Deep hypothermic circulatory arrest during cardiac surgery: Effects on cerebral blood flow and cerebral oxygenation in children

Deep hypothermic circulatory arrest during cardiac surgery: Effects on cerebral blood flow and cerebral oxygenation in children Colin K. Phoon, MPhil,

MD Baltimore,

AId.

Surgery for congenital heart disease has evolved from simple ligation of the patent ductus arteriosus to repair of complex constellations of lesions in neonates. One technique that has facilitated repair in the pediatric patient is deep hypothermic circulatory arrest. Deep hypothermia is thought to protect the brain from ischemic insult by reducing the cerebral metabolic rate and maintaining pH and intracellular stores of high-energy phosphates. In addition, total circulatory arrest allows both a relatively bloodless operative field and decannulation of the heart and vessels, thereby improving surgical exposure. These methods allow surgical repair of most complex lesions within the “standard” time limit of 60 minutes.l It is thought that currently employed levels of hypothermia, rate of cooling, anesthetic management, and use of muscle relaxants optimally prepare the patient for hypothermic circulatory arrest.l Most children do very well once they are beyond the immediate postoperative period, which is evidence of the excellent cerebral protection afforded by deep hypothermic circulatory arrest. Nevertheless, investigators have raised concerns about potential neurologic and developmental sequelae including seizures, motor weakness, hemiparesis, tremor, and choreoathetoid syndrome.2 Fundamental to defining the limits of deep hypothermic circulatory arrest is an understanding of its influence on cerebral blood flow and cerebral oxygenation. Data on these factors in children have appeared only sporadically, but there is promising technology that allows noninvasive, continuous monitoring of cerebral oxygenation and blood volume From the Department of Pediatrics, The Johns Hopkins Hospital. Received for publication Oct. 19, 1992; accepted Dec. 1, 1992. Reprint requests: Division of Pediatric Cardiology, University of California, San Francisco, Medical Center, San Francisco, CA 94143. AM HEART J 1993;125:1739. Copyright $) 1993 by Mosby-Year Book, Inc. 0002.8703/93/$1.00 + .lO 4/l/45618

even during deep hypothermic circulatory arrest. In recent studies3-5 we have determined that during circulatory arrest, the infant brain experiences low but continuous metabolism as reflected by a curvilinear decrease in oxyhemoglobin saturation, but that anesthetic management before arrest, including deep hypothermia, allows hyperoxygenation of hemoglobin, These patterns seen during cardiopulmonary bypass and arrest, and after arrest, may yield new insights into the mechanisms of cerebral protection and cerebrovascular hemodynamics in the young child undergoing surgery. This review will attempt to (1) summarize current knowledge of the changes seen with deep hypothermic circulatory arrest in cerebral blood flow and cerebral oxygenation, (2) compare these patterns with patterns seen in ischemic/anoxic cerebral damage, and (3) indicate important areas for future research. Emphasis will be placed on the arrest state itself and the postarrest period. ANESTHETIC

AND SURGICAL

METHODS

At the Children’s Hospital of Philadelphia and other centers around the country, currently employed techniques of deep hypothermic circulatory arrest start with surface cooling of the patient to approximately 30” C via cool ambient room temperatures and ice bags placed around the head. Core cooling to 15” C is accomplished with cardiopulmonary bypass. Hemodilution and so-called “alphastat” (body temperature uncorrected) pH regulation are thought to play roles in optimizing hemodynamits. Muscle relaxants such as pancuronium further reduce whole-body oxygen consumption. Some centers, by means of electroencephalography, also monitor suppression of brain activity during anesthesia and hyp0thermia.l MEASUREMENT

OF CEREBRAL

BLOOD

FLOW

Techniques most often employed in laboratory and clinical settings are shown in Table I. Only clinical 1739

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Table

I. Measurement

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of cerebral

blood flow

Method

June 1993 Heart Journal

--.Measurement

(time

frame!

Setting

Kefrrenws -_I-

Radioactive

microspheres

Electromagnetic Aowmeters Inert gas uptake, or quantitative tracer Near-infrared reflectance spectroscopy

Flow to end organs. by microsphere entrapment (window) Flow in any single vessel, e.g., sagittal sinus (continuous) Flow, according to Fick principle (window) Trends in total hemoglobin volume in microvascular beds (continuous)

