Cardiac index Žlower panel. was reduced at both levels of LBNP, but more markedly during LBNP of 20 mm Hg Ž P - 0.05 between levels.. ) P 0.05, ) ) P - 0.01, ) ) ) P - 0.001.
The main finding of the present study is that a mild reduction of central blood volume, induced by low levels of LBNP, is associated with a significant reduction of jejunal mucosal perfusion in healthy awake humans. This result indicates that baroreceptor reflexes may be involved in the mechanisms compromising intestinalrjejunal mucosal perfusion in states of central hypovolemia and low cardiac output. In addition, our findings suggest that it may be possible to use this semi-quantitative technique to detect severe jejunal mucosal hypoperfusion in critically ill patients.
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4.1. Baseline jejunal perfusion A recent study, combining laser Doppler flowmetry with intestinal manometry, has indicated that intestinal perfusion increases during peristalsis Ži.e. MMC. in fasted humans w43x. Although we did not have a measure of motor activity, periods of intestinal peristalsis are easily identified in a laser Doppler record due to these sudden perfusion increases, sometimes in combination with movement artifacts. We were therefore able to choose 10 min periods of intestinal quiescence for the calculation of a ‘minimum jejunal mucosal flux value’. The wide range of individual coefficients of variation between subjects during this period Ž9–38%. is mainly due to different degrees of cyclic oscillation in the LDF signal. As shown in Fig. 2, these oscillations are pronounced in some subjects and absent in others and they also differ in amplitude and frequency. This phenomenon has previously been described in laser Doppler recordings from canine gastric and intestinal mucosa with a frequency of 2.5–3.5 cycles miny1 Žcompare frequency Fig. 2a. w25,26x. It has been found to be independent of respiration, blood pressure and total blood flow and is considered to represent mucosal blood flow w26x. Cyclic microvascular flow velocity changes with the frequency of 4–7 cycles miny1 have also been demonstrated with intravital microscopy in the rat gastric mucosa w17x. These cyclic perfusion changes were attributed to tonus changes in the feeder arterioles or precapillary sphincters in the mucosa and are referred to as Õasomotion. Vasomotion in human duodenal mucosa has recently been described with LDF-technique, with the frequency of 3.6–4.3 cycles miny1 w44x. In porcine jejunal mucosa regular changes in oxygenation with the frequency of 3.4–5 cycles miny1 has been shown, due to vasomotion w13,15x. These regular changes were absent in jejunal serosal registrations, indicating that vasomotion in the jejunum is a mucosal phenomenon. Although LDF yields no absolute blood flow values, LDF flux data have been used to calculate absolute blood flow values in the human jejunum which correlated well with values simultaneously obtained with total venous outflow technique in the range of 0–50 ml miny1 100 gy1 w3x. Mucosalrsubmucosal LDF has also been found to correlate to other techniques for absolute blood flow measurement, such as electromagnetic flow probes w38x, hydrogen gas clearance and microsphere techniques w29x. Against this background, the finding of a fairly reproducible minimum jejunal mucosal flux value Žas compared to the marked variability in resting cutaneous perfusion, related to thermoregulation; cf. Fig. 2. of 72 " 6 PU suggests that values below 2 SD Ž- 32 PU. could be taken to indicate a significant jejunal mucosal hypoperfusion. Future clinical studies will reveal whether this lower limit can identify subjectsrsituations with a significantly reduced perfusion. The present findings thus provide a basis for using this
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technique in a clinical setting, for instance in the monitoring of patients in intensive care units. In comparison with microsphere and clearance techniques, laser Doppler flowmetry offers the advantage of continuous monitoring. The technique is, on the other hand, limited by the artifacts caused by intestinal peristalsis when used in awake healthy subjects. In the present study group, two out of thirteen subjects had to be excluded from analysis due to lack of sufficiently long periods of intestinal quiescence. Preliminary findings suggest, however, that this is less of a problem in studies on patients under general anesthesia or sedated patients in the intensive care. 4.2. Effects of central hypoÕolemia As mentioned in the introduction, studies using the ICG clearance technique have demonstrated a hepatomesenteric vasoconstric-tion in man during LBNP 7–20 mm Hg, with reductions in hepatomesenteric blood flow ranging from 4.5 w23x to 21% w10x. The principal new finding of the present study is that mild LBNP elicits an