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To Autoregulate or Not to Autoregulate—That is No Longer the Question
To Autoregulate or Not to Autoregulate—That is No Longer the Question Gorm Greisen, MD, DMSc In the late 1970s, high cerebral blood flow was perceived as a cause of intracranial hemorrhage in the preterm infant. Intracranial hemorrhage was diagnosed by computed tomography and ultrasound found to be frequent not only in babies who died. Hemorrhage was soon linked to cerebral palsy in survivors. The analogy was hypertensive hemorrhagic stroke in the adult. Cerebral hemorrhage was perceived as the major (preventable) cause of brain injury in the preterm baby. An immature cerebral autoregulation or a vulnerability of the autoregulation exposed by preceding hypoxia or ischemia therefore became a focus of neonatal brain research in the 1980s. Over the years the focus has changed, first to the pathogenesis of hypoxicischemic brain injury, then to the effects of pCO2, and now 30 years later to a more comprehensive, less clearly hypothesis-driven exploration of the multitude of factors involved in cerebral blood flow and oxygenation. Meanwhile, some basic questions regarding autoregulation remain unanswered, and some concepts from the 1970s still direct clinical practice. Semin Pediatr Neurol 16:207-215 © 2009 Elsevier Inc. All rights reserved.
Survival of the Small Preterm with Brain Injury: The Neonatologist’s Challenge With rapidly evolving neonatal intensive care allowing survival of ever-smaller babies, the question of brain injury and survival of handicapped children became a prime concern for my mentor, Bent Friis-Hansen. He had been the head of the Department of Neonatology at Rigshospitalet since its establishment in 1965. Although his primary research field was body water during growth1 and nutrition, he had faced the practical aspects of neonatal care and soon supervised the implementation of mechanical ventilation of newborns with respiratory distress.2 Two years after Gregory had shown the benefits of continuous positive airway pressure (CPAP), Jens Kamper3 and Friis-Hansen report mortality as low as 32% in intubated babies with birth weight less than 1500 g. This success led to concerns.
Cerebral Blood Flow: The Mecca was Copenhagen Copenhagen in Denmark, 50 km south of the castle of Hamlet, was the origin of the use of radioactive isotopes to meaFrom the Department of Neonatology, Rigshospitalet, Copenhagen, Denmark. Address reprint requests to Gorm Greisen, MD, DMSc, Department of Neonatology, Rigshospitalet 5024, Blegdamsvej 9, 2100 Copenhagen Ø, Denmark. E-mail: [email protected]
1071-9091/09/$-see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.spen.2009.09.002
sure cerebral blood flow (CBF). Niels A Lassen4 obtained the first data in man in 1955 using the inert gas krypton. The inert gas xenon was first used to measure muscle blood flow by clearance after local injection. In 1965, his group published methods to measure regional cerebral blood flow in man by intracarotid injection5 or inhalation6 and by external detection of the gamma radiation. These methods became standard because regional values could be obtained (which is not possible with the Kety–Schmidt method using jugular venous blood sampling), and because it was no longer necessary to cannulate the jugular vein. The radiation resulting from the use of these isotopes was modest. As a result, clinical physiology was thriving in Copenhagen, and the methods were applied to a wide range of physiological questions and clinical problems.
A Simple Experiment Thus, it was natural for Hans C. Lou, with an interest in pediatric neurology and newly employed in the Department of Neonatology, to take up the challenge to use the 133Xe clearance method to examine the role of CBF in perinatal brain injury. He placed an umbilical arterial catheter during clinical care to advance the catheter to the left carotid artery, the innominate artery or the aortic arch, and to inject 0.5 mCi 133Xe dissolved in 1 mL of normal saline. The catheter was withdrawn to its normal position thereafter. A scintillation detector was held over the head during the following 60 seconds. The count rate was plotted on a semilogarithmic 207
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208 graph. In this situation, the simple slope from 15 to 60 seconds, determined by eye and a ruler, is a robust measure of clearance and only needed the assumption of the brain– blood partition coefficient to allow the estimation of CBF in milliliters/100 g/min.
The First Robust Data on CBF in the Human Newborn The first publication from the collaboration of Lou et al7 was in 1977. It is the data from 8 newborns, shortly after birth. For Hans Lou, it was publication number 9, for Bent FriisHansen number 53, and for Niels Lassen number 238, available on PubMed. It thus came out of a significant collaborative experience in clinical science. The paper focuses on the surprisingly low values of CBF, in the newborn with values as low as 20 mL/100 g/min. The result of this “early slope” refers to the areas of the brain with the highest flow, the cortex, and central gray matter in the small newborn brain, and was less than a third of normal adult values and much less than the values routinely obtained in the newborn lamb, the most popular animal model in perinatal research at the time. A link was made to the low systolic blood pressure measured simultaneously by ultrasound Doppler, and a statistically significant correlation between CBF and blood pressure was presented. The interpretation was that perinatal distress induces circulatory compromise through depletion of glycogen in the myocardium, leading to arterial hypotension and then to cerebral ischemia and the well-known brain injury after birth asphyxia. In the discussion section of the paper, the authors has mentioned the possibility of arterial hypertension leading to cerebral hemorrhage, and refer to a paper of Hambleton and Wigglesworth (1976).8 Dr Wigglesworth had suggested a link between blood flow and cerebral hemorrhage by examination of injection specimens in the dissecting microscope. Injection of barium gelatin solution was used from the arterial side followed by clearing of the tissue with the Spalteholz technique. The typical origin of hemorrhage was found to be the capillary or the capillary-venous junction in the germinal matrix. This finding had led to a comprehensive model for hemorrhagic and ischemic lesions in the newborn brain.9
The Change in Focus: From Ischemia to Hemorrhage The next publication of the Copenhagen group included data from 19 newborns,10 of which 8 were the same as the previous publication. The correlation between CBF and blood pressure was now significant at the P ⬍ 0.0001 level, and the correlation was the same in infants with perinatal distress and those with postnatal distress only (presumed respiratory distress syndrome). The focus in this paper was on the impairment of autoregulation and on the risk of hemorrhage due to transmittance of arterial pressure to the capillaries in the germinal matrix. This publication has received 509 citations to date, compared with 85 citations of the 1977 publication.
This shift of focus should be observed in the light of the discovery that intraventricular hemorrhage (IVH) was a frequent event in very low birth weight (VLBW) infants. IVH was put on the agenda by a publication by Lu Ann Papile11 in 1978. It came as a surprise that 40% of all VLBW infants developed IVH, and that most were asymptomatic and survived. The new focus was emphasized in another paper published by Lou et al12 under the heading “hypothesis” in the Lancet: “Is arterial hypertension crucial for the development of cerebral haemorrhage in the premature infant?” At the end of the paper, the use of sedatives was suggested to reduce blood pressure increases due to spontaneous activity, handling, or seizures.
The Use of Sedatives to Limit Arterial Hypertension The proposal of using sedatives to reduce the risk of hypertension was opposed as a potentially dangerous practice by Dr Wigglesworth13 in the correspondence section of the Lancet, stressing the danger of the Charybdis of hypotension and cerebral ischemia. The group from Copenhagen and Dr Wigglesworth’s group from the Hammersmith in London had exchanges of letters of correspondence,14,15 but agreed on the idea that the cerebral circulation was exquisitely sensitive to changes in arterial blood pressure. One, not explicit, reason for the proposal of sedation was the long-standing interest in phenobarbitone of the Professor of Obstetrics at Rigshospitalet at the time, Dyre Trolle. Dr Trolle had demonstrated that bilirubin conjugation could be induced in newborn infants with rhesus disease by giving phenobarbitone to the pregnant woman. He had extended this practice to all low birth weight infants and to administration of phenobarbitone for the first 3 days after birth. In 1968, he reported a reduction in first week mortality. The study partly used historical controls and partly simultaneous controls from the sister Department of Obstetrics in the hospital. Although this was not science of current-day standards, it was published in the Lancet.16 In 1978, he published, with his colleague in the sister department and with Friis-Hansen, the benefit of a cocktail of betamethasone, ritodrine (a tocolytic), and phenobarbitone to the pregnant woman before preterm birth.17 Again the methodology used historical and contemporary controls, but the effect on respiratory distress syndrome and mortality seemed specific for the group with gestational age below 34 weeks.
My Haphazard Entry Into Neonatology In February 1980, I was employed as a junior physician (reservelæge) in the Department of Neonatology. Unemployment among young medical graduates was high, and I got this opportunity partly because I had served 2 years as a district medical officer in Zambia, replacing my military service, and partly because I had shown pregraduate interest in
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research and published a paper on drug clearance as a measure of liver function; Friis-Hansen had worked in Zambia as a nutrition specialist for world health organization.18 In the beginning, I needed a job and a salary to feed my family. Friis-Hansen suggested that Dr Minna Block Petersen and I should try ultrasound to diagnose IVH, as reported by the University College London group in London the previous year.19 During the summer, I heard Dr Volpe in Gotenburg as he received a Swedish Paediatric Society prize. That event opened the world of neonatal neurology to me. Minna and I received training from a colleague from the Department of Obstetric Ultrasound and borrowed an ultrasound machine outside office hours, and from September 1980 to March 1982 we performed a prospective study on IVH in infants less than 1500 g; and we also found a prevalence of 40%.20 We have followed this cohort at 2, 4, and 18 years.