methods will be discussed here. The most commonly used clinical means of determining cerebral blood flow is based on Kety’s original estimates of flow, monitoring uptake of an inert gas and extrapolating from the Fick principle by: cerebral blood flow = (flow)/(arteriovenous difference of gas concentration).6-g For instance, a known amount of xenon 133 is injected into the brain, and detectors are then used to monitor the radioactive decay. This method can only be used to make “spot” measurements because of the need for arteriovenous cannulation and blood collection. Near-infrared reflectance spectroscopy is a recently developed optical technique that allows assessment of the volume of hemoglobin in the microvascular bed.iO-l3 The technique relies on the relative transparency of bone and overlying skin to infrared wavelengths12s 14-16and on relative absorption peaks of deoxyhemoglobin at 760 nm, as well as an isobestic point for oxy- and deoxyhemoglobin at 800 nm. A probe containing light-emitting diodes and a sensing diode is placed over the tissue to be interrogated. Because the instrument is sensitive to all hemoglobin and because the arterial and venous vasculature accounts for only a small percentage of the total blood volumei I8 near-infrared reflectance spectroscopy examines primarily the microcirculation. By monitoring the absorption of the reflected light at 800 nm, we can detect trends in the total (oxyand deoxy-) hemoglobin volume noninvasively and continuously; thus with a constant hematocrit value, changes in absorption follow changes in vascular volume. By observing blood volume we can infer data about cerebral blood flow or cerebral perfusion. Indeed blood volume has been shown to correlate highly (1. = 0.96,p < 0.001) with cerebral blood flow.ig The advantages of near-infrared reflectance spectroscopy are it is noninvasive, nonradioactive, and atraumatic. In addition, it has a fast response time2’ and demonstrates good reproducibility.3-” ASSESSMENTOFCEREBRALOXYGENATION

A summary of many of the techniques used to assess the adequacy of cerebral oxygenation is provided

..- .-.

Laboratory

7,9,63,64

Laboratory Clinical Clinical

9,62

67.8 lo-16,20

in Table II. One of the earliest and still most widely utilized indexes of oxygenation is the oxygen extraction ratio, or arteriovenous oxygen difference.g It is clear that at any given cerebral blood flow measurement, changes in the cerebral metabolic rate will directly affect the amount of oxygen extracted from the arteriolar circulation and will reflect the adequacy of cerebral perfusion. Investigators have used sagittal sinus oxygen content or jugular venous oxygen content subtracted from systemic or arterial oxygen content: the cross-brain extraction. Continuous monitoring is possible with gas tension probes such as those measuring Pas. Microelectrodes must be inserted into brain parenchyma, however. Whereas the cross-brain extraction reflects global oxygenation, POZ probes obtain only specific regional data. pH probes are mechanically similar to gas tension probes in that they too must be inserted into cerebral parenchyma. Inadequacy of cerebral perfusion presumably leads to a build-up of metabolic waste including lactic acid, which produces a more acidic environment. Therefore the lower pH implies inadequate cerebral perfusion.21 Similar to heart and skeletal muscle, the brain when injured will spill creatine kinase into the circulation. Recently Ekroth et a1.22 and Rossi et a1.23*s4 have developed a two-site labeled monoclonal antibody assay specific for the isoenzymes CK-BB (specific for brain), CK-MM (skeletal muscle), and CK-MB (heart). The technique permits far less cross reactivity among the isoenzymes than previous assays. Their studies have demonstrated that the CK-BB enzyme is a specific marker for brain injury. Measurement of intracellular phosphate stores may also provide evidence of the adequacy or inadequacy of cerebral oxygenation. Intracellular phosphates may be assessed by means of biochemical assay or more recently nuclear magnetic resonance imaging. 25,26 Near-infrared reflectance spectroscopy is also capable of monitoring microvascular cerebral hemoglobin oxygenation and possibly the intracellular cytochrome aas redox state. The technique thus allows direct monitoring of cerebral oxygenation. The dual-

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Table

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II. Measurement of cerebral oxygenation Measurements

Method Oxygen extraction Gas tension probes pH probes

ratio

CK-BB Near-infrared spectroscopy Other

CK, creatine

reflectance

kinase;

MRI,

magnetic

Arteriovenous oxygen difference (continuous) Partial pressure of oxygen, etc., in tissues (window) Tissue pH, which presumably changes with build-up of metabolic waste (window) CK isoenzyme specific for brain, spilled during tissue injury (window) Trends in microvascular oxyhemoglobin saturation and/or cytochrome aaa oxidative state (continuous) Intracellular phosphate stores, via biochemical assay or MRI (window) resonance

BLOOD

References

Clinical Laboratory Laboratory

63 21 21

Clinical

22,23,24

Clinical

8,10-16,20,27-29

Clinical/laboratory

26,30,57

imaging.

wavelength spectrometer designed by Chance et al.lOTl1 measures absorption peaks at 760 nm (peak for deoxyhemoglobin) and 800 nm (isobestic point for oxy- and deoxyhemoglobin); the difference between the two wavelengths reflects the hemoglobin oxygenation state corrected for changes in total (oxy- and deoxyhemoglobin) volume. The same principles apply to monitoring of the cytochrome aa redox state, in which the relative absorption peak lies at 830 nm.27 Because this cytochrome is the final mitochondrial oxygen receptor, changes in its redox state ought to reflect the adequacy of oxygen delivery.12a i3, 28 However, its signal is much weaker than that of hemoglobin, and algorithms are required to correct for overlapping signals.15 Its usefulness continues to be controversia1,2gT3o although recent results appear promising.31 Oxygenation data reflect the adequacy of cerebral blood flow, so that it is more meaningful to be able to look at both oxygenation and concurrent cerebral blood flow. Of course the two are interrelated inasmuch as the cerebral metabolic rate is the product of cerebral blood flow and the arteriovenous oxygen difference. Thus the most informative studies must assess two of the three variables (cerebral blood flow, arteriovenous oxygen difference, and cerebral metabolic rate) before statements about the adequacy of cerebral oxygenation can be made. CEREBRAL