intestinal vasoconstriction. The instantaneous jejunal mucosal perfusion decrease, in parallel with the cutaneous vasoconstriction known to be neurally mediated, suggests that a neural reflex is responsible for this jejunal mucosal vasoconstriction. This notion is further supported by the finding that the increase in hepatomesenteric vascular resistance normally accompanying upright tilting is essentially absent following surgical splanchnic sympathectomy w48x. Unloading of cardiopulmonary baroreceptors in all probability constitutes a large part of the afferent link of this reflex Žcf. Section 1., but involvement also of arterial baroreceptors in the reflex responses to mild LBNP cannot be excluded, despite only minor and inconsistent blood pressure changes recorded in our experiments w30,42x. The finding that significant reductions in jejunal mucosal perfusion can be elicited by moderate changes in central blood volume during mild LBNP is intriguing from a clinical point of view, and may provide one mechanism for the intestinal ischemia often developing in critically ill patients, for instance after massive haemorrhage or after long-lasting extra-corporeal circulation. We found no obvious explanation for the occasional finding of LBNP-induced increases in jejunal mucosal perfusion in one of the two intestinal probes Žwhile perfusion remained unchanged or decreased in the other channel.. One possible mechanism for this regional hyperemia could be that mechanical stimulation of the mucosa elicited a local reflex dilatation, which in studies in cat has been found to depend on the release of 5HT w6x. However, repeated tractions of the probe in cranial direction at the end of each experimental session was never associated with hyperemic responses, arguing against the above finding being caused by mechanically activated reflexes. An-
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other possible mechanism for regional hyperemia is that the relative contribution from the villus part of the mucosa may vary between LDF probe positions. Since electrical sympathetic nerve stimulation in cats w41x and man w18x has been shown to induce a redistribution of blood flow from the muscularis layer and crypt region of the mucosa towards the villus portion, probe positions where the flux value was dominated by villus flow could show an increased perfusion during sympatho-excitatory reflexes. It is also worth noting that opposing stimulus-induced perfusion changes in two LDF probes placed closely together on the same tissue has previously been found in skin w11,33x and in the central nervous system ŽGazelius, unpubl. obs... 4.3. Limitations of the study In comparison with a previous animal study on intestinal blood flow changes Žwith LDF technique. during electrical splanchnic sympathetic stimulation w2x, the duration of our stimulation was short and did not allow us to study the so called autoregulatory escape effect during LBNP, or the reactive hyperemia in the recovery period. The short LBNP duration was chosen to minimize the risk for commencing peristalsis during the maneuver. A limitation of the LDF technique is that the exact measuring depth in the intestinal wall is unknown. The measuring depth depends partly on biophysical factors such as the absorption and scattering of light in the investigated tissue and partly on instrumental design factors; fibre diameter and distance between the transmitting and receiving fibres and the wave length of the light used. Studies on the influence of different probe designs on measurements of the intestinal wall w22x estimated the measuring depth to be less than 2.4 mm for a probe of our design Žfibre separation 250 m m, core diameter 120 m m.. Since our LDF equipment uses a light of longer wave length Ž780 nm. than the one used by Johansson and coworkers Ž633 nm., our measuring depth could be extended. Given a thickness of the human mucosa and submucosa together of approximately 1.5–2.5 mm w7,37x, a small contribution from blood flow in the muscularis layer to our registered flux value cannot be excluded. However, LDF recordings from the mucosal approach with different LDF equipments are generally considered to be dominated by mucosalrsubmucosal blood flow w8,9,12,25,26,29,39x. In conclusion, the present study illustrates that the previously described hepatomesenteric reflex vasoconstriction induced by mild central hypovolemia includes a significant reduction in human jejunal mucosal perfusion. This reflex may provide one mechanism for the intestinal ischemia often occurring in hypovolemic critically ill patients. In general, laser Doppler flowmetry of intestinal perfusion may be a useful tool in critically ill patients for detection and treatment of mucosal ischemia, which is considered to be an important mechanism for the development of multiple organ failure.
