The quest to prove or disprove the theory of ‘autoregulation' has stimulated much neonatal research using a variety of techniques and methods. The study presented by Boylan et al. in this issue of Pediatric Research is another such study. They employ sophisticated techniques (coherent averaging and linear regression) devised by the medical physicists in the team (1, 2). Essentially the methods analyze cerebral blood flow velocity (CBFV) changes, captured by Doppler ultrasound, in response to spontaneous and transient changes in systemic blood pressure. The crux of their findings is that, within the limitations of the numbers of infants studied, the pattern of CBFV responses seen in preterm infants and neurologically sick term infants are similar but are different to the responses of the neurologically normal term infants. The inference is that the groups have differing cerebral hemodynamic controls.
The second thrust of the paper is to place their findings into the concepts of autoregulation. They use the terms ‘static' to be synonymous with ‘classical' and equate their study to what they describe as ‘dynamic' control. In the adult literature the term ‘static' refers to CBF(V) responses to pharmacologically altered blood pressure and ‘dynamic' autoregulation refers to responses to maneuvers such as cuff inflation and deflation around a limb (3, 4), as described by Aaslid et al. (5). If one scrutinizes the literature on autoregulation, it becomes evident that the above uses of the terms static, dynamic, and classical are somewhat misleading.
It is clear that the previous concept of ‘autoregulation' is very limited, and we need to consider a much broader scheme of events. Just as standing upright is not dependent on the integrity of one system alone. A patient who fells over may have pathology, for example, of prorioception, a cerebral tumor or a cardiac arrhythmia. A failure of ‘autoregulation,' perceived as the development of a cerebral hemorrhage or an area of ischemia, may also be the result of a failure at one of several levels. The patient may not fall when standing still but does on walking or running. Similarly in cerebral hemodynamics there is evidence of differing processes in play, there are base-line, on-going fine tuning of CBF(V), which we could call static, versus controls of responses to external stimuli, which we could call ‘dynamic.' It is this latter scenario that was originally studied and perceived as autoregulation.
The definition of autoregulation produced by Lessen in 1959 (6) was ‘the ability to maintain cerebral blood flow in the face of a changing cerebral perfusion pressure.' This definition was based upon the classical experiments of Mogens Fog in the 1930s (7–9). He used a technique previously described by Forbes in 1928 (10). Fog created a window in the skull of cats to directly observe changes in the pial vessels' diameters in response to various stimuli. By what ever means the systemic blood pressure was decreased; stimulation of the carotid sinus and depressor nerves; peripheral stimulation of the vagus; or by arterial hemorrhage, he noted an immediate vasoconstriction of the pial vessels followed within 1.5 to 2 min by a secondary vasodilatation to restore the blood flow. On increasing the systemic blood pressure, by an injection of epinephrine or by splanchnic stimulation or by clamping the abdominal aorta, the reverse changes were seen in the pial vessels. He noted too that the compensatory mechanism only persisted over a range of blood pressures (110–140). It is this ability of cerebral vessels to constrict or dilate in response to a sustained change in perfusion pressure, to maintain cerebral blood flow, over the time-frame described, which should rightly be called ‘classical autoregulation.'
A number of animal studies followed using a variety of direct, but highly invasive techniques of measurement of blood pressure and blood flow to study the characteristics in different species of this type of response. They studied its time course, site of control, and possible controlling or confounding variables (11–17). The time frame, with some minor species variability, always demonstrated an immediate, passive response followed by a second response between 10 s to 1–2 min later to restore the blood flow to a steady state.
Studies in humans have many ethical constraints; however, Nomes et al. (18, 19) demonstrated in neurosurgical patients a similar time course for such responses in humans. Gotoh et al. (20) demonstrated in patients with Shy-Drager Syndrome, an autonomic neuropathy, that they were unable to maintain their CBF in response to a change in posture but they could to changes in carbon dioxide. This illustrates an important point that different controlling mechanisms exist for different stimuli.
The ethical considerations in neonates are even more taxing than those in adults. However, many valiant ethical attempts have been made to study this population. The paper by Lou et al. (21), referred to by Boylan et al. is often quoted as the evidence of a failure of autoregulation in preterm infants. However, in this study 19 preterm (29–33 weeks gestation) infants had only one measurement each of CBF, measured by the Xe-133 technique, along with a simultaneous recording of the blood pressure. The data points for each baby were compared with the rest in the group to create cross-sectional data of CBF and blood pressure. Sixteen of the infants had low pHs, 12 had high Paco2, and 7 were described as asphyxiated. This cross-sectional data does not represent autoregulatory changes as described by Fog.