Setting

(time frame)

FLOW STUDIES

Nearly 20 years ago, Rudy et a1.32 measured the distribution of the cardiac output during cardiopulmonary bypass, during deep hypothermic circulatory arrest, and after circulatory arrest. Adolescent rhesus monkeys were studied with the radioactive microsphere technique; each underwent 60 minutes of total circulatory arrest after core cooling to 15” C. The investigators found that both absolute and relative cerebral flow decreased significantly during core cooling and arrest and remained depressed at 5 min-

utes after arrest and up to 60 minutes after weaning off cardiopulmonary bypass (cerebral blood flow was approximately half the baseline value). They did not observe any reactive hyperemia, as might be expected after anoxic cerebral damage. More recently Greeley et a1.33,34 have utilized xenon clearance to study cerebral blood flow in children undergoing cardiac surgery. They compared patients undergoing deep hypothermia with and without arrest. Cerebral blood flow as expected decreased during cardiopulmonary bypass and core cooling in both groups compared with baseline values. In the group without arrest, the cerebral blood flow increased beyond the prebypass baseline value after weaning off bypass. Yet they found that cerebral blood flow remained significantly depressed in the group with arrest, in the immediate postarrest period, and after weaning off bypass. Their more recent studies34 demonstrated a reduced cerebral metabolic rate and decreased oxygen extraction, suggesting defects in oxygen utilization or delivery after deep hypothermic circulatory arrest. The investigators concluded that cerebral reperfusion after arrest is impaired and speculated that in a brain in which metabolism is depressed after arrest, the body may be preserving a “metabolic autoregulation” (coupling of flow and metabolism).33 They declined to comment on why the metabolic rate is depressed after arrest, although ischemic damage may be one explanation, On the other hand, the investigators did postulate that “abnormal reperfusion after [total circulatory arrest]” may be one mechanism for cerebral dysfunction.33 Interestingly they found no correlation between the duration of arrest and changes in cerebral blood flow, although they admitted that this lack of statistical significance may have been due to beta error.33 It is notable that although the two groups did not demonstrate statistical significance in age or anesthetic management, their age ranges and the lesions operated on were generally different. The impact of these

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differences on their results is unknown. Despite these methodologic difficulties, which are difficult to avoid. their study remains an important one for comparing groups with and without who undergo similar anesthetic and surgical management at one institution. In our studies we have not measured cerebral blood flow, per se; rather we have utilized near-infrared reflectance spectroscopy to assess changes in hemoglobin volume in neonates and children undergoing deep hypothermic circulatory arrest.s-” The results are qualitatively similar to those obtained with cerebral blood flow in the previously mentioned studies. The blood volume decreased with the institution of cardiopulmonary bypass and cooling. We then found that in these children, blood volume decreased almost linearly over the first 20 minutes, with a plateau occurring by approximately 30 minutes; thus despite cessation of blood flow to the brain, microvascular hemoglobin volume fell over a period of minutes before stabilizing. With reinstitution of bypass, the blood volume rapidly returned to prearrest on-bypass levels, with no evidence of levels above baseline. The blood volume continued to rise slowly toward baseline values as the patients were warmed and after they came off bypass. There was no evidence of postarrest reactive hyperemia. Thus results of these few studies corroborate one another. Predictable patterns of cerebral blood flow (or changes in microvascular volume) appear to be: (1) a decrease in cerebral blood flow/blood volume with core cooling, likely the result of the increase in cerebrovascular resistance,6, 35,36 inasmuch as decreases in blood volume are also likely due to hemodilution and systemic venous decompression with right atria1 cannulation, (2) a reduction in blood volume over a period of minutes with deep hypothermic circulatory arrest, and (3) cerebral blood flow or blood volume below that seen before bypass/cooling once off circulatory arrest for at least 60 minutes after arrest. None of these studies was able to demonstrate a postarrest hyperemia. No studies have followed t,he trends in cerebral blood flow or blood volume beyond the immediate operative period, however, and it is not known when cerebral perfusion returns to the baseline level. If deep hypothermic circulatory arrest leads to ischemic damage, then the patterns of flow after deep hypothermic circulatory arrest may mimic those seen in normothermic ischemic damage. In studies of newborn dogs,37 neonatal lambs3s young piglets,25, 3g and adult dogs,40-42 rabbits,43 and rats,44 investigators generally have been able to demonstrate early hyperemia (at approximately 5 minutes after ischemia) followed by a period of hypoperfusion. Only