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Cardiopulmonary bypass impairs small intestinal transport and increases gut permeability, Ann. Thorac. Surg. 55 Ž1993. 1080–1086. S.L. Ohri, S. Somasundaram, Y. Koak, A. MacPherson, B.E. Keogh, K.M. Taylor, I. Menzies, I. Bjarnason, The effect of intestinal hypoperfusion on intestinal absorption and permeability during cardiopulmonary bypass, Gastroenterology 106 Ž1994. 318–323. R. Rea, B.G. Wallin, Sympathetic nerve activity in arm and leg muscles during lower body negative pressure in humans, J. Appl. Physiol. 66 Ž1989. 2778–2781. M.H. Ross, E.J. Reith, Histology. A Text and Atlas. Harper and Row, New York, 1985, pp. 462–463. A.P. Shepherd, G.L. Riedel, Continuous measurement of intestinal mucosal blood flow by laser-Doppler velocimetry, Am. J. Physiol. 242 Ž1982. G668–G672. A.P. Shepherd, G.L. Riedel, Intramural distribution of intestinal blood flow during sympathetic stimulation, Am. J. Physiol. 24 Ž1988. H1091–H1095. G. Sundlof, ¨ B.G. Wallin, The variability of muscle nerve sympathetic activity in resting recumbent man, J. Physiol. 272 Ž1977. 383–397. J. Svanvik, Mucosal hemodynamics in the small intestine of the cat during regional sympathetic vasoconstrictor activation, Acta Physiol. Scand. 89 Ž1973. 19–29. J.A. Taylor, J.R. Halliwill, T.E. Brown, J. Hayano, D.L. Eckberg, Non-hypotensive hypovolemia reduces ascending aortic dimensions in humans, J. Physiol. 483 Ž1995. 289–298. M. Thollander, P.M. Hellstrom, T.H. Svensson, B. Gazelius, ¨ Haemodynamic changes in the small intestine correlate to migrating motor complex in humans, Eur. J. Gastroenterol. Hepatol. 8 Ž1996. 777–785. M. Thollander, P.M. Hellstrom, ¨ B. Gazelius, Semi-invasive laserDoppler flowmetry technique, Int. J. Microcirc. 17 Ž1997. 15–21. A. Tripathi, E.R. Nadel, Forearm skin and muscle vasoconstriction during lower body negative pressure, J. Appl. Physiol. 60 Ž1986. 1535–1541. G. Vantrappen, J. Janssens, J. Hellemans, Y. Ghoos, The interdigestive motor complex of normal subjects and patients with bacterial overgrowth of the small intestine, J. Clin. Invest. 59 Ž1977. 1158– 1166. R.G. Victor, W.N. Leimbach Jr., Effects of lower body negative pressure on sympathetic discharge to leg muscles in humans, J. Appl. Physiol. 63 Ž1987. 2558–2562. R.W. Wilkins, J.W. Culbertson, F.J. Ingelfinger, The effect of splanchnic sympathectomy in hypertensive patients upon estimated hepatic blood flow in the upright as contrasted with the horizontal position, J. Clin. Invest. 30 Ž1951. 312–317. R.P. Zoller, A.L. Mark, F.M. Abboud, P.G. Schmid, D.D. Heistad, The role of low pressure baroreceptors in reflex vasoconstrictor responses in man, J. Clin. Invest. 51 Ž1972. 2967–2972.