The Need for New Data—For a Noninvasive Method At that time, Dr Wimberley was the research fellow of Dr Friis-Hansen Dr Wimberley’s research area was the oxygen binding of hemoglobin F. As a side-job he took care of the new microcomputer-based continuous clinical data monitoring system of the department, and he was able to publish a weak correlation between arterial pressure peaks and cerebral hemorrhage.21 But what was really needed was more data on CBF. It was necessary to be able to measure CBF several times and at times other than during umbilical arterial catheterization. The procedure had also been criticized. Noninvasive 133Xe clearance had been performed using intravenous injection in the adult, but required complex data analysis to correct for the noninstantaneous input of tracer to the brain. Friis-Hansen therefore bought a “cerebrograph,” ie, a prototype instrument, including a scintillation detection system (Fig 1) and a tabletop computer.
The Early Days of Computer-Based Signal Analysis This was an opportunity. I became a research fellow in early 1982, I think because I had taken the ultrasound studies forward and because I had a bachelor’s degree in computer science besides my medical degree and had begun helping out with the cerebrograph. It had come with a program implementing the inhalation/i.v. injection 133Xe clearance method for adults (Obrist). Although this method was used by Younkin et al22 from Philadelphia, and in a simplified version by Laura Ment,23 the analysis was not appropriate and the results were falsely high due to scattered radiation from the lungs, a situation more important in the small ill newborn for several reasons, including right-to-left ductal shunting, chest-wall contribution to the input-function, and the relatively small gray matter compartment and relatively low CBF.24
Figure 1 Cerebral blood flow is measured by 133Xe clearance in a preterm ventilated infant. One scintillation detector is placed over the head and 1 detector over the chest. The syringe contains 133Xe in saline and is connected to an intravenous line. The lead shield limits the scattered radiation from the syringe to the fields of measurement.
An Improvised Cross-Atlantic Collaboration: Doppler Ultrasound vs Xenon Clearance I presented some of my early methodological insights and solutions at the International Child Neurology Association meeting in Copenhagen in May 1982, to 10 people in a lecture theater. I realized that my data, the result of months of work, was not of interest to anybody. Over the years this impression has been reinforced; methodological scrutiny takes a quiet atmosphere. During the congress I contacted those 3 others presenting data on neonatal CBF: Henrietta Bada, Donald Younkin, and Patricia Ellison. Patricia responded, visited our department, asked why we did not use the much simpler method of Doppler ultrasound, and later she came back with her machine so that we could do a comparative study of my 133Xe clearance method, Patricia’s continuous wave machine, and a range-gated Doppler machine that we found on a shelf in the Department of Thoracic Surgery. The correlation coefficients between 0.4 and 0.8 for the various Doppler measures25 was important for the burgeoning field of Doppler studies of neonatal cerebral circulation. We computed a prediction interval of ⫾50% for a single measurement, but contrary to this number the work has most often been mentioned as a support for the validity of Doppler ultrasound. Henrietta Bada in the accompanying editorial noticed that some correlation was not surprising as both are
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measures of CBF, and it was not surprising that the results are not identical because the methods are very different.
An Afterthought on Methodology for Clinical Research We continued to use Doppler ultrasound ourselves.26 I tried coanalysis of Doppler and blood pressure in the frequency domain, but in the end I became convinced that Doppler data on flow velocity could be impossible to interpret in CBF when arterial cross sectional area was dynamically regulated.27 Doppler was convincingly used to document hypoperfusion in the preterm with severe left-to-right shunt due to patent ductus28 and hyperperfusion in severe hypoxicischemic encephalopathy.29 These clinically important CBF abnormalities are now being “discovered” by near-infrared spectroscopy.30,31 So, Doppler ultrasound data are perhaps underrated. In retrospect, we should have proceeded to study the arterial reactivity and thus to refine the Doppler ultrasound method. I probably saw the 2 methods as competing at the time, when they were complementary. Ultrasound scanners with Doppler capability are widely available, whereas the 133Xe clearance method was taken up by only a single new research group and is now completely out of use. Lately, ultrasound has been used to estimate volume flow by combining Doppler with imaging for measurement of arterial diameter.32 It is still too early to know if this methodology will be taken up more widely.
A Valid “Non-Invasive” Measure of Cerebral Blood Flow in the Preterm Newborn The brain– blood partition coefficient of xenon is less in the unmyelinated newborn brain compared with the adult, because xenon is lipophilic. I did the measurements by homogenizing fresh post-mortem specimens of white and gray matter. I settled for a method of analysis after more than a year of measurements, analyzing, programming, and simulation of sensitivity to errors. This method was derived from the twocompartment analysis, ie, it measures flow to the white as well as the gray matter of the brain. Although each of these was very sensitive to the various sources of error, their weighted mean proved robust. The problem was that there was no gold standard to check against. Although the first data obtained by positron emission tomography had been published in 1983,33 the absolute numbers of this method depend on accurate timing of several blood samples within 60 seconds, obviously impossible to do to perfection. After cross-checking the input function with results obtained by exhaled air and repeated blood sampling of the 15 minutes of 133Xe clearance made possible by the collaboration with Ole Pryds some years later34 (Fig 2), I came to believe that we had established a golden standard. The mean CBF value in healthy preterm newborns was 15-20 mL/100 g/min,35 or about 40% of normal values for adults. Our research ethics committee declined to permit us to study normal term in-
Figure 2 The count rate over the chest in a case with extreme rightto-left shunting and loading of chest wall tissue with tracer (heavy line). The input function calculated by the algorithm for adults assumes no tracer in the lung (and therefore in arterial blood) from 10 min. The input function from the modified algorithm for newborns is in between. The dots represent scaled tracer concentrations in timed arterial blood samples. There is reasonable agreement with the modified algorithm.
fants, and it was therefore with relief that Lotte Skov, Ole Pryds, and I found quantitative agreement with near-infrared spectroscopy,36 and later that I read the results obtained by volumetric Doppler by a research group in Tubingen37 on healthy newborns ranging from 32 to 42 weeks tying in well with ours. Meanwhile, estimation of cerebrovenous oxygen saturation by near-infrared spectroscopy has confirmed that arteriovenous oxygen extraction is the same in newborn infants as it is in adults38-40 ie, that the low CBF matches the low cerebral oxygen metabolism of the immature newborn human brain.
Back to Cerebral Ischemia: Looking for the Evidence in the Form of Electrical Failure During the mid-eighties, brain imaging and neurodevelopmental follow-up had moved the focus from IVH to periventricular leukomalacia; furthermore, the etiology of intraventricular intraparenchymal hemorrhage was no longer observed as a simple extension of the germinal layer hemorrhage,41 and hemorrhage without white matter damage was suggested to have no such importance for neurodevelopmental outcome. Thus, ischemic injury became the focus again, and I started to search for the electric ischemic threshold. It had been shown that electrical failure occurs at a higher threshold compared with cellular damage.42 First we tried visually evoked responses; they were unaffected at global flow levels well below 10 mL/100 g/min.43,44 Our colleagues in Lund had experience using the cerebral function monitor in newborn infants, and we learned from them, using an
To autoregulate or not to autoregulate instrument we found on a shelf in the Department of Thoracic Anaesthesia. Indeed, the electroencephalographic signal (EEG) is often unduly discontinuous in sick preterm infants. We were again disappointed to observe cortical EEG activity in the form of burst suppression in infants with global CBF as low as 5 mL/100 g/min.45 Significant background activity, however, in a continuous or even discontinuous pattern was unusual at a CBF below 7 mL/100 g/min. Background activity is likely to reflect thalamo– cortical coordination, and it is therefore possible that its absence reflects ischemia and dysfunction of the white matter. One possible explanation for the spontaneous EEG being affected, whereas evoked potentials were not, may be that the visual tracts project through white matter that is less exposed to ischemia, as indicated by the fact that the neurodevelopmental consequences of white matter injury only include blindness if the injury is very severe. The question, however, cannot be said to be settled; although the 7 mL/100 g/min represents about 50% of the normal resting CBF in preterm infants (Fig 3), just as the electrical threshold of 20 mL/100 g/min in gray matter in the baboon is about 50% of normal resting level,42 this fact does not explain how the preterm human cortex can continue to generate bursts below 50% of normal resting CBF.