Further neonatal studies have used Xe-133 (22, 23), jugular occlusive plethysmography (24), and Doppler ultrasound (25–28) All of these studies have their specific difficulties. Often cross-sectional data were gathered. Xe-133 cannot be used to make the rapidly repeating measurements of CBF which are required to capture the classical autoregulatory responses described by Fog, nor can one guarantee that outer confounding variables known to alter CBF will not have changed between the repeated measurements. Boylan et al. imply that the problem with some studies was the time it took to alter the blood pressure that resulted in the measurements being taken some time apart. The Xe-133 studies of Pryds et al. (22, 23) looked at spontaneous blood pressure changes and the difficulty was the time-lag of the Xe-133 technique. Further, the confounding variables known to change CBF(V) are typically, Paco2, and hematocrit. However, the main variable, which confused many earlier studies, was to take measurements of blood pressure and CBF(V) from an individual over consecutive days. This abolished the problem of cross-sectional data but both CBF(V) and blood pressure increase physiologically over the first few days of life, so an observation of a rising blood pressure and CBF(V) is not evidence of a failure of autoregulation.
Doppler ultrasound is the one technique that can capture the changes in hemodynamics over the necessary time-frame of autoregulatory changes within an individual. The difficulties of Doppler are that essentially it is a measure of velocity and not flow, and that a change in the angle of insonnation will alter the velocity reading without a true change within the baby. The latter problem has been overcome by the use of fixed probes at a constant angle (29), which then allows observation of changes in hemodynamics without necessarily implying measurement of flow. It is the information gathered from Doppler studies that has produced evidence that there are several different intrinsic patterns of changing CBFV that are quite different in time-frame from those witnessed in changes provoked by external stimuli.
The well-described CBFV changes seen in babies at rest with no external stimuli applied are 1) the beat-to beat variability seen by Perlman et al. and studied in relationship to synchronous breathing during artificial ventilation (30, 31), and 2) Slow wave cyclical changes in CBFV, occurring at 3–6 cycles per minute (32, 33). Kitney and co-workers have described similar cyclical oscillations in other physiological parameters, such as heart rate and temperature (34–38). These spontaneous changes in CBFV suggest that there are constant fine tuning processes, which, because of their very differing time-frames, probably represent differing underlying controls to each other and differing controls to the changes witnessed after differing external stimuli such as posture change (39) or the stimuli employed by Fog.
Furthermore, there is another group of external stimuli, which are known to alter CBF, namely carbon dioxide, acidosis, and metabolic demand, which indirectly alter perfusion pressure and may have other modes of action upon CBF and should be considered separately in any study.
The place of the CBFV changes recorded by Boylan et al. belongs within the intrinsic, spontaneous group of CBFV changes. They provide further important evidence of the differences between preterm and term infants. However, these changes are in no way similar to the responses provoked by studies of external stimuli with sustained changes in perfusion pressure, such as seen in changes of posture (39) or the studies of Aaslid et al. (5). These latter studies witnessed changes akin to those provoked by Fog, and are of the ‘classical' autoregulatory type. The different groups of changes are likely to have different underlying physiological and pathological mechanisms.
References
Reynolds KJ, Panerai RB, Kelsall AW, Rennie JM, Evans DH 1997 Spectral pattern of neonatal cerebral blood flow velocity: comparison with spectra from blood pressure and heart rate. Pediatr Res 41: 276–284
Panerai RB, Rennie JM, Kelsall AW, Evans DH 1998 Frequency domain analysis of cerebral autoregulation from spontaneous fluctuations in arterial blood pressure. Meal Biol Eng Comput 36: 315–322
Tiecks FP, Lam AM, Aaslid R, Newell DW 1995 Comparison of static and dynamic cerebral autoregulation measurements. Stroke 26: 1014–1019
Strebel S, Lam AM, Matta B, Mayberg TS, Aaslid R, Newell DW 1995 Dynamic and static cerebral autoregulation during isoflurane, desflurane, and propofol anesthesia. Anesthesiology 83: 66–76
Aaslid R, Lindegaard K-F, Sorteberg W, Nomes H 1989 Cerebral autoregulation dynamics in humans. Stroke 20: 45–52
Lassen NA 1959 Cerebral blood flow and oxygen consumption in man. Physiological Review Am J Physiol 39: 183–233
Fog M 1937 Cerebral circulation. Arch Neurol Psychiatry 37: 351–364
Fog M 1938 The relationship between the blood pressure and the tonic regulation of the pial arteries. J Neurol Psych 1: 187–197
Fog M 1939 Cerebral circulation II. Arch Neurol Psychiatry 41: 260–268
Forbes HS 1928 Cerebral circulation; observation and measurement of pial vessels. Arch Neurol Psychiatry 19: 751–761