Baroreceptor-mediated reduction of jejunal mucosal perfusion, evaluated with endoluminal laser Doppler flowmetry in conscious humans Anders Thoren ´ b
a,)
, Sven-Erik Ricksten a , Stefan Lundin a , Bertil Gazelius c , Mikael Elam
b
a Department of Anaesthesiology and IntensiÕe Care, Sahlgrenska UniÕersity Hospital, S-413 45 Goteborg, Sweden ¨ Institute of Clinical Neuroscience, Department of Clinical Neurophysiology, Sahlgrenska UniÕersity Hospital, Goteborg, Sweden ¨ c Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden
Received 3 February 1997; revised 18 September 1997; accepted 9 October 1997
Abstract Reduction of central blood volume elicits a peripheral vasoconstrictor reflex in various tissues including skin, skeletal muscle and the hepatomesenteric region. The aim of the present study was to investigate whether this reaction includes a decreased perfusion of the jejunal mucosa in man. Laser Doppler flowmetry ŽLDF. was used to monitor jejunal mucosal and skin perfusion simultaneously in eleven healthy volunteers. LDF recordings were performed during quiescent Žphase 1. periods of the migrating motor complex. Seven subjects demonstrated cycling changes of jejunal mucosal perfusion Žvasomotion.. The average minimum jejunal flux value was 72 " 6 perfusion units. The average intraindividual coefficient of variation was 18 " 2%. Lower body negative pressure ŽLBNP. was used to elicit controlled reductions of central blood volume. LBNP of 10 mm Hg induced a 12 " 4% Ž P - 0.05. decrease in jejunal perfusion and a 43 " 11% Ž P - 0.001. decrease in cutaneous perfusion. Corresponding responses to LBNP of 20 mm Hg were 17 " 5% Ž P - 0.01. and 37 " 10% Ž P - 0.01. reductions in jejunal mucosal and skin perfusion, respectively. Cardiac index was significantly reduced by the LBNP procedure, whereas heart rate remained unchanged and blood pressure changes were minor and inconsistent. These findings indicate that the reflex vasoconstriction induced by mild central hypovolemia includes a significant reduction of jejunal mucosal perfusion in supine resting humans. This reflex may provide one mechanism for the intestinal ischemia often occurring in critically ill patients. q 1998 Elsevier Science B.V. Keywords: Jejunal mucosal vasoconstriction; Laser Doppler flowmetry; Lower body negative pressure; Sympathetic reflex; Vasomotion
1. Introduction A decrease in central blood volume in humans elicits a baroreflex mediated peripheral vasoconstriction, mainly via unloading of cardiopulmonary Žlow pressure. receptors w49x. Experimental reduction of central blood volume by applying lower body negative pressure ŽLBNP. has been shown to elicit vasoconstriction of the vascular beds in both skin and muscle w24,45x. In microneurographic recordings, sympathetic vasoconstrictor fibres to the muscle vascular bed in both arm and leg have been found to respond to graded LBNP with an instantaneous and sustained increase in firing rate w36,40,47x. Several studies using indocyanine green clearance ŽICG. technique have indicated that the reflex vasoconstriction by LBNP-induced central hypovolemia also includes the )
Corresponding author. Tel.: q46 31 601000; fax: q46 31 413862.
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hepatomesenteric vascular bed w1,10,23x. However, this method does not allow a differentiation between intestinal and hepatic blood flow. Since intestinal ischemia is considered a risk factor in critically ill patients during hypovolemia and different shock states w31x, the evaluation of whether reductions in central blood volume may elicit intestinal vasoconstriction is of major clinical importance. Laser Doppler flowmetry is an established method for monitoring tissue perfusion w16,32x. It has been used so far mainly for evaluation of the cutaneous circulation. In recent years, however, the technique has also been used in other tissues, including the gastrointestinal tract. In man the method has been used for perfusion studies in the gastric, duodenal, jejunal, ileal and colonic intestinal wall, during laparatomy w3,4,21,27x or by the use of endoscopy w4,5,14,19,20,28,34,35 x. In a recent study in the duodenum w43x the LDF probe was positioned endoluminally using fluoroscopy.
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The specific aim of the present study was to elucidate whether an LBNP-induced reduction of central blood volume elicits a jejunal mucosal vasoconstriction in man. A general aim was to evaluate the feasibility of continuous monitoring of jejunal mucosal perfusion in awake subjects. Our results show that the vasoconstrictor response induced by central hypovolemia does involve jejunal mucosal perfusion.