An Expensive Sidetrack: Flow Imaging Niels Lassen was my official opponent, and during my thesis defense, just before Christmas 1989, he discussed the problem of assessment of blood flow to white matter, the tissue that seemed to be at real risk. As a result, Friis-Hansen and I obtained funding to have a single photon emission computed tomography scanner built particularly for the study of the newborn brain. The scanner was mobile and made it possible to come to the incubator and study ill infants without disturbing intensive care, and it had fan-bean collimation di-
211 rected to a minimal field of view to optimize spatial resolution (necessary to pick out white matter) and at the same time to minimize radiation exposure. Friis-Hansen was pensioned in 1990, and so I became responsible for our research program. The radiation issues took me for real into the field of research ethics and into public debate. We had permission to expose ill newborn infants to a maximum of 5 mSv. We had this permission because the chair of the committee argued that there was a possibility that the images could be of benefit to the individual child; even though this chance was small, it made it easier for the committee and for the parents to accept the small but definite cancer risk of radiation. Klaus Børch became my research fellow and invested his energy and his talents for numerical analysis into this new and dark field; dark because hot spots are much easier to deal with on isotope scans compared with areas that are cold and dark. The important result was that blood flow to the white matter is indeed much below global average. Compared with human adults and perinatal animals, the contrast between white and gray matter was surprisingly high. Carefully attending to the problems of quantitation, the rate of blood flow to white matter flow was only 17% (95% confidence limits 12-22) of that to gray matter.46 This measure is also significantly lower compared with that in any of the commonly used experimental animals, dog pup 33%, piglet 44%, and lamb 77%; it corresponds to the extraordinary large volume of the central white matter in the preterm human infant and underlines the need for caution when data from animals are put into clinical perspective. Never data, obtained by magnetic resonance imaging with arterial spin labeling, indicate a smaller difference between blood flow to gray and white matter.47 First however, this study was performed in preterm infants at term age, and second, this method is heavily dependent on the arrival time of the arterial input, which is difficult to set right in a lowly perfused region. The best ways to move on with this question would be either to use the new third generation
Figure 3 Lefthand part: cerebral blood flow (CBF) in 42 preterm infants during the first week of life according to the level of respiratory support.35 Note the logarithmic scale for CBF and the X-axes at 5 and 2.5 mL/100 g/min, respectively. (NIL, no respiratory support, CPAP, continuous positive airway pressure, IMV, mechanical ventilation with a rate less than 30/min, IPPV, mechanical ventilation at faster rate). The horizontal line represents the mean between 15 and 20 mL/100 g/min in the 11 infants without support. Right hand part: CBF in 33 preterm infants during mechanical ventilation according to classification of amplitude integrated electroencephalographic45 (FT indicates flat trace, BS, burst suppression, DC, discontinuous, CA, continuous activity, SEIZ, seizures). Most cases with CBF below 7 mL/100 g/min (50% of normal resting values) had burst suppression electroencephalographic activity only.
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212 positron emission tomography scanners or to use nonradioactive xenon clearance.
Confirming CO2 as the Major Determinant of CBF Cerebral arteries and arterioles constrict with hypocapnia and dilate with hypercapnia. In normocapnic adults, small changes in arterial carbon dioxide tension (PaCO2) result in a change in CBF by 30%/kPa (4%/mm Hg). Similar reactivity in the normal term human neonate had been demonstrated by the method of venous occlusion plethysmography.48,49 Although simple and quantitative, this method is dependent on the expansibility of the skull and has several limitations. Therefore, it was important when we were able to show that CO2 reactivity was also present on the second day of life in stable preterm ventilated infants without major germinal layer hemorrhage by l33Xe after intravenous injection.43 This finding showed that low CBF prevailed in preterm infants with respiratory distress despite the existence of a vasodilatory reserve in these infants.
Hypocapnia, Periventricular Leukomalacia, and Cerebral Palsy I realized that hypocapnia could be a most important risk factor for brain injury in the preterm infant. I had observed some cases of severe inadvertent hyperventilation when I looked for patients for my research projects. Thus, I planned a case-control study. I identified a group of 7 surviving infants discharged over a period of 18 months who had at least 1 arterial blood gas pressure with PCO2 less than 2 kPa (15 mm Hg) and 2 reference groups. Hans Lou did the neuropediatric evaluation, blinded to their neonatal course. The 3 cases of cerebral palsy were all in the hyperventilated group.50,51 In the same year, the association between hypocapnia and periventricular leukomalacia in preterm infants was reported from Canada.52 Similar associations were reported several time in the following years, but several follow-up studies of term infants treated for persistent pulmonary hypertension by hyperventilation had not shown a major problem with cerebral palsy. Furthermore, hyperventilation was not considered dangerous for the brain in adult intensive care or anesthesia. Therefore, when CO2 supplementation during exposure to hypoxia reduced brain injury in the Levene model of stroke in the 7-day-old rat,53 I placed the evidence together with Robert Vannucci,54 proposing the simple concept of hypoxia– hypocapnia leading to hypoxiaischemia leading to cellular necrosis, and cystic periventricular leukomalacia leading to cerebral palsy. It has been proposed that the pathogenesis may also involve the more subtle mechanisms of apoptosis. In newborn pigs, hyperventilation induces the expression of Bax (a proapoptotic protein) without simultaneous induction of the antiapoptotic bcl-2 protein. Furthermore, hyperventilation increased the concentration of conjugated dienes as evidence of plasma membrane
peroxidation and hyperventilation increased deoxyribonucleic acid-fragmentation.55,56
A “Natural” Experiment At Rigshospitalet, mild hyperventilation of preterm infants was intended during the early 1980s. The aim was to prevent IVH by extending the autoregulatory plateau.57 Furthermore, a new combined transcutaneous oxygen and CO2 electrode was used in the department. The electrode was developed by Radiometer, Copenhagen. The prototype instrument electrode showed the pCO2 on the screen without temperature correction, because it was still uncertain how the correction was to be performed. The pCO2 at 44 degrees Celsius of the skin under the electrode is higher than the value corrected to 37 degrees Celsius body temperature, and thus sometime false reassurance was the result. In 1985-1986, the treatment policy at Rigshospitalet in Copenhagen was changed from almost routine intubation and mechanical ventilation of very preterm babies to primary nasal CPAP,58 after the experience from Odense59 where the use of nasal CPAP had been developed as the primary management, even in the most premature infants (Fig 4). Fifteen years later, data from the routine registration of cerebral palsy showed a decrease in the incidence of cerebral palsy in children born at 31 weeks of gestation or less from 123 to 83 per 1000 for the periods 1983-1986 and 1987-1990 for the region of Eastern Denmark.60 This decrease was exclusively due to a decrease in the number of children with cerebral palsy who had been cared for at Rigshospitalet in the neonatal period. The decrease was from 87 to 47 (Fig 5). Sadly, in the history of neonatal neurology, the decision of changing treatment policy at Rigshospitalet did not come from me or from the rising evidence of the risk of hyperventilation-induced brain injury, but from a failed attempt of active treatment of a few very immature
Figure 4 The number of in-born children with gestational age below 30 weeks born in Rigshospitalet in Copenhagen and admitted for neonatal care in the period 1983-1989. During 1986, a change of policy regarding the early management of preterm infants was implemented. As a result, the fraction of infants who were mechanically ventilated decreased from three-quarters to one-quarter. Mortality gradually declined over the period.
To autoregulate or not to autoregulate
Figure 5 The number of preterm children (GA ⬍37 weeks) with cerebral palsy in the Eastern Region of Denmark, according to year and hospital of birth. Hospitals differed much in size. Hospital A is Rigshospitalet in Copenhagen. This hospital received antenatal referrals for threatened preterm birth, complications of pregnancy, and fetal malformations from most other hospitals in the region. Total number of preterm births in the two 4-year periods was 5893 and 6580, respectively. For comparison, the rate of cerebral palsy in term infants stayed the same over the 2 periods, at 1.5 per 1000 live births.
infants and the resultant protest from a strong group of nurses. The Department housed a culture of family involvement and of minimizing suffering, which was the motivation of the “minimally invasive” treatment strategy. It was our good luck that the hypercapnia and the apneic attacks that are part of letting very premature infants breathe spontaneously did not carry an epidemic of major IVH in its wake.
213 sure changes spontaneously. A statistically insignificant regression coefficient was taken as absence of evidence for loss of autoregulation. More recent research uses near-infrared spectroscopy. This allows continuous monitoring of cerebral oxygenation, and changes in cerebral oxygenation are taken as a measure of changes in CBF.63-65 One result of this development has been confirmation of the relation between absence of autoregulation and brain injury or death. The other important result has been that statistically significant correlation is frequent in preterm infants during intensive care. However, NIRS allows collection of much more data in each infant, and therefore statistically significant correlation between flow and pressure can be achieved even when the functional relation is relatively weak. In reality, the flat part of the autoregulatory plateau may never be truly horizontal; what matters is how much it is tilted (Fig 6). In fact, the confidence interval of the pressure-flow relation of our early studies did not exclude a considerable tilt, and therefore my own conclusion that autoregulation was present (⫽perfect)66 was simplistic. Furthermore, the issue has become more complex by the link between cardiac output and cerebral hemorrhage,67 and the likelihood that the adrenergic mechanisms involved during circulatory compromise also act on the cerebral circulation to reduce CBF.68,69 A correlation has been demonstrated between cardiac output as measured by superior vena cave flow and cerebral oxygenation as measured by near-infrared spectroscopy.70
The CBF-arterial Blood Pressure Relation: To Autoregulate or Not Neither my first results point to a direct association between arterial blood pressure and CBF35,43 nor did those of Ole Pryds. Ole followed me as Friis-Hansen’s research fellow, and in a large study on ventilated preterm infants he was able to discriminate between those who did not develop IVH (who did autoregulate) and those who did (who did not autoregulate).61 Furthermore, Ole studied asphyxiated term infants and found the same pattern; those who did not develop brain injury did autoregulate, and those who developed did not autoregulate.62 In conclusion, the normal human brain can autoregulate, even if premature, and if the infant is ill.