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McPhee et al.“’ found that the cerebral blood flow after asphyxic insult returned to baseline from the hyperemia after approximately 20 minutes and could not show a hypoperfused state. The hypoperfused state has been followed for as long as 30 minutes after ischemia in adult dogs”’ and 90 minutes in piglets.2” It is noteworthy that the degree of hypoperfusion correlated with the duration of ischemia in one study.4” Near-infrared reflectance spectroscopy has also documented a “transient.” hyperemia after brief anoxia in cats.lfi These studies show that the hyperemic peak likely occurs within 5 minutes after normothermic asphyxia, and it is unclear whether Rudy et al.“’ and Greeley et al.““, s4 assessed cerebral blood flow within 5 minutes after cessation of deep hypothermic circulatory arrest. Neither study may have assessed cerebral blood flow within a short enough period of time after arrest, although continuous recordings in our studies (manuscript in preparation) indicate that there is no reactive hyperemia after deep hypothermic circulatory arrest. The studies investigating deep hypothermic circulatory arrest, however, do demonstrate hypoperfusion beyond the immediate postarrest period compared with baseline prearrest prebypass levels, a result similar to that in studies of ischemia. As early as 1961 Edmunds and Folkman4” observed the cerebral metabolic rate after deep hypothermic circulatory arrest and found an increase of 41 St in the postarrest period. However, the study was completed several years before anesthetic and surgical management allowed for a good degree of clinical success; in other words their techniques, especially of cardiopulmonary bypass, were likely to be quite different from those currently used and may have affected the outcomes. Greeley et a1.xY4 more recently determined that the cerebral metabolic rate is depressed after circulatory arrest, out of proportion to the reduced cerebral blood flow, such that oxygen extraction is also reduced. Several recent studies”“, 36,ss,41 have shown a decrease in cerebral metabolic rates with ischemic damage in a variety of species including neonatal lambs3s piglets,“” and children.36 Michenfelder and Milde4’ have proposed that since the cerebral blood flow/cerebral metabolic rate ratios remained stable throughout the study period and since sagittal sinus venous Pas levels remained adequate, cerebral blood flow is determined by the cerebral metabolic rate; in other words there exists metabolic autoregulation in Greeley’s phraseology. It is remarkable that the cerebral metabolic rate correlated with the duration of ischemia (r = -0.74, p < O.OOl), suggesting that

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ischemia leads to cell injury and/or death with a consequent decrease in energy utilization.41 However, the concern that the hypoperfusion state might itself lead to neuronal injury42l 46 was not substantiated,41 since cerebral blood flow appeared to be tied directly to the cerebral metabolic rate. LaManna et a1.40failed to demonstrate a correlation between the duration or magnitude of this hypoperfusion and neurologic deficits or mortality. On the other hand, Snyder et a1.47 discovered that the venous oxygen content was decreased after ischemic insult, so that the cerebral blood flow/cerebral metabolic rate ratio was not maintained in dogs subjected to 15 minutes of normothermic circulatory arrest; the reasons for the discrepancy between these findings and results of other more recent studies is unclear. Frewen et a1.36 found no significant decrease in cerebral blood flow despite decreases in the cerebral metabolic rate in terminally brain-damaged children compared with those who recovered; however, the numbers were exceedingly small in the study (three in each group). Although late hypoperfusion with a depressed cerebral metabolic rate is hypothesized to result from metabolic coupling, it is unclear whether decreases in the cerebral metabolic rate result in decreases in cerebral blood blood flow or vice versa. We can speculate therefore that the hypoperfusion seen after circulatory arrest may be the body’s response to a depressed cerebral metabolic rate, perhaps caused by ischemic damage during the arrest period. The findings of Greeley et a1.33,34 that hypothermia alone without arrest allows cerebral blood flow to return to normal after weaning off bypass suggest that the depressed cerebral blood flow is not due to hypothermic conditions but rather to the period of circulatory arrest itself. Even if we speculate that the cerebral metabolic rate is depressed because of the arrest state, however, the extent or significance of this damage, given the conflicting nature of longterm studies, remains to be determined. The significance of the lack of an early hyperemic peak is also unclear. It is possible that the early postarrest hyperemia results from the vasodilatation caused by the accumulation of hydrogen ions during asphyxia38, 42,48 or possibly from a vasodilatory effect of oxygen free radicals. 4g-51 Because hypothermia does blunt cerebral blood flow,269 33,35 it is possible that the early hyperemic peak is abolished by the still-cool state in the early postarrest period. Interestingly, in studies of low-flow.bypass, cerebral blood flow did rise beyond prearrest baseline levels in the “early” postarrest period,33y 52 so that hypothermia may not be solely responsible for the blunting of the hyperemic peak after arrest. In addition, with alpha-

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stat anesthetic management and minimal increases in metabolites, the pH may be better maintained,31 contributing to less cerebral vasodilatation. It is also possible that there is no significant accumulation of vasodilatory metabolites to produce a hyperemic peak. If oxygen free radicals do play a role in mediating cerebral damage and vasodilation,4g-51 then the blunting of the hyperemic peak may in fact be protective. Furthermore, other studiesS3, 54 have shown that hyperemia may play a role in producing cerebral edema, so that the blunting of the hyperemic peak after deep hypot,hermic circulatory arrest may also exert protective effects by minimizing such edema. Our basic premises are that deep hypothermic circulatory arrest works well, with a low incidence of neurologic deficits, and that the brain after 30 minutes of circulatory arrest must suffer complete anoxia. 5, 55 However, it has been shown that the brain can endure long periods of anoxia given the proper postasphyxia circulatory environment.46, 56 Thus the blunting of the hyperemic peak may play a very important role in protective recirculatory hemodynamits. CEREBRAL