2. Methods
2.2. Simulated hypoÕolemia The lower part of the body, up to the iliac crest, was placed in the LBNP box. To prevent air leakage a flexible broad rubber band was taped to the skin of the lower abdomen and trunk. The LBNP box was closed and a vacuum cleaner was used to apply repeated suction of 10 and 20 mm Hg. The pressure inside the box was monitored by a pressure transducer calibrated against a mercury column. A stable level of 10 or 20 mm Hg suction was reached within 10 s. 2.3. Study design
Experiments were performed on 13 healthy volunteers Ž6 male, 7 female; mean age 32.7 years, range 24–48. after an over-night fast. Informed consent was given by all subjects and the investigation was approved by the Human Ethics Committee at the University of Goteborg. ¨ 2.1. Laser Doppler flowmetry Tissue perfusion was monitored with laser Doppler flowmeters ŽLDF; Periflux PF 4001 for jejunal and PF 2b for skin perfusion, Perimed AB, Jarfalla ¨ ¨ .. Intestinal perfusion was monitored with a custom build probe developed for the study. Two sets of three fiberoptic channels were incorporated in a catheter with an outer diameter of 5 mm. The fibres have a diameter of 150 m m and the fibre center separation within the sets of three fibres is 200 m m. Light with the wavelength of 780 nm is guided in one fibre of each set, ending 23 mm Ždistal. and 123 mm Žproximal., respectively, from the tip of the catheter. Two fibres of each set receive the Doppler-broadened and backscattered light from the tissue and transmit it to the photodetectors, allowing the monitoring of perfusion in two separate intestinal positions. The catheter was placed endoluminally under fluoroscopic guidance, using the nasogastric route, with the two sets of LDF fibres positioned approximately 10–40 cm distal to the ligament of Treitz. Skin perfusion was simultaneously monitored, with a conventional probe placed on the volar aspect of a finger tip Ždig II or III.. For all flux measurements, a time constant of 0.2 s and a band width of 12 kHz was used and calibration was performed as recommended by the manufacturer. The output signal of the flowmeter yields no absolute blood flow value, but shows relative changes in the flux of blood cells Žfor technical details and evaluation of the flowmeter see Refs. w14,30x.. Heart rate was recorded continuously during the experiments. Cardiac output and blood pressure responses to LBNP were recorded in a separate session Žcf. below.; cardiac output was measured non-invasively in all subjects with the transthoracic electrical impedance technique ŽBiomed NCCOM3-R7. and blood pressure oscillometrically every 25 s ŽCardiocap II-2S, Datex..
LDF recordings of intestinal perfusion were only analyzed in periods with stable pulse-synchronous flux waves ŽFig. 1., without movement artefacts or intestinal peristalsis. Such quiescent periods in fasting humans are called phase 1, and constitute the initial part of ‘the migrating motor complex’ ŽMMC.. It is followed by a period of irregular contractions Žphase 2. and subsequently a period of intense regular contractions Žphase 3.. These three phases form the MMC and migrate from the duodenum towards the colon w43,46x. All perfusion values presented in this study are calculated from phase 1 periods starting one minute after phase 3 activity and ending with the onset of phase 2. The obtained LDF flux values from the proximal and distal fibres were averaged.
Fig. 1. Laser Doppler records of jejunal perfusion Župper two traces. and radial arterial pressure Žlower trace. recorded simultaneously, illustrating the pulse-synchronous nature of jejunal flux waves.
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to reach adequate suction level excluded from analysis. LBNP analysis included three minutes following the termination of LBNP. The number of LBNP trials were determined by the amount of phase 1 activity exhibited by the subjects and ranged from 0–3 trials for 10 and 20 mm Hg of LBNP, respectively. Repeated trials were averaged for each subject before the statistical analysis. LBNP epochs where sharp increases in the perfusion signal, indicating motor activity or optical discoupling, occurred during the provocation were excluded from analysis. At least 20 min of recovery was allowed between LBNP maneuvers. The parallel monitoring of skin perfusion during LBNP maneuvers was performed as an ‘internal control’, to ensure that the procedure elicited reflex skin vasoconstriction. Due to the limited number of phase 1 periods suitable for LDF recordings during LBNP Žcf. Section 3., the changes in cardiac index and blood pressure during LBNP were established in a separate recording session on the same individuals and responses to three 1 min periods of 10 and 20 mm Hg LBNP, respectively, were recorded. Separate measurements of LBNP-induced cardiac output changes were considered justified, given a very limited intra- and interindividual variability of these changes Žcf. Fig. 4, lower panel.. 2.4. Analysis All values are presented as mean " SEM. Statistical comparisons were made between control period Ž1 min. and LBNP period Ž1 min. and also between LBNP periods Ž10 and 20 mm Hg.. Two way ANOVA for repeated measures was used for the evaluation of perfusion and
Fig. 2. Records of jejunal perfusion during MMC phase 1 in Ža. a subject exhibiting pronounced vasomotion Ž2.7–3.3 cycles miny1 . and Žb. a subject without apparent mucosal vasomotion. Skin perfusion lacks obvious vasomotion in both subjects. Note also the marked difference in resting skin perfusion between subjects.