A More Useful Concept: Autoregulation as a Quantity Rather Than a Quality In these studies, the presence of autoregulation was tested by regression of changes in CBF as a function of changes in blood pressure. This method was made possible by 2 or more measurements in each infant and by the fact that blood pres-
Figure 6 Drawing of the concept of autoregulation. The heavy line has a relatively flat middle part. A percentage change in blood pressure results in a much smaller percentage change in cerebral blood flow. In practice, this means that change of blood pressure within the range of this slope will have not much effect on CBF, and yet the slope is positive, and accurate data will reveal a statistically significant relationship. The relation is stronger below the lower “knee.” The thin curve has a steeper slope, yet still a well-defined knee. Changes in blood pressure in the middle part of the curve have larger but still limited effect on flow. Is autoregulation present? Autoregulation is a question of degree and should be quantified.
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A Final Point of Relevance for Research Ethics and Clinical Practice What matters is how much CBF can be increased by raising blood pressure in an ill preterm infant. Some data on this exists71-74 and suggests that this increase is moderate. In this context, the paucity of experimental manipulation of blood pressure with CBF or cerebral oxygenation as the endpoint is a shame. Autoregulation has been tested by infusion of noradrenaline in adults with bacterial meningitis.75 In neonatal research, however, the idea from the 1970s of IVH caused by hypertensive peaks has shadowed this possibility. At the same time, multiple studies have manipulated pCO2, and now in hindsight have caused more perturbations to the cerebral circulation. Similarly, the idea of hypertension causing cerebral hemorrhage still influences clinical practice, and many clinicians probably consider blood pressure more important than pCO2 as a determinant for CBF. This is also a shame.
Acknowledgment Hans Lou, in particular, is thanked for his eager openness whenever I was critical about his earlier work.76 That has held true over the following years of collaboration. Hans has always worked for a new perspective and better insight.
References 1. Friis-Hansen B: Body water compartments in children: Changes during growth and related changes in body composition. Pediatrics 28:169181, 1961 2. Cooke R, Lunding M, Lomholdt NF, et al: Respiratory failure in the newborn. The techniques and results of intermittent positive pressure ventilation. Acta Pædiatrica Scand 56:498-508, 1967 3. Kamper J, Baekgaard P, Peitersen B, et al: (Treatment of respiratory distress syndrome with continuous positive airway pressure). Ugeskr Laeger 135:2207-2211, 1973 4. Lassen NA, Munck O: The cerebral blood flow in man determined by the use of radioactive krypton. Acta Physiol Scand 33:30-49, 1955 5. Ingvar DH, Lassen NA: Methods for cerebral blood flow measurements in Man. Br J Anaesth 37:216-224, 1965 6. Jensen KB, Hoedt-Rasmussen K, Sveinsdottir E, et al: Regional cerebral blood flow determined by inhalation of xenon-133. Summary of a methodological study. Acta Neurol Scand Suppl 13:309-310, 1965 7. Lou HC, Lassen NA, Friis-Hansen B: Low cerebral blood flow in hypotensive perinatal distress. Acta Neurol Scand 56:343-352, 1977 8. Hambleton G, Wigglesworth JS: Origin of intraventricular haemorrhage in the preterm infant. Arch Dis Child 51:651-659, 1976 9. Wigglesworth JS, Pape KE: An integrated model for haemorrhagic and ischaemic lesions in the newborn brain. Early Hum Dev 2:179-199, 1978 10. Lou HC, Lassen NA, Friis-Hansen B: Impaired autoregulation of cerebral blood flow in the distressed newborn infant. J Pediatr 94:118-121, 1979 11. Papile LA, Burstein J, Burstein R, et al: Incidence and evolution of subependymal and intraventricular hemorrhage: A study of infants with birthweights less than 1, 500 gm. J Pediatr 92:529-534, 1978 12. Lou HC, Lassen NA, Friis-Hansen B: Is arterial hypertension crucial for the development of cerebral haemorrhage in premature infants? Lancet 1:1215-1217, 1979 13. Wigglesworth JS: Prevention of cerebral hemorrhage in preterm infants. Lancet 2:256, 1979
G. Greisen 14. Wigglesworth JS: Low cerebral blood flow: A risk factor in the neonate. J Pediatr 97:513, 1980 15. Friis-Hansen B, Lou HC: Reply. J Pediatr 97:513-514, 1980 16. Trolle D: A possible drop in first-week-mortality rate for low-birthweight infants after phenobarbitone treatment. Lancet 2:1123-1124, 1968 17. Osler M, Faero O, Friis-Hansen B, et al: Prevention of the respiratory distress syndrome (RDS) by antepartum glucocorticoid (betamethasone) therapy combined with phenobarbitone and ritodrine. Dan Med Bull 25:225-229, 1978 18. Greisen G, Andreasen PB: Two-compartment analysis of plasma elimination of phenazone in normals and in patients with cirrhosis of the liver. Acta Pharm Toxicol 38:49-52, 1976 19. Pape KE, Blackwell RJ, Cusick G, et al: Ultrasound detection of brain damage in preterm infants. Lancet 1:1261-1264, 1979 20. Greisen G, Petersen MB: Intraventricular haemorrhage and method of delivery of VLBW infants. J Perinat Med 11:67-73, 1983 21. Wimberley PD, Lou HC, Pedersen H, et al: Hypertensive peaks in the pathogenesis of intraventricular hemorrhage in the newborn. Abolition by phenobarbitone sedation. Acta Paediatr Scand 71:537-542, 1982 22. Younkin DP, Reicich M, Jaggi J, et al: Noninvasive method of estimating human newborn regional cerebral blood flow. J Cereb Blood Flow Metab 2:415-420, 1982 23. Ment L, Ehrenkranz RA, Lange RC, et al: Alterations in cerebral blood flow in preterm infants with intraventricular hemorrhage. Pediatrics 68:763-769, 1981 24. Greisen G, Fredriksen PS, Mali J, et al: Analysis of cranial 133 xenon clearance in the newborn by the two-compartment model. Scand J Clin Lab Invest 44:239-250, 1984 25. Greisen G, Ellison PH, Johansen K, et al: Cerebral blood flow in the newborn infant. Comparison of Doppler ultrasound and 133 xenon clearance. J Pediatr 104:411-417, 1984 26. Greisen G, Pryds O, Rosén I, et al: Poor reversibility of EEG abnormality in hypotensive, preterm neonates. Acta Paediatr Scand 77:785-790, 1988 27. Greisen G: Analysis of cerebro-arterial Doppler flow velocity waveforms from newborn infants: Towards an index of cerebro-vascular resistance. J Perinat Med 14:181-187, 1986 28. Perlman JM, Hill A, Volpe JJ: The effect of patent ductus arteriosus on flow velocity in the anterior cerebral arteries: Ductal steal in the premature newborn infant. J Pediatr 99:767-771, 1981 29. Levene MI, Sands C, Grindulis H, et al: Comparison of two methods of predicting outcome in perinantal asphyxia. Lancet 1:67-69, 1985 30. Toet MC, Lemmers PM, van Schelven LJ, et al: Cerebral oxygenation and electrical activity after birth asphyxia: Their relation to outcome. Pediatrics 117:333-339, 2006 31. Lemmers PM, Toet MC, van Bel F: Impact of patent ductus arteriosus and subsequent therapy with indomethacin on cerebral oxygenation in preterm infants. Pediatrics 121:142-147, 2008 32. Ehehalt S, Kehrer M, Goelz R, et al: Cerebral blood flow volume measurement with ultrasound: Interobserver reproducibility in preterm and term neonates. Ultrasound Med Biol 31:191-196, 2005 33. Volpe JJ, Herscovitch P, Perlman JM, et al: Positron emission tomography in the newborn: Extensive impairment of regional cerebral blood flow with intraventricular hemorrhage and hemorrhagic intracerebral involvement. Pediatrics 72:589-601, 1983 34. Greisen G, Pryds O: Intravenous 133Xe clearance in preterm neonates with respiratory distress. Internal validation of CBF infinity as a measure of global cerebral blood flow. Scand J Clin Lab Invest 48:673-678, 1988 35. Greisen G: Cerebral blood flow in preterm infants during the first week of life. Acta Paediatr Scand 75:43-51, 1986 36. Skov L, Pryds O, Greisen G: Estimating cerebral blood flow in newborn infants: Comparison of near infrared spectroscopy and 133Xe clearance. Pediatr Res 30:570-573, 1991 37. Kehrer M, Krageloh-Mann I, Goelz R, et al: The development of cerebral perfusion in healthy preterm and term neonates. Neuropediatrics 34:281-286, 2003