OXYGENATION

STUDIES

Much of the earlier work focused on the effects of hypothermia, and on improved surgical and anesthetic management,l and only scattered reports on the effects of deep hypothermic circulatory arrest on cerebral oxygenation appeared. In 1968 Kramer et a1.57demonstrated maintenance of adenosine triphosphate stores in the brain with deep hypothermic circulatory arrest. More than 10 years later Norwood et a1.26 showed that cerebral pH, high-energy phosphates, and adenosine triphosphate were well maintained with deep hypothermic but not normothermic ischemia. Only recently, however, have investigators begun to study the effects of the arrest period on cerebral oxygenation patterns. Since 1986 Ekroth et a1.22and Rossi et a1.23j24 have published results of several studies that measured isoenzyme CK-BB levels, a marker for brain injury, in children undergoing cardiac surgery. All studies found significant increases in the amount of CK-BB after arrest. Two earlier studies compared an arrest group with a closed-chest group; the effects of hypothermic bypass could not be separated from those of arrest, since there was no appropriate nonarrested, on-bypass control group.z2, 23 In both of these studies the amount of CK-BB isoenzyme correlated significantly with the length of the ischemic period, although enzyme levels did not rise significantly until arrest periods exceeded 60 minutes. Most recently a report was published comparing 27 children divided

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into groups with hypothermic arrest and low-flow hypothermia. Surprisingly there were no differences in CK-BB levels or patterns or pH values throughout the study period. 24 The average arrest time was 46 minutes; the average low-flow bypass time was 35 minutes. The results are surprising and intriguing and suggest that deep hypothermic circulatory arrest does not incur an additional oxygen debt or cerebral injury beyond that of cardiopulmonary bypass. Although the most recent study was the only one to have a true control population, that work could be criticized on the grounds of population heterogeneity with significant differences in weight and lesions between the two groups. Unfortunately, as in other studies,“, 33 these differences are difficult to avoid, inasmuch as the nature of the lesions typically determines the age of the repair. In addition, CK-BB in the neonatal period comprises a higher proportion of all CK isoenzymes and may have confounded the results.24 Multiple regression analysis, however, indicated that age and size could not explain the changes in the CK-BB concentration. The results are intriguing, but the clinical significance of increased CK-BB levels remains to be seen. Furthermore, the possibility that deep hypothermic circulatory arrest produces no more damage than hypothermic bypass without arrest needs further investigation. In a wide-ranging study assessing intracerebral pH and Pas throughout surgery, Watanabe et al.sl compared dogs undergoing nonpulsatile low-flow hypothermia, pulsatile low-flow bypass, and circulatory arrest. POT decreased significantly more with arrest, than during low-flow hypothermic bypass; however, with reinstitution of circulation the POZ returned to baseline levels. The pH decreased in all three groups with the institution of hypothermic bypass. Interestingly the pH in the arrest group remained low even after reinstitution of circulation to approximately 40 minutes after arrest, whereas the low-flow groups showed trends toward baseline, the pulsatile group more so. Interpretations of the persistently depressed pH include (1) an ongoing oxygen debt leading to lactic acid build-up, and (2) increased intracerebral Pcos as a result of an increased cerebral metabolic rate, contributing to a lower pH. The group concluded that pulsatile low-flow bypass afforded greater protection than nonpulsatile bypass, and both of these were greater than circulatory arrest. However, the standard deviations were rather large and the number of subjects (N = 8) was rather low. Near-infrared reflectance spectroscopy has recently been able to shed more insight into the kinetics of hemoglobin deoxygenation during and after hypothermic arrest. Initial studies by Kurth et al.3s*

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showed in neonates that cerebral hemoglobin oxygenation increased beyond the baseline level during cooling/bypass, then decreased curvilinearly (plateauing at about 35 minutes) with arrest. The levels of oxyhemoglobin rapidly rose with reinstitution of bypass and returned to but did not exceed prearrest levels. This pattern of hyperoxygenation with cooling/bypass, curvilinear deoxygenation, and reoxygenation with bypass/rewarming was notably similar to that seen in Watanabe’s study of brain tissue P02.~l It is thought that the decreased cerebral metabolic rate with perhaps increased tissue oxygen “stores” (perhaps in the form of more saturated microvascular hemoglobin) contributes to the hyperoxygenation with cooling. The decompression of the microvascular space and the continued albeit low cerebral metabolic rate during hypothermic arrest contribute to the curvilinear fall in oxyhemoglobin. Extending the observation period to approximately 30 minutes after weaning off bypass, we have found similar kinetics in older children aged 2.5 to 39 months.5 Although cerebral hemoglobin oxygenation levels returned to baseline after arrest, they did not exhibit the hyperoxygenation of the coolinglprearrest period, a pattern similar to that in neonates. Thus levels of cerebral oxygenation were lower in the postarrest period than in the immediate prearrest, period. On the other hand, the blood volume had also exhibited a blunted response in the early postarrest period (unpublished observations). Therefore it is possible that either decreased oxygen delivery (i.e., decreased cerebral blood flow or decreased blood volume, leading to increased oxygen extraction), or increased oxygen utilization or both contributed to the lower cerebral hemoglobin oxygenation. Indeed, because rewarming begins immediately after arrest ceases and bypass is reinstituted, there is no period truly comparable to t,he prearrest cooled stage; thus increased oxygen utilization in the immediate postarrest period is a likely factor in the lack of a hyperoxic peak. Of note, Wilson et al.“” also observed no hyperoxic peak with deep hypothermic circulatory arrest. Although we did monitor blood volume simultaneously with cerebral hemoglobin oxygenation, we could not calculate the ratio of blood volume to cerebral hemoglobin oxygenation, which would be analogous to (cerebral blood flow)/(arteriovenous oxygen difference), because the dual-wavelength spectrophotometer can follow only trends in blood volume and hemoglobin oxygenation. Thus it is not clear from our data which direction the cerebral metabolic rate took after deep hypothermic circulatory arrest. Greeley et al.“4 and Bracey et al.5g found t.hat ce-