A ten minute long period of phase 1 was required to establish a ‘minimum jejunal mucosal flux value’. When subjects exhibited longer or several phase 1 periods, the period with the lowest mean flux value was chosen. An intraindividual coefficient of variation was also calculated during this period. LBNP trials during phase 1 were preceded by a 70 s control period, with the last 10 s excluded to avoid influence of arousal reactions during announcing of the LBNP. LBNP was performed for 70 s, with the first 10 s needed
Fig. 3. Parallel jejunal mucosal Župper two traces. and skin Žlower trace. vasoconstriction during an LBNP of 10 mm Hg, all three records returning to control perfusion level after termination of the stimulation.
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hemodynamic changes during LBNP. P - 0.05 was considered statistically significant.
3. Results Two subjects were excluded from analysis due to extensive intestinal peristalsis, resulting in a lack of sufficiently long phase 1 Žquiescent. periods to calculate a minimum flux value or to perform LBNP maneuvers. The remaining eleven subjects had an average minimum jejunal mucosal flux value of 72 " 6 perfusion units ŽPU.. The average coefficient of variation was 18 " 2%. The intraindividual variation was in part due to cyclic changes in mucosal flux values during phase 1, exhibited by seven subjects Ž64%, Fig. 2a,b..
3.1. Perfusion during LBNP Flux values in the control period before LBNP were higher than the minimum flux value mentioned above, averaging 92 " 8 PU. LBNP of 10 mm Hg was performed on nine subjects and LBNP of 20 mm Hg was performed on 8 subjects. During LBNP of 10 mm Hg perfusion decreased in eight subjects and increased in one, yielding an average perfusion decrease of 12 " 4% Ž P - 0.05. ŽFigs. 3 and 4.. During LBNP of 20 mm Hg, perfusion decreased in six subjects, increased in one and remained unchanged in one, resulting in an average reduction of 17 " 5% Ž P - 0.01. ŽFig. 4.. The difference in reduction of perfusion between the two LBNP levels was not significant. A similar decrease in skin perfusion was found at both LBNP levels, the average reduction being 43 " 11% Ž P 0.001. and 37 " 10% Ž P - 0.01. ŽFigs. 3 and 4., during LBNP 10 and 20 mm Hg, respectively. 3.2. LBNP effects on hemodynamics Resting heart rate averaged 57 " 2 in the study group, and remained unaffected during LBNP. Cardiac index decreased ŽFig. 4. with 6 " 3% Ž P - 0.05. and 17 " 2% Ž P - 0.001. during LBNP 10 and 20 mm Hg, respectively Ž P - 0.05 between LBNP levels.. Pulse pressure only tended to decrease during LBNP 10 mm Hg Ždown 2.0 " 2.3 mm Hg, ns., but decreased 4.3 " 2.0 mm Hg during LBNP 20 mm Hg Ž P - 0.001.. Mean arterial blood pressure was reduced during LBNP 10 mm Hg Ž3.9 " 3.5 mm Hg, P - 0.01., but not significantly reduced during LBNP 20 mm Hg Ž2.7 " 4.4 mm Hg, ns.. 3.3. RecoÕery Jejunal mucosal perfusion reached control level within 2–3 min after the termination of LBNP, skin perfusion within 1 min and hemodynamic variables within 2 min.
4. Discussion
Fig. 4. Mean perfusion reductions recorded from the jejunal mucosa Župper panel. and skin Žmiddle panel. during LBNP of 10 ŽB. and 20 Žv . mm Hg, respectively. Both jejunal mucosal and skin vasoconstrictor responses were significant, and similar at both LBNP levels. Cardiac index Žlower panel. was reduced at both levels of LBNP, but more markedly during LBNP of 20 mm Hg Ž P - 0.05 between levels.. ) P 0.05, ) ) P - 0.01, ) ) ) P - 0.001.