To autoregulate or not to autoregulate 38. Skov L, Pryds O, Greisen G, et al: Estimation of cerebral venous saturation in newborn infants by near infrared spectroscopy. Pediatr Res 33:52-55, 1993 39. Buchwald FF, Kesje K, Greisen G: Measurement of cerebral oxyhaemoglobin saturation and jugular blood flow in term healthy newborn infants by near-infrared spectroscopy and jugular venous occlusion. Biol Neonate 75:96-100, 1999 40. Yoxall CW, Weindling AM: Measurement of cerebral oxygen consumption in the human neonate using near infrared spectroscopy: Cerebral oxygen consumption increases with advancing gestational age. Pediatr Res 44:283-290, 1998 41. Gould SJ, Howard S, Hope PL, et al: Periventricular intraparenchymal cerebral haemorrhage in preterm infants: The role of venous infarction. J Pathol 151:197-202, 1987 42. Branston NM, Ladds A, Symon L, et al: Comparison of the effects of ischaemia on early components of somatosensory evoked potentials in brainstem, thalamus, and cerebral cortex. J Cereb Blood Flow Metab 4:68-81, 1984 43. Greisen G, Trojaborg W: Cerebral blood flow, PaCO2 changes, and visual evoked potentials in mechanically ventilated infants. Acta Paediatr Scand 76:394-400, 1987 44. Pryds O, Greisen G: Preservation of single-flash visual evoked potentials at very low cerebral oxygen delivery in preterm infants. Pediatr Neurol 6:151-158, 1990 45. Greisen G, Pryds O, Low CBF: Discontinuous EEG activity, and periventricular brain injury in ill, preterm neonates. Brain Dev 11:164168, 1989 46. Børch K, Greisen G: Blood flow distribution in the normal human preterm brain. Pediatr Res 43:28-33, 1998 47. Miranda MJ, Olofsson K, Sidaros K: Noninvasive measurements of regional cerebral perfusion in preterm and term neonates by magnetic resonance arterial spin labelling. Pediatr Res 60:359-363, 2006 48. Leahy FAN, Cates D, MacCallum M, et al: Effect of CO2 and 100% O2 on cerebral blood flow in preterm infants. J Appl Physiol 48:468-472, 1980 49. Rahilly PM: Effects of 2% carbon dioxide. 0.5% carbon dioxide and 100% oxygen on cranial blood flow of the human neonate. Pediatrics 66:685-689, 1980 50. Greisen G, Munck H, Lou HM: Hypocarbia cause ischaemic brain damage in the preterm infant? Lancet 2:460, 1986 51. Greisen G, Munck H, Lou H: Severe hypocarbia in preterm infants and neurodevelopmental deficit. Acta Paediatr Scand 76:401-04, 1987 52. Calvert SA, Hoskins EM, Fong KW, et al: Etiological factors associated with the development of periventricular leukomalacia. Acta Paediatr Scand 76:254-259, 1987 53. Vannucci RC, Towfighi J, Heitjan DF, et al: Carbon dioxide protects the perinatal brain from hypoxic-ischaemic damage: An experimental study in the immature rat. Pediatrics 95:868-874, 1995 54. Greisen G, Vannucci RC: Is periventricular leukomalacia a result of hypoxic ischaemic injury? Hypocapnia and the preterm brain. Biol Neonate 79:194-200, 2001 55. Fritz KI, Ashraf QM, Mishra OMP, et al: Effect of moderate hypocapnic ventilation on nuclear DNA fragmentation and energy metabolism in the cerebral cortex of newborn piglets. Pediatr Res 50:586-589, 2001 56. Pirot AL, Fritz KI, Mishra OP, et al: Effects of severe hypocapnia on expression of bax and bcl-2 proteins, DNA-fragmentation, and mem-
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brane peroxidation products in cerebral cortical mitochondria of newborn piglets. J Neonatol 91:20-27, 2007 Lou HC, Phibbs RH, Wilson SL, et al: Hyperventilation at birth may prevent early periventricular haemorrhage. Lancet 1:1407-1407, 1982 Jacobsen T, Grønvall J, Petersen S, et al: “Minitouch” treatment of very low birth weight infants. Acta Paediatr 82:934-938, 1993 Kamper J, Ringsted C: Early treatment of idiopathic respiratory distress syndrome using binasal continuous positive airway pressure. Acta Paediatr Scand 79:581-586, 1990 Topp M, Uldall P, Greisen G: Cerebral palsy births in eastern Denmark, 1987-90: Implications for neonatal care. Paediatr Perinat Epidemiol 15:271-277, 2001 Pryds O, Greisen G, Lou H, et al: Heterogeneity of cerebral vasoreactivity in preterm infants supported by mechanical ventilation. J Pediatr 115:638-645, 1989 Pryds O, Greisen G, Lou H, et al: Vasoparalysis is associated with brain damage in asphyxiated term infants. J Pediatr 117:119-125, 1990 Tsuji M, Saul P, du Plessis A, et al: Cerebral intravascular oxygenation correlates with mean arterial pressure in critically ill premature infants. Pediatrics 106:625-632, 2000 Soul JS, Hammer PE, Tsuji M, et al: Fluctuating pressure-passivity is common in the cerebral circulation of sick premature infants. Pediatr Res 61:467, 2007 Wong FY, Leung TS, Austin T, et al: Impaired autoregulation in preterm infants identified by using spectially resolved spectroscopy. Pediatrics 121:e604-e611, 2008 Greisen G: Autoregulation of cerebral blood flow in newborn babies. Early Hum Dev 81:423-428, 2005 Kluckow M, Evans N: Low superior vena cava flow and intraventricular haemorrhage in preterm infants. Arch Dis Child Fetal Neonat Ed 82: F188-F194, 2000 Hernandez MJ, Hawkins RA, Brennan RW: Sympathetic control of regional cerebral blood flow in the asphyxiated newborn dog, in Heistad DD, Marcus ML (eds): Cerebral Blood Flow, Effects of Nerves and Neurotransmitters. New York, Elsevier, 1982, pp 359-366 Goblerud JM, Wagerle LC, Delivoria-Papadopoulos M: Sympathetic nerve modulation of regional cerebral blood flow during asphyxia in newborn piglets. Am J Physiol 260:H1575-H1580, 1991 Moran M, Miletin J, Pichova K, et al: Cerebral tissue oxygenation index and superior vena cava blood flow in the very low birthweight infant. Acta Paediatr 98:43-46, 2009 Lundstrøm K, Pryds O, Greisen G: The haemodynamic effects of dopamine and volume expansion in sick preterm infants. Early Hum Dev 57:157-163, 2000 Jayasinghe D, Gill AB, Levene MI: CBF reactivity in hypotensive and normotensive preterm infants. Pediatr Res 54:848-853, 2003 Munro MJ, Walker AM, Barfield CP: Hypotensive extremely low birthweight infants have reduced cerebral blood flow. Pediatrics 114:15911596, 2004 Pellicer A, Valverde E, Elorza MD, et al: Cardiovascular support for low birthweight infants and cerebral hemodynamics: A randomized, blinded, clinical trial. Pediatrics 115:1501-1512, 2005 Møller K, Tofteng F, Quist T, et al: Cerebral blood flow and metabolism during infusion of noradrenaline and propofol in patients with bacterial meningitis. Stroke 35:1333-1339, 2004 Greisen G: Cerebral blood flow in mechanically ventilated preterm infants. Dan Med Bull 37:124-132, 1990
Survival of the Small Preterm with Brain Injury: The Neonatologist’s Challenge With rapidly evolving neonatal intensive care allowing survival of ever-smaller babies, the question of brain injury and survival of handicapped children became a prime concern for my mentor, Bent Friis-Hansen. He had been the head of the Department of Neonatology at Rigshospitalet since its establishment in 1965. Although his primary research field was body water during growth1 and nutrition, he had faced the practical aspects of neonatal care and soon supervised the implementation of mechanical ventilation of newborns with respiratory distress.2 Two years after Gregory had shown the benefits of continuous positive airway pressure (CPAP), Jens Kamper3 and Friis-Hansen report mortality as low as 32% in intubated babies with birth weight less than 1500 g. This success led to concerns.