Volume 125, Number 6 American Heart Journal

rebral hemoglobin oxygenation actually decreased on cooling during bypass, decreased further with arrest, but returned to baseline levels after weaning from bypass. This was also true for bypass patients without arrest. However, studies of cytochrome aas31,34s5g showed persistently depressed levels of oxidized cytochrome despite a return of cerebral hemoglobin oxygenation to baseline levels. Their conclusion was that oxygen availability (reflected in cerebral hemoglobin oxygenation) was not deficient but the persistence of intracellular oxygen depletion signaled an oxygen debt incurred during arrest. Possibly neuronal cell damage affected uptake of oxygen. Interestingly the extent to which cytochrome aag recovered after weaning off bypass was not influenced by the duration of arrest.5g However, in a follow-up study comparing low flow with arrest, greater intracellular hypoxia was seen in the group with arrest.31 The meaning of the persistently reduced cytochrome aas in Bracey’s studies5g is unclear. In the ischemic normothermic model, Rosenthal et a1.13 found that “complete” ischemia produced reduced cytochrome aas, which with reperfusion returned to the oxidized state within seconds (baseline). “Incomplete” ischemia produced less reduced cytochrome, with a partial return to baseline even during the ischemic period. Piantadosi et a1.16 showed that after brief cerebral anoxia, cytochrome aa reoxidized faster than in skeletal muscle, and at low oxygen tensions aa was better maintained. In addition, with hemorrhagic hypotension the cytochrome aa oxidative state showed more stability than that in muscle and, with reinfusion of volume, a faster recovery. The limitations of monitoring cytochrome aas levels have already been discussed. In addition, the spectrometer used by Bracey’s group5’ does not have the advantage of correcting for blood volume (Greeley WJ: personal communication), and therefore the decrease in cerebral hemoglobin oxygenation during cooling is most likely explained by the rapid decrease in blood volume that accompanies institution of bypass and onset of hypothermia. It is clear that institution of cardiopulmonary bypass and cooling must bring with it “hyperoxygenated” microvascular hemoglobin; both arterial and venous saturations rise steeply, indicating greater oxygen availability and reduced oxygen consumption.3-51 21 In near-infrared reflectance spectroscopic studies of adults experiencing brief periods of normothermic circulatory arrest, Smith et a1.20 found that reperfusion of the brain after more than 37 seconds of arrest resulted in a hyperoxic peak; however, none of the fibrillatory events lasting less than 37 seconds produced a postarrest hyperoxia. The hyperoxic peak

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was attributed to hyperemia, reduced tissue utilization of oxygen, or both. Hyperemia, although corrected for in dual-wavelength spectroscopy, may contribute to hyperoxia because the oxygen extraction ratio would be lower. In other models of ischemic brain, the timing of the hyperoxic peak does seem to be related to the duration of the ischemia. * It is well known that ischemic injury to the decreased metabolic requirebrain produces ments.25, 36s38,41 Rosenberg38 found a decreased oxygen extraction ratio in the ischemic group of neonatal lambs; the results suggested available oxygen that is simply not utilized. In a study by Laptook et a1.25 both the cerebral oxygen uptake and cerebral metabolic rates were reduced after ischemia in piglets followed for up to 90 minutes after insult. Notably, however, high-energy phosphate levels including nucleoside triphosphate levels all decreased with circulatory arrest, and pH returned to baseline 2 hours after reperfusion. Michenfelder and Milde41 found slightly different results in that oxygen extraction remained stable, and cerebral blood flow/cerebral metabolic rate ratios remained essentially constant regardless of the duration of the ischemia. These were adult dogs, and they may have had control mechanisms different from those in the pediatric population. Frewen et a1.,36 in an anecdotal study of three surviving and three nonsurviving children with head injuries, demonstrated a significantly lower cerebral metabolic rate and oxygen extraction ratio in the nonsurvivors; they suggested that these changes in metabolism occur with neuronal damage. Nevertheless, all of these studies suggest that oxygen availability is not the problem and the body does not aggravate cerebral injury by hypoperfusing its brain after insult. One interpretation of the data in children undergoing deep hypothermic circulatory arrest is that their brains do not suffer from a significant ischemic insult, since oxygen utilization is not reduced (which should have resulted in greater cerebral hemoglobin oxygenation, that is, hyperoxic levels after arrest). However, studies demonstrate that the brain must become anoxic after 30 minutes (at the most) of deep hypothermic circulatory arrest.21y 55Rewarming after deep hypothermic circulatory arrest requires several minutes, and the relative hypothermia should produce a decreased utilization of oxygen, so that we cannot attribute the lack of hyperoxia to the hypothermic conditions, per se. However, the lack of a

*References

12, 13, 20, 28, 60, and 61.