The main finding of the present study is that a mild reduction of central blood volume, induced by low levels of LBNP, is associated with a significant reduction of jejunal mucosal perfusion in healthy awake humans. This result indicates that baroreceptor reflexes may be involved in the mechanisms compromising intestinalrjejunal mucosal perfusion in states of central hypovolemia and low cardiac output. In addition, our findings suggest that it may be possible to use this semi-quantitative technique to detect severe jejunal mucosal hypoperfusion in critically ill patients.
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4.1. Baseline jejunal perfusion A recent study, combining laser Doppler flowmetry with intestinal manometry, has indicated that intestinal perfusion increases during peristalsis Ži.e. MMC. in fasted humans w43x. Although we did not have a measure of motor activity, periods of intestinal peristalsis are easily identified in a laser Doppler record due to these sudden perfusion increases, sometimes in combination with movement artifacts. We were therefore able to choose 10 min periods of intestinal quiescence for the calculation of a ‘minimum jejunal mucosal flux value’. The wide range of individual coefficients of variation between subjects during this period Ž9–38%. is mainly due to different degrees of cyclic oscillation in the LDF signal. As shown in Fig. 2, these oscillations are pronounced in some subjects and absent in others and they also differ in amplitude and frequency. This phenomenon has previously been described in laser Doppler recordings from canine gastric and intestinal mucosa with a frequency of 2.5–3.5 cycles miny1 Žcompare frequency Fig. 2a. w25,26x. It has been found to be independent of respiration, blood pressure and total blood flow and is considered to represent mucosal blood flow w26x. Cyclic microvascular flow velocity changes with the frequency of 4–7 cycles miny1 have also been demonstrated with intravital microscopy in the rat gastric mucosa w17x. These cyclic perfusion changes were attributed to tonus changes in the feeder arterioles or precapillary sphincters in the mucosa and are referred to as Õasomotion. Vasomotion in human duodenal mucosa has recently been described with LDF-technique, with the frequency of 3.6–4.3 cycles miny1 w44x. In porcine jejunal mucosa regular changes in oxygenation with the frequency of 3.4–5 cycles miny1 has been shown, due to vasomotion w13,15x. These regular changes were absent in jejunal serosal registrations, indicating that vasomotion in the jejunum is a mucosal phenomenon. Although LDF yields no absolute blood flow values, LDF flux data have been used to calculate absolute blood flow values in the human jejunum which correlated well with values simultaneously obtained with total venous outflow technique in the range of 0–50 ml miny1 100 gy1 w3x. Mucosalrsubmucosal LDF has also been found to correlate to other techniques for absolute blood flow measurement, such as electromagnetic flow probes w38x, hydrogen gas clearance and microsphere techniques w29x. Against this background, the finding of a fairly reproducible minimum jejunal mucosal flux value Žas compared to the marked variability in resting cutaneous perfusion, related to thermoregulation; cf. Fig. 2. of 72 " 6 PU suggests that values below 2 SD Ž- 32 PU. could be taken to indicate a significant jejunal mucosal hypoperfusion. Future clinical studies will reveal whether this lower limit can identify subjectsrsituations with a significantly reduced perfusion. The present findings thus provide a basis for using this
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technique in a clinical setting, for instance in the monitoring of patients in intensive care units. In comparison with microsphere and clearance techniques, laser Doppler flowmetry offers the advantage of continuous monitoring. The technique is, on the other hand, limited by the artifacts caused by intestinal peristalsis when used in awake healthy subjects. In the present study group, two out of thirteen subjects had to be excluded from analysis due to lack of sufficiently long periods of intestinal quiescence. Preliminary findings suggest, however, that this is less of a problem in studies on patients under general anesthesia or sedated patients in the intensive care. 4.2. Effects of central hypoÕolemia As mentioned in the introduction, studies using the ICG clearance technique have demonstrated a hepatomesenteric vasoconstric-tion in man during LBNP 7–20 mm Hg, with reductions in hepatomesenteric blood flow ranging from 4.5 w23x to 21% w10x. The principal new finding of the present study is that mild LBNP elicits an intestinal vasoconstriction. The instantaneous jejunal mucosal perfusion decrease, in parallel with the cutaneous