Cerebral Blood Flow: The Mecca was Copenhagen Copenhagen in Denmark, 50 km south of the castle of Hamlet, was the origin of the use of radioactive isotopes to meaFrom the Department of Neonatology, Rigshospitalet, Copenhagen, Denmark. Address reprint requests to Gorm Greisen, MD, DMSc, Department of Neonatology, Rigshospitalet 5024, Blegdamsvej 9, 2100 Copenhagen Ø, Denmark. E-mail: [email protected]
1071-9091/09/$-see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.spen.2009.09.002
sure cerebral blood flow (CBF). Niels A Lassen4 obtained the first data in man in 1955 using the inert gas krypton. The inert gas xenon was first used to measure muscle blood flow by clearance after local injection. In 1965, his group published methods to measure regional cerebral blood flow in man by intracarotid injection5 or inhalation6 and by external detection of the gamma radiation. These methods became standard because regional values could be obtained (which is not possible with the Kety–Schmidt method using jugular venous blood sampling), and because it was no longer necessary to cannulate the jugular vein. The radiation resulting from the use of these isotopes was modest. As a result, clinical physiology was thriving in Copenhagen, and the methods were applied to a wide range of physiological questions and clinical problems.
A Simple Experiment Thus, it was natural for Hans C. Lou, with an interest in pediatric neurology and newly employed in the Department of Neonatology, to take up the challenge to use the 133Xe clearance method to examine the role of CBF in perinatal brain injury. He placed an umbilical arterial catheter during clinical care to advance the catheter to the left carotid artery, the innominate artery or the aortic arch, and to inject 0.5 mCi 133Xe dissolved in 1 mL of normal saline. The catheter was withdrawn to its normal position thereafter. A scintillation detector was held over the head during the following 60 seconds. The count rate was plotted on a semilogarithmic 207
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208 graph. In this situation, the simple slope from 15 to 60 seconds, determined by eye and a ruler, is a robust measure of clearance and only needed the assumption of the brain– blood partition coefficient to allow the estimation of CBF in milliliters/100 g/min.
The First Robust Data on CBF in the Human Newborn The first publication from the collaboration of Lou et al7 was in 1977. It is the data from 8 newborns, shortly after birth. For Hans Lou, it was publication number 9, for Bent FriisHansen number 53, and for Niels Lassen number 238, available on PubMed. It thus came out of a significant collaborative experience in clinical science. The paper focuses on the surprisingly low values of CBF, in the newborn with values as low as 20 mL/100 g/min. The result of this “early slope” refers to the areas of the brain with the highest flow, the cortex, and central gray matter in the small newborn brain, and was less than a third of normal adult values and much less than the values routinely obtained in the newborn lamb, the most popular animal model in perinatal research at the time. A link was made to the low systolic blood pressure measured simultaneously by ultrasound Doppler, and a statistically significant correlation between CBF and blood pressure was presented. The interpretation was that perinatal distress induces circulatory compromise through depletion of glycogen in the myocardium, leading to arterial hypotension and then to cerebral ischemia and the well-known brain injury after birth asphyxia. In the discussion section of the paper, the authors has mentioned the possibility of arterial hypertension leading to cerebral hemorrhage, and refer to a paper of Hambleton and Wigglesworth (1976).8 Dr Wigglesworth had suggested a link between blood flow and cerebral hemorrhage by examination of injection specimens in the dissecting microscope. Injection of barium gelatin solution was used from the arterial side followed by clearing of the tissue with the Spalteholz technique. The typical origin of hemorrhage was found to be the capillary or the capillary-venous junction in the germinal matrix. This finding had led to a comprehensive model for hemorrhagic and ischemic lesions in the newborn brain.9
The Change in Focus: From Ischemia to Hemorrhage The next publication of the Copenhagen group included data from 19 newborns,10 of which 8 were the same as the previous publication. The correlation between CBF and blood pressure was now significant at the P ⬍ 0.0001 level, and the correlation was the same in infants with perinatal distress and those with postnatal distress only (presumed respiratory distress syndrome). The focus in this paper was on the impairment of autoregulation and on the risk of hemorrhage due to transmittance of arterial pressure to the capillaries in the germinal matrix. This publication has received 509 citations to date, compared with 85 citations of the 1977 publication.
This shift of focus should be observed in the light of the discovery that intraventricular hemorrhage (IVH) was a frequent event in very low birth weight (VLBW) infants. IVH was put on the agenda by a publication by Lu Ann Papile11 in 1978. It came as a surprise that 40% of all VLBW infants developed IVH, and that most were asymptomatic and survived. The new focus was emphasized in another paper published by Lou et al12 under the heading “hypothesis” in the Lancet: “Is arterial hypertension crucial for the development of cerebral haemorrhage in the premature infant?” At the end of the paper, the use of sedatives was suggested to reduce blood pressure increases due to spontaneous activity, handling, or seizures.
The Use of Sedatives to Limit Arterial Hypertension The proposal of using sedatives to reduce the risk of hypertension was opposed as a potentially dangerous practice by Dr Wigglesworth13 in the correspondence section of the Lancet, stressing the danger of the Charybdis of hypotension and cerebral ischemia. The group from Copenhagen and Dr Wigglesworth’s group from the Hammersmith in London had exchanges of letters of correspondence,14,15 but agreed on the idea that the cerebral circulation was exquisitely sensitive to changes in arterial blood pressure. One, not explicit, reason for the proposal of sedation was the long-standing interest in phenobarbitone of the Professor of Obstetrics at Rigshospitalet at the time, Dyre Trolle. Dr Trolle had demonstrated that bilirubin conjugation could be induced in newborn infants with rhesus disease by giving phenobarbitone to the pregnant woman. He had extended this practice to all low birth weight infants and to administration of phenobarbitone for the first 3 days after birth. In 1968, he reported a reduction in first week mortality. The study partly used historical controls and partly simultaneous controls from the sister Department of Obstetrics in the hospital. Although this was not science of current-day standards, it was published in the Lancet.16 In 1978, he published, with his colleague in the sister department and with Friis-Hansen, the benefit of a cocktail of betamethasone, ritodrine (a tocolytic), and phenobarbitone to the pregnant woman before preterm birth.17 Again the methodology used historical and contemporary controls, but the effect on respiratory distress syndrome and mortality seemed specific for the group with gestational age below 34 weeks.
My Haphazard Entry Into Neonatology In February 1980, I was employed as a junior physician (reservelæge) in the Department of Neonatology. Unemployment among young medical graduates was high, and I got this opportunity partly because I had served 2 years as a district medical officer in Zambia, replacing my military service, and partly because I had shown pregraduate interest in
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research and published a paper on drug clearance as a measure of liver function; Friis-Hansen had worked in Zambia as a nutrition specialist for world health organization.18 In the beginning, I needed a job and a salary to feed my family. Friis-Hansen suggested that Dr Minna Block Petersen and I should try ultrasound to diagnose IVH, as reported by the University College London group in London the previous year.19 During the summer, I heard Dr Volpe in Gotenburg as he received a Swedish Paediatric Society prize. That event opened the world of neonatal neurology to me. Minna and I received training from a colleague from the Department of Obstetric Ultrasound and borrowed an ultrasound machine outside office hours, and from September 1980 to March 1982 we performed a prospective study on IVH in infants less than 1500 g; and we also found a prevalence of 40%.20 We have followed this cohort at 2, 4, and 18 years.
The Need for New Data—For a Noninvasive Method At that time, Dr Wimberley was the research fellow of Dr Friis-Hansen Dr Wimberley’s research area was the oxygen binding of hemoglobin F. As a side-job he took care of the new microcomputer-based continuous clinical data monitoring system of the department, and he was able to publish a weak correlation between arterial pressure peaks and cerebral hemorrhage.21 But what was really needed was more data on CBF. It was necessary to be able to measure CBF several times and at times other than during umbilical arterial catheterization. The procedure had also been criticized. Noninvasive 133Xe clearance had been performed using intravenous injection in the adult, but required complex data analysis to correct for the noninstantaneous input of tracer to the brain. Friis-Hansen therefore bought a “cerebrograph,” ie, a prototype instrument, including a scintillation detection system (Fig 1) and a tabletop computer.
The Early Days of Computer-Based Signal Analysis This was an opportunity. I became a research fellow in early 1982, I think because I had taken the ultrasound studies forward and because I had a bachelor’s degree in computer science besides my medical degree and had begun helping out with the cerebrograph. It had come with a program implementing the inhalation/i.v. injection 133Xe clearance method for adults (Obrist). Although this method was used by Younkin et al22 from Philadelphia, and in a simplified version by Laura Ment,23 the analysis was not appropriate and the results were falsely high due to scattered radiation from the lungs, a situation more important in the small ill newborn for several reasons, including right-to-left ductal shunting, chest-wall contribution to the input-function, and the relatively small gray matter compartment and relatively low CBF.24
Figure 1 Cerebral blood flow is measured by 133Xe clearance in a preterm ventilated infant. One scintillation detector is placed over the head and 1 detector over the chest. The syringe contains 133Xe in saline and is connected to an intravenous line. The lead shield limits the scattered radiation from the syringe to the fields of measurement.