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Heart Journal

postarrest hyperemic peak may lead to a higher oxygen extraction ratio and may result in a blunting of the hyperoxic peak. It is possible that the lack of hyperoxia after arrest prevents damage potentially mediated by oxygen radicals (Kurth CD: personal communications). DO hypothermia and/or arrest disturb these mechanisms, which allow adequate perfusion in the face of reduced utilization? Does reduced utilization mean irreversible brain damage? No studies have followed the events in the brain over the next several hours to days after ischemic insult. In the immediate and early postarrest periods, we see a lack of hyperoxia even with a lack of hyperemia, whereas ischemic brains exhibit both hyperoxia and hyperemia. In children undergoingdeephypothermiccirculatoryarrest,postarrest hypoperfusion coupled with increased oxygen utilization implies a loss of “metabolic autoregulation.” The clinical significance of this implication is not yet clear.

congenital cardiac lesions in children. The arrested state has concerned the surgeon, cardiologist, and anesthesiologist alike, and yet deep hypothermic circulatory arrest has been highly successful with a low incidence of neurologic sequelae. Studies of cerebral blood flow and cerebral oxygenation demonstrate that the arrested hypothermic brain does not develop the immediate postarrest hyperemia or hyperoxia seen in normothermic ischemic brain models. However, both hypothermic and normothermic ischemic brains exhibit hypoperfusion beyond the immediate recirculation period, likely coupled with a reduced cerebral metabolic rate. That the hypothermic arrested brain likely becomes anoxic and recovery of the anoxic brain depends in large part on recirculatory hemodynamics suggests that the lack of hyperemia and hyperoxia may play more major roles than was previously believed. The mechanism of protection may be related to suppression of oxygen free radicals.

FUTURE

I thank Catherine Neill, MD, FRCP, of the Division ric Cardiology, for her critical review of the manuscript.

CONSIDERATIONS

Important considerations for future work include continued measurement of the cerebral metabolic rate in the postarrest period. These data may provide further insight into the maintenance of metabolic autoregulation with deep hypothermic circulatory arrest. It would also be important to follow the patterns of cerebral metabolic rate, cerebral blood flow, and oxygenation beyond the immediate postoperative period and into the early phases of surgical recovery. Hypothermia (and possibly deep hypothermic circulatory arrest) abolishes the autoregulation seen in the normal brain.4”, 52,Q Hossmann et a1.46,56 have demonstrated neuronal survivability after up to 60 minutes of total normothermic anoxia and speculated that circulatory factors after asphyxia hinder recovery. If this is true, then anesthetic and surgical research will need to define the optimal hemodynamits in the postarrest period, since we cannot rely on the body to maintain cerebral homeostasis necessarily. Ideally the hemodynamics would be coupled with the cerebral metabolic rate in the postarrest period. Studies on intracellular phosphates before, during, and after deep hypothermic circulatory arrest may provide insight into the mechanisms of protection or damage. Further studies on the effects of free radical scavengers on reperfusion damage would also be helpful. SUMMARY

Deep hypothermic circulatory arrest has become an essential technique to allow repair of complex