Yoshida K, Meyer JS, Sakamato K, Handa J 1966 Autoregulation of cerebral blood flow. Electromagnetic flow measurements during acute hypertension in the monkey. Circ Res 726–738
Symon L, Crockard HA, Dorsch NW, Branston NM, Juhasz J 1975 Local cerebral blood flow in vascular reactivity in chronic stable stroke in baboons. Stroke 6: 482–492
Symon L, Held K, Dorsch NWC 1973 A study of regional autoregulation in the cerebral circulation to increase perfusion pressure in normocapnia and hypercapnia. Stroke 4: 139–147
Bell BA, Symon L, Branston NM 1985 Cerebral blood flow and time thresholds for the formation of ischemic cerebral oedema, and effect of reperfusion in baboons. J Neurosurg 62: 31–41
Kontos HA, Wei EP, Navarl RM, Levasseur JE, Rosenblum WI, Patterson JL Jr 1978 Responses of cerebral arteries and arterioles to acute hypotension and hypertension. Am J Physiol 234: H371–H383
Busija DW, Heistad DD, Marcus ML 1980 Effects of sympathetic nerves on cerebral vessels during acute, moderate increases in arterial pressure in dogs and cats. Circ Res 46: 696–702
Baumbach GL, Heistad DD 1983 Effects of sympathetic stimulation and changes in arterial pressure on segmental resistance of cerebral vessels in rabbits and cats. Circ Res 52: 527–533
Nomes H, Wikeby P 1977 Cerebral arterial blood flow & aneurysm surgery. Part I: Local arterial flow dynamics. J Neurosurg 47: 810–818
Nomes H, Knutzen HB, Wikeby P 1977 Cerebral arterial blood flow and aneurysm surgery. Part II. Induced hypotension and autoregulatory capacity. J Neurosurg 47: 819–827
Gotoh F, Ebihara S-I, Toyoda M, Shinohara Y 1971–72 Role of autonomic nervous system in autoregulation of human cerebral circulation. Eur Neurol 6: 203–207
Lou HC, Lassen NA, Fnis-Hansen B 1979 Impaired autoregulation of cerebral blood flow in distressed newborn infants. J Pediatr 94: 118–121
Pryds O, Griesen G, Lou H, Friis-Hansen B 1989 Heterogeneity of cerebral vasoreactivity in preterm infants supported by mechanical ventilation. J Pediatr 115: 638–645
Pryds O, Andersen GE, Friis-Hansen B 1990 Cerebral blood flow reactivity in spontaneously breathing preterm infants shortly after birth. Acta Paediatr Scand 79: 391–396
Milligan DWA 1980 Failure of autoregulation and intraventricular haemorrhage in preterm infants. Lancet 1: 896–898
Ahmann PA, Dykes FD, Lazzara A, Holt PJ, Giddens DP, Carrigan TA 1983 Relationship between pressure passivity and subependymal intraventricular hemorrhage as assessed by pulsed Doppler ultrasound. Pediatrics 72: 665–669
Jorch G, Jorch N 1987 Failure of autoregulation of cerebral blood flow in neonates studied by pulsed Doppler ultrasound of the internal carotid artery. Eur J Pediatr 146: 468–472
Rosenknantz TS, Diana D, Munson J 1988 Regulation of cerebral blood flow velocity in non-asphyxiated, very low birth weight infants with hyaline membrane disease. J Perinatol 8: 303–308
Ramaekers VTh, Casaer P, Daniels H, Marchal G 1990 Upper limits of brain blood flow autoregulation in stable infants of various conceptional age. Early Hum Dev 24: 249–258
Fenton A, Evans DH, Levene MI 1990 On-line cerebral blood flow velocity and blood pressure measurements in neonates: a new method. Arch Dis Child 65: 11–14
Perlman JM, McMenamin JB, Volpe JJ. Fluctuating CBFV in RDS 1983 Relation to the development of intraventricular hemorrhage. N Engl J Med 309: 204–209
Perlman JM, Goodman S, Kreusser KL, Volpe JJ 1985 Reduction in IVH by elimination of fluctuating cerebral blood flow velocity in preterm infants with respiratory distress syndrome. N Engl J Med 312: 1353–1357
Anthony MY, Evans DH, Levene MI 1991 A study of cyclical variations in cerebral blood flow velocity. Arch Dis Child 66: 12–16
Caughtrey H, Rennie JM, Evans DH 1992 Postnatal evolution of slow variability in cerebral blood flow velocity. Arch Dis Child 67: 412–415
Hyndman BW, Kitney RI, Sayers BmcA 1971 Spontaneous rhythms in physiological controls systems. Nature 233: 339–341
Kitney RI 1975 An analysis of the non-linear behaviour of the human thermal vasomotor control system. J Theor Biol 52: 231–248
Kitney RI 1979 A non-linear model for studying oscillations in the blood pressure control system. J Biomed Eng 2: 89–99
Kitney RI 1984 New findings in the analysis of heart rate variability in infants. Automedica 5: 289–310
Kitney RI, Rompleman O 1980 The Study of Heart-Rate Variability. Oxford University Press, Oxford, pp 59–77, 81–106.
Anthony MY, Evans DH, Levene MI 1993 Neonatal cerebral blood flow velocity responses to changes in posture. Arch Dis Child 69: 304–308
Szymonowicz W, Walker AM, Yu VY, Stewart ML, Cannata J, Cussen L 1990 Regional cerebral blood flow after hemorrhagic hypotension in the preterm, near-term, and term newborn lamb. Pediatr Res 28: 222–228
Ramaekers VTh, Casaer P, Daniels H, Marchal G 1990 Upper limits of brain blood flow autoregulation in stable infants of various conceptional age. Early Hum Dev 24: 249–258
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Anthony, M. Cerebral Autoregulation in Sick Infants. Pediatr Res 48, 3–5 (2000). https://doi.org/10.1203/00006450-200007000-00003
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DOI: https://doi.org/10.1203/00006450-200007000-00003