An Improvised Cross-Atlantic Collaboration: Doppler Ultrasound vs Xenon Clearance I presented some of my early methodological insights and solutions at the International Child Neurology Association meeting in Copenhagen in May 1982, to 10 people in a lecture theater. I realized that my data, the result of months of work, was not of interest to anybody. Over the years this impression has been reinforced; methodological scrutiny takes a quiet atmosphere. During the congress I contacted those 3 others presenting data on neonatal CBF: Henrietta Bada, Donald Younkin, and Patricia Ellison. Patricia responded, visited our department, asked why we did not use the much simpler method of Doppler ultrasound, and later she came back with her machine so that we could do a comparative study of my 133Xe clearance method, Patricia’s continuous wave machine, and a range-gated Doppler machine that we found on a shelf in the Department of Thoracic Surgery. The correlation coefficients between 0.4 and 0.8 for the various Doppler measures25 was important for the burgeoning field of Doppler studies of neonatal cerebral circulation. We computed a prediction interval of ⫾50% for a single measurement, but contrary to this number the work has most often been mentioned as a support for the validity of Doppler ultrasound. Henrietta Bada in the accompanying editorial noticed that some correlation was not surprising as both are
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measures of CBF, and it was not surprising that the results are not identical because the methods are very different.
An Afterthought on Methodology for Clinical Research We continued to use Doppler ultrasound ourselves.26 I tried coanalysis of Doppler and blood pressure in the frequency domain, but in the end I became convinced that Doppler data on flow velocity could be impossible to interpret in CBF when arterial cross sectional area was dynamically regulated.27 Doppler was convincingly used to document hypoperfusion in the preterm with severe left-to-right shunt due to patent ductus28 and hyperperfusion in severe hypoxicischemic encephalopathy.29 These clinically important CBF abnormalities are now being “discovered” by near-infrared spectroscopy.30,31 So, Doppler ultrasound data are perhaps underrated. In retrospect, we should have proceeded to study the arterial reactivity and thus to refine the Doppler ultrasound method. I probably saw the 2 methods as competing at the time, when they were complementary. Ultrasound scanners with Doppler capability are widely available, whereas the 133Xe clearance method was taken up by only a single new research group and is now completely out of use. Lately, ultrasound has been used to estimate volume flow by combining Doppler with imaging for measurement of arterial diameter.32 It is still too early to know if this methodology will be taken up more widely.
A Valid “Non-Invasive” Measure of Cerebral Blood Flow in the Preterm Newborn The brain– blood partition coefficient of xenon is less in the unmyelinated newborn brain compared with the adult, because xenon is lipophilic. I did the measurements by homogenizing fresh post-mortem specimens of white and gray matter. I settled for a method of analysis after more than a year of measurements, analyzing, programming, and simulation of sensitivity to errors. This method was derived from the twocompartment analysis, ie, it measures flow to the white as well as the gray matter of the brain. Although each of these was very sensitive to the various sources of error, their weighted mean proved robust. The problem was that there was no gold standard to check against. Although the first data obtained by positron emission tomography had been published in 1983,33 the absolute numbers of this method depend on accurate timing of several blood samples within 60 seconds, obviously impossible to do to perfection. After cross-checking the input function with results obtained by exhaled air and repeated blood sampling of the 15 minutes of 133Xe clearance made possible by the collaboration with Ole Pryds some years later34 (Fig 2), I came to believe that we had established a golden standard. The mean CBF value in healthy preterm newborns was 15-20 mL/100 g/min,35 or about 40% of normal values for adults. Our research ethics committee declined to permit us to study normal term in-
Figure 2 The count rate over the chest in a case with extreme rightto-left shunting and loading of chest wall tissue with tracer (heavy line). The input function calculated by the algorithm for adults assumes no tracer in the lung (and therefore in arterial blood) from 10 min. The input function from the modified algorithm for newborns is in between. The dots represent scaled tracer concentrations in timed arterial blood samples. There is reasonable agreement with the modified algorithm.
fants, and it was therefore with relief that Lotte Skov, Ole Pryds, and I found quantitative agreement with near-infrared spectroscopy,36 and later that I read the results obtained by volumetric Doppler by a research group in Tubingen37 on healthy newborns ranging from 32 to 42 weeks tying in well with ours. Meanwhile, estimation of cerebrovenous oxygen saturation by near-infrared spectroscopy has confirmed that arteriovenous oxygen extraction is the same in newborn infants as it is in adults38-40 ie, that the low CBF matches the low cerebral oxygen metabolism of the immature newborn human brain.
Back to Cerebral Ischemia: Looking for the Evidence in the Form of Electrical Failure During the mid-eighties, brain imaging and neurodevelopmental follow-up had moved the focus from IVH to periventricular leukomalacia; furthermore, the etiology of intraventricular intraparenchymal hemorrhage was no longer observed as a simple extension of the germinal layer hemorrhage,41 and hemorrhage without white matter damage was suggested to have no such importance for neurodevelopmental outcome. Thus, ischemic injury became the focus again, and I started to search for the electric ischemic threshold. It had been shown that electrical failure occurs at a higher threshold compared with cellular damage.42 First we tried visually evoked responses; they were unaffected at global flow levels well below 10 mL/100 g/min.43,44 Our colleagues in Lund had experience using the cerebral function monitor in newborn infants, and we learned from them, using an
To autoregulate or not to autoregulate instrument we found on a shelf in the Department of Thoracic Anaesthesia. Indeed, the electroencephalographic signal (EEG) is often unduly discontinuous in sick preterm infants. We were again disappointed to observe cortical EEG activity in the form of burst suppression in infants with global CBF as low as 5 mL/100 g/min.45 Significant background activity, however, in a continuous or even discontinuous pattern was unusual at a CBF below 7 mL/100 g/min. Background activity is likely to reflect thalamo– cortical coordination, and it is therefore possible that its absence reflects ischemia and dysfunction of the white matter. One possible explanation for the spontaneous EEG being affected, whereas evoked potentials were not, may be that the visual tracts project through white matter that is less exposed to ischemia, as indicated by the fact that the neurodevelopmental consequences of white matter injury only include blindness if the injury is very severe. The question, however, cannot be said to be settled; although the 7 mL/100 g/min represents about 50% of the normal resting CBF in preterm infants (Fig 3), just as the electrical threshold of 20 mL/100 g/min in gray matter in the baboon is about 50% of normal resting level,42 this fact does not explain how the preterm human cortex can continue to generate bursts below 50% of normal resting CBF.
An Expensive Sidetrack: Flow Imaging Niels Lassen was my official opponent, and during my thesis defense, just before Christmas 1989, he discussed the problem of assessment of blood flow to white matter, the tissue that seemed to be at real risk. As a result, Friis-Hansen and I obtained funding to have a single photon emission computed tomography scanner built particularly for the study of the newborn brain. The scanner was mobile and made it possible to come to the incubator and study ill infants without disturbing intensive care, and it had fan-bean collimation di-
211 rected to a minimal field of view to optimize spatial resolution (necessary to pick out white matter) and at the same time to minimize radiation exposure. Friis-Hansen was pensioned in 1990, and so I became responsible for our research program. The radiation issues took me for real into the field of research ethics and into public debate. We had permission to expose ill newborn infants to a maximum of 5 mSv. We had this permission because the chair of the committee argued that there was a possibility that the images could be of benefit to the individual child; even though this chance was small, it made it easier for the committee and for the parents to accept the small but definite cancer risk of radiation. Klaus Børch became my research fellow and invested his energy and his talents for numerical analysis into this new and dark field; dark because hot spots are much easier to deal with on isotope scans compared with areas that are cold and dark. The important result was that blood flow to the white matter is indeed much below global average. Compared with human adults and perinatal animals, the contrast between white and gray matter was surprisingly high. Carefully attending to the problems of quantitation, the rate of blood flow to white matter flow was only 17% (95% confidence limits 12-22) of that to gray matter.46 This measure is also significantly lower compared with that in any of the commonly used experimental animals, dog pup 33%, piglet 44%, and lamb 77%; it corresponds to the extraordinary large volume of the central white matter in the preterm human infant and underlines the need for caution when data from animals are put into clinical perspective. Never data, obtained by magnetic resonance imaging with arterial spin labeling, indicate a smaller difference between blood flow to gray and white matter.47 First however, this study was performed in preterm infants at term age, and second, this method is heavily dependent on the arrival time of the arterial input, which is difficult to set right in a lowly perfused region. The best ways to move on with this question would be either to use the new third generation
Figure 3 Lefthand part: cerebral blood flow (CBF) in 42 preterm infants during the first week of life according to the level of respiratory support.35 Note the logarithmic scale for CBF and the X-axes at 5 and 2.5 mL/100 g/min, respectively. (NIL, no respiratory support, CPAP, continuous positive airway pressure, IMV, mechanical ventilation with a rate less than 30/min, IPPV, mechanical ventilation at faster rate). The horizontal line represents the mean between 15 and 20 mL/100 g/min in the 11 infants without support. Right hand part: CBF in 33 preterm infants during mechanical ventilation according to classification of amplitude integrated electroencephalographic45 (FT indicates flat trace, BS, burst suppression, DC, discontinuous, CA, continuous activity, SEIZ, seizures). Most cases with CBF below 7 mL/100 g/min (50% of normal resting values) had burst suppression electroencephalographic activity only.
G. Greisen
212 positron emission tomography scanners or to use nonradioactive xenon clearance.