vasoconstriction known to be neurally mediated, suggests that a neural reflex is responsible for this jejunal mucosal vasoconstriction. This notion is further supported by the finding that the increase in hepatomesenteric vascular resistance normally accompanying upright tilting is essentially absent following surgical splanchnic sympathectomy w48x. Unloading of cardiopulmonary baroreceptors in all probability constitutes a large part of the afferent link of this reflex Žcf. Section 1., but involvement also of arterial baroreceptors in the reflex responses to mild LBNP cannot be excluded, despite only minor and inconsistent blood pressure changes recorded in our experiments w30,42x. The finding that significant reductions in jejunal mucosal perfusion can be elicited by moderate changes in central blood volume during mild LBNP is intriguing from a clinical point of view, and may provide one mechanism for the intestinal ischemia often developing in critically ill patients, for instance after massive haemorrhage or after long-lasting extra-corporeal circulation. We found no obvious explanation for the occasional finding of LBNP-induced increases in jejunal mucosal perfusion in one of the two intestinal probes Žwhile perfusion remained unchanged or decreased in the other channel.. One possible mechanism for this regional hyperemia could be that mechanical stimulation of the mucosa elicited a local reflex dilatation, which in studies in cat has been found to depend on the release of 5HT w6x. However, repeated tractions of the probe in cranial direction at the end of each experimental session was never associated with hyperemic responses, arguing against the above finding being caused by mechanically activated reflexes. An-
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other possible mechanism for regional hyperemia is that the relative contribution from the villus part of the mucosa may vary between LDF probe positions. Since electrical sympathetic nerve stimulation in cats w41x and man w18x has been shown to induce a redistribution of blood flow from the muscularis layer and crypt region of the mucosa towards the villus portion, probe positions where the flux value was dominated by villus flow could show an increased perfusion during sympatho-excitatory reflexes. It is also worth noting that opposing stimulus-induced perfusion changes in two LDF probes placed closely together on the same tissue has previously been found in skin w11,33x and in the central nervous system ŽGazelius, unpubl. obs... 4.3. Limitations of the study In comparison with a previous animal study on intestinal blood flow changes Žwith LDF technique. during electrical splanchnic sympathetic stimulation w2x, the duration of our stimulation was short and did not allow us to study the so called autoregulatory escape effect during LBNP, or the reactive hyperemia in the recovery period. The short LBNP duration was chosen to minimize the risk for commencing peristalsis during the maneuver. A limitation of the LDF technique is that the exact measuring depth in the intestinal wall is unknown. The measuring depth depends partly on biophysical factors such as the absorption and scattering of light in the investigated tissue and partly on instrumental design factors; fibre diameter and distance between the transmitting and receiving fibres and the wave length of the light used. Studies on the influence of different probe designs on measurements of the intestinal wall w22x estimated the measuring depth to be less than 2.4 mm for a probe of our design Žfibre separation 250 m m, core diameter 120 m m.. Since our LDF equipment uses a light of longer wave length Ž780 nm. than the one used by Johansson and coworkers Ž633 nm., our measuring depth could be extended. Given a thickness of the human mucosa and submucosa together of approximately 1.5–2.5 mm w7,37x, a small contribution from blood flow in the muscularis layer to our registered flux value cannot be excluded. However, LDF recordings from the mucosal approach with different LDF equipments are generally considered to be dominated by mucosalrsubmucosal blood flow w8,9,12,25,26,29,39x. In conclusion, the present study illustrates that the previously described hepatomesenteric reflex vasoconstriction induced by mild central hypovolemia includes a significant reduction in human jejunal mucosal perfusion. This reflex may provide one mechanism for the intestinal ischemia often occurring in hypovolemic critically ill patients. In general, laser Doppler flowmetry of intestinal perfusion may be a useful tool in critically ill patients for detection and treatment of mucosal ischemia, which is considered to be an important mechanism for the development of multiple organ failure.
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