of Pediat-

REFERENCES

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33. Greeley WJ, Ungerleider RM, Smith LR, Reves JG. The effects-of deep hypothermic cardiopulmonary bypass and total circulatory arrest on cerebral blood flow in infants and children. J Thorac Cardiovasc Surg 1989;97:737-45. WJ, Bracey VA, Ungerleider RM, Greibel JA, Kern 34. Greeley FH, Boyd JL, Reves JG, Piantadosi CA. Recovery of cerebral metabolism and mitochondrial oxidative state is delayed after hypothermic circulatory arrest. Circulation 1991;84(suppl 111):400-6. 35. Busija DW, Leffler CW. Hypothermia reduces cerebral metabolic rate and cerebral blood flow in newborn piglets. Am J Physiol 1987;253:H869-73. 36. Frewen TC. Sumabat WO. Del Maestro RF. Cerebral blood flow, metabolic rate, and cross-brain oxygen consumption in brain injury. J Pediatr 1985;107:510-13. AJ, Kotagal UR, Kleinman LI. Cerebrovascular he37. McPhee modynamics during and after recovery from acute asphyxia in the newborn dog. Pediatr Res 1985;19:645-50. AA. Cerebral blood flow and 02 metabolism after 38. Rosenberg asphyxia in neonatal lambs. Pediatr Res 1986;20:778-82. 39. Goplerud JM, Wagerle LC, Delivoria-Papadopoulos M. Regional cerebral blood flow response during and after acute asphyxia in newborn piglets. J Appl Physiol 1989;66:2827-32. 40. LaManna JC, Crumrine RC, Jackson DL. No correlation between cerebral blood flow and neurologic recovery after reversible total cerebral ischemia in the dog. Exp Neurol 1988;101:234-47. 41. Michenfelder JD, Milde JH. Postischemic canine cerebral blood flow appears to be determined by cerebral metabolic needs. J Cereb Blood Flow Metab 1990;10:71-6. 42. Miller CL, Lampard DG, Alexander K, Brown WA. Local cerebral blood flow following transient cortical ischemia. I. Onset of impaired reperfusion within the first hour following global ischemia. Stroke 1980;11:534-41. 43. Fischer EG, Ames A, Lorenzo AV. Cerebral blood flow immediately following brief circulatory stasis. Stroke 1979;10:423-7. 44. Blomqvist P, Wieloch T. Ischemic brain damage in rats following cardiac arrest using a long-term recovery model. J Cereb Blood Flow Metab 1985;5:420-31. 45. Edmunds LH, Folkman JF. Cerebral metabolism during profound hypothermia and circulatory arrest. J Surg Res 1961;1:201-12. 46. Hossmann KA, Kleihues P. Reversibility of brain damage. Arch Neurol 1973;29:375-84. 47. Snyder JV, Nemoto EM, Carroll RG, Safar P. Global ischemia in dogs: intracranial pressures, brain blood flow and metabolism. Stroke 1975;6:21-7. 48. Lassen NA. The luxury perfusion syndrome and its possible relation to acute metabolic acidosis within the brain. Lancet 1966;1113-5. 49. Kontos HA, Wei EP, Dietrich WD, Navari RM, Povilshock JT, Ghatak NR, Ellis EF, Patterson JL. Mechanism of cerebral arteriolar abnormalities after acute hypertension. Am J Physiol 1981;240:H511-27. 50. McCord JM. Oxygen derived free radicals in post ischemic tissue injury. N Engl J Med 1985;312:159-63. 51. Wei EP, Dietrich WD, Povlishock JT, Navari RM, Kontos HA, Functional, morphological, and metabolic abnormalities of the cerebral microcirculation after concussive brain injury in cats. Circ Res 1980;46:37-47. 52. Steven JM, Kurth CD, Nicolson SC, Phoon C, Chance B. Continuous noninvasive assessment of brain oxygenation and blood volume during cardiopulmonary bypass in children undergoing ASD closure [Abstract]. Anesthesiology 1990;73: A456. 53. Heiss WD, Hayawaka T, Waltz AG. Patterns of changes of blood flow and relationship to infarction in experimental cerebral ischemia. Stroke 1976;7:454-9. 54. Mchedlishvili G, Kapuscinski A, Nikolaishvili L. Mechanisms of post-ischemic brain edema: contribution of circulatory factors. Stroke 1976;7:410-16. 55. Perna AM, Gardner TJ, Tabaddor K, Brawley RK, Gott VL.

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June 1993 Heart Journal

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Rrs

Directional atherectomy: Combining research and intervention

1980:2:10X%.

basic

Donald C. MacLeod, MB, ChB, MRCP,” Marcel de Jong,b Victor A. Umans, MD,a Javier Escaned, MD,b Robert-Jan van Suylen, MD,” Patrick W. Serruys, MD, PhD,” and Pim J. de Feyter, MD, PhD” Rotterdam, The Netherlands

In 1985 Simpson et al1 first described the percutaneous transluminal removal of atheromatous material from peripheral arteries by means of a novel catheter system. The technique was given the term “directional atherectomy,” denoting the selective excision of obstructive luminal atheroma to distinguish it from surgical endarterectomy. Initial experience indicated that directional atherectomy could be performed safely and effectively and might be an attractive alternative to conventional balloon angioplasty in certain circumstances.2, 3 Developments in the atherectomy catheter and the design of suitable From the “Cardiac Catheterization Laboratory, Thoraxcenter, and the Departments of bExperimental Cardiology and CPathology, Erasmus University, Rotterdam, The Netherlands. Received

for publication

October

Reprint requests: Pim J. de Feyter, Thoraxcenter, Erasmus University, The Netherlands.

21, 1992; accepted

AM J HEART 1993;125:1748. Copyright 3 1993 by Mosby-Year Book, 0002.8703/93/$1.00 + .lO 4/l/45619

1748

December

1, 1992.

MD, PhD, Catheterization Laboratory, P.O. Box 1738, 3000 DR Rotterdam,

Inc.

guiding catheters allowed the extension of the technique to the coronary arteries in 1986.4 Recently, directional coronary atherectomy has undergone comparison with coronary balloon angioplasty in a multicenter prospective, randomized trial, the CAVEAT study. After brief discussion of the technical aspects and clinical use of directional atherectomy, this article will focus on the application of atherectomy as a route to research. TECHNICAL

DETAILS

The Simpson AtheroCath (Devices for Vascular Intervention, Redwood City, Calif.) incorporates a rigid metal cylinder a short distance from the distal tip (Fig. 1). This cylinder is windowed longitudinally on one side and carries an eccentric balloon on the other. Within the cylinder is a cup-shaped cutter that can travel the length of the window; the cutter is advanced and retracted by a hollow drive cable. The most distal part of the cylinder serves as a collection chamber. Proximally, the drive cable connects with a hand-held, battery-operated motor that spins at