Confirming CO2 as the Major Determinant of CBF Cerebral arteries and arterioles constrict with hypocapnia and dilate with hypercapnia. In normocapnic adults, small changes in arterial carbon dioxide tension (PaCO2) result in a change in CBF by 30%/kPa (4%/mm Hg). Similar reactivity in the normal term human neonate had been demonstrated by the method of venous occlusion plethysmography.48,49 Although simple and quantitative, this method is dependent on the expansibility of the skull and has several limitations. Therefore, it was important when we were able to show that CO2 reactivity was also present on the second day of life in stable preterm ventilated infants without major germinal layer hemorrhage by l33Xe after intravenous injection.43 This finding showed that low CBF prevailed in preterm infants with respiratory distress despite the existence of a vasodilatory reserve in these infants.
Hypocapnia, Periventricular Leukomalacia, and Cerebral Palsy I realized that hypocapnia could be a most important risk factor for brain injury in the preterm infant. I had observed some cases of severe inadvertent hyperventilation when I looked for patients for my research projects. Thus, I planned a case-control study. I identified a group of 7 surviving infants discharged over a period of 18 months who had at least 1 arterial blood gas pressure with PCO2 less than 2 kPa (15 mm Hg) and 2 reference groups. Hans Lou did the neuropediatric evaluation, blinded to their neonatal course. The 3 cases of cerebral palsy were all in the hyperventilated group.50,51 In the same year, the association between hypocapnia and periventricular leukomalacia in preterm infants was reported from Canada.52 Similar associations were reported several time in the following years, but several follow-up studies of term infants treated for persistent pulmonary hypertension by hyperventilation had not shown a major problem with cerebral palsy. Furthermore, hyperventilation was not considered dangerous for the brain in adult intensive care or anesthesia. Therefore, when CO2 supplementation during exposure to hypoxia reduced brain injury in the Levene model of stroke in the 7-day-old rat,53 I placed the evidence together with Robert Vannucci,54 proposing the simple concept of hypoxia– hypocapnia leading to hypoxiaischemia leading to cellular necrosis, and cystic periventricular leukomalacia leading to cerebral palsy. It has been proposed that the pathogenesis may also involve the more subtle mechanisms of apoptosis. In newborn pigs, hyperventilation induces the expression of Bax (a proapoptotic protein) without simultaneous induction of the antiapoptotic bcl-2 protein. Furthermore, hyperventilation increased the concentration of conjugated dienes as evidence of plasma membrane
peroxidation and hyperventilation increased deoxyribonucleic acid-fragmentation.55,56
A “Natural” Experiment At Rigshospitalet, mild hyperventilation of preterm infants was intended during the early 1980s. The aim was to prevent IVH by extending the autoregulatory plateau.57 Furthermore, a new combined transcutaneous oxygen and CO2 electrode was used in the department. The electrode was developed by Radiometer, Copenhagen. The prototype instrument electrode showed the pCO2 on the screen without temperature correction, because it was still uncertain how the correction was to be performed. The pCO2 at 44 degrees Celsius of the skin under the electrode is higher than the value corrected to 37 degrees Celsius body temperature, and thus sometime false reassurance was the result. In 1985-1986, the treatment policy at Rigshospitalet in Copenhagen was changed from almost routine intubation and mechanical ventilation of very preterm babies to primary nasal CPAP,58 after the experience from Odense59 where the use of nasal CPAP had been developed as the primary management, even in the most premature infants (Fig 4). Fifteen years later, data from the routine registration of cerebral palsy showed a decrease in the incidence of cerebral palsy in children born at 31 weeks of gestation or less from 123 to 83 per 1000 for the periods 1983-1986 and 1987-1990 for the region of Eastern Denmark.60 This decrease was exclusively due to a decrease in the number of children with cerebral palsy who had been cared for at Rigshospitalet in the neonatal period. The decrease was from 87 to 47 (Fig 5). Sadly, in the history of neonatal neurology, the decision of changing treatment policy at Rigshospitalet did not come from me or from the rising evidence of the risk of hyperventilation-induced brain injury, but from a failed attempt of active treatment of a few very immature
Figure 4 The number of in-born children with gestational age below 30 weeks born in Rigshospitalet in Copenhagen and admitted for neonatal care in the period 1983-1989. During 1986, a change of policy regarding the early management of preterm infants was implemented. As a result, the fraction of infants who were mechanically ventilated decreased from three-quarters to one-quarter. Mortality gradually declined over the period.
To autoregulate or not to autoregulate
Figure 5 The number of preterm children (GA ⬍37 weeks) with cerebral palsy in the Eastern Region of Denmark, according to year and hospital of birth. Hospitals differed much in size. Hospital A is Rigshospitalet in Copenhagen. This hospital received antenatal referrals for threatened preterm birth, complications of pregnancy, and fetal malformations from most other hospitals in the region. Total number of preterm births in the two 4-year periods was 5893 and 6580, respectively. For comparison, the rate of cerebral palsy in term infants stayed the same over the 2 periods, at 1.5 per 1000 live births.
infants and the resultant protest from a strong group of nurses. The Department housed a culture of family involvement and of minimizing suffering, which was the motivation of the “minimally invasive” treatment strategy. It was our good luck that the hypercapnia and the apneic attacks that are part of letting very premature infants breathe spontaneously did not carry an epidemic of major IVH in its wake.
213 sure changes spontaneously. A statistically insignificant regression coefficient was taken as absence of evidence for loss of autoregulation. More recent research uses near-infrared spectroscopy. This allows continuous monitoring of cerebral oxygenation, and changes in cerebral oxygenation are taken as a measure of changes in CBF.63-65 One result of this development has been confirmation of the relation between absence of autoregulation and brain injury or death. The other important result has been that statistically significant correlation is frequent in preterm infants during intensive care. However, NIRS allows collection of much more data in each infant, and therefore statistically significant correlation between flow and pressure can be achieved even when the functional relation is relatively weak. In reality, the flat part of the autoregulatory plateau may never be truly horizontal; what matters is how much it is tilted (Fig 6). In fact, the confidence interval of the pressure-flow relation of our early studies did not exclude a considerable tilt, and therefore my own conclusion that autoregulation was present (⫽perfect)66 was simplistic. Furthermore, the issue has become more complex by the link between cardiac output and cerebral hemorrhage,67 and the likelihood that the adrenergic mechanisms involved during circulatory compromise also act on the cerebral circulation to reduce CBF.68,69 A correlation has been demonstrated between cardiac output as measured by superior vena cave flow and cerebral oxygenation as measured by near-infrared spectroscopy.70
The CBF-arterial Blood Pressure Relation: To Autoregulate or Not Neither my first results point to a direct association between arterial blood pressure and CBF35,43 nor did those of Ole Pryds. Ole followed me as Friis-Hansen’s research fellow, and in a large study on ventilated preterm infants he was able to discriminate between those who did not develop IVH (who did autoregulate) and those who did (who did not autoregulate).61 Furthermore, Ole studied asphyxiated term infants and found the same pattern; those who did not develop brain injury did autoregulate, and those who developed did not autoregulate.62 In conclusion, the normal human brain can autoregulate, even if premature, and if the infant is ill.
A More Useful Concept: Autoregulation as a Quantity Rather Than a Quality In these studies, the presence of autoregulation was tested by regression of changes in CBF as a function of changes in blood pressure. This method was made possible by 2 or more measurements in each infant and by the fact that blood pres-
Figure 6 Drawing of the concept of autoregulation. The heavy line has a relatively flat middle part. A percentage change in blood pressure results in a much smaller percentage change in cerebral blood flow. In practice, this means that change of blood pressure within the range of this slope will have not much effect on CBF, and yet the slope is positive, and accurate data will reveal a statistically significant relationship. The relation is stronger below the lower “knee.” The thin curve has a steeper slope, yet still a well-defined knee. Changes in blood pressure in the middle part of the curve have larger but still limited effect on flow. Is autoregulation present? Autoregulation is a question of degree and should be quantified.
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A Final Point of Relevance for Research Ethics and Clinical Practice What matters is how much CBF can be increased by raising blood pressure in an ill preterm infant. Some data on this exists71-74 and suggests that this increase is moderate. In this context, the paucity of experimental manipulation of blood pressure with CBF or cerebral oxygenation as the endpoint is a shame. Autoregulation has been tested by infusion of noradrenaline in adults with bacterial meningitis.75 In neonatal research, however, the idea from the 1970s of IVH caused by hypertensive peaks has shadowed this possibility. At the same time, multiple studies have manipulated pCO2, and now in hindsight have caused more perturbations to the cerebral circulation. Similarly, the idea of hypertension causing cerebral hemorrhage still influences clinical practice, and many clinicians probably consider blood pressure more important than pCO2 as a determinant for CBF. This is also a shame.
Acknowledgment Hans Lou, in particular, is thanked for his eager openness whenever I was critical about his earlier work.76 That has held true over the following years of collaboration. Hans has always worked for a new perspective and better insight.
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