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Ann Thorac Surg 1995;59:880-886
© 1995 The Society of Thoracic Surgeons

Cerebral Blood Flow During Cardiopulmonary Bypass: Influence of Temperature and pH Management Strategy

Division of Cardiac Surgery and Department of Anesthesiology/Critical Care Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland

Accepted for publication December 9, 1994.

	Abstract

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Because disordered autoregulation of cerebral blood flow may underlie neurologic injury associated with cardiopulmonary bypass (CPB), we studied the effects of normothermic (37°C) and hypothermic (18°C) CPB on cerebral vascular reactivity in 6 to 8-week-old piglets. Hypothermic CPB animals were subdivided into alpha-stat and pH-stat groups (n = 6 animals each group) according to acid-base management protocol. Cerebral blood flow (CBF), cerebral oxygen consumption (CMRO₂), cerebral vascular resistance (CVR), and CBF response to hypercapnia were examined before, during, and 1 hour after CPB and used to calculate CVR per millimeter of mercury change in arterial partial pressure of CO₂: (CVR_normocapnia - CVR_hypercapnia)/(PaCO_{2 hypercapnia} - PaCO_{2 normocapnia}). Before CPB, CBF, CMRO₂, and vascular reactivity to elevated CO₂ were similar in the three groups; these parameters remained unchanged by normothermic CPB. However, during hypothermic CPB, CBF and CMRO₂ decreased in both alpha-stat and pH-stat groups; in the alpha-stat group, CBF decreased from 27 +/- 5 mL • min^-1 • 100 g^-1 (normothermic CPB) to 5 +/- 1 mL • min^-1 • 100 g^-1 (hypothermic CPB) (p < 0.05) and CMRO₂ decreased from 1.8 +/- 0.21 to 0.24 +/- 0.04 mL • min^-1 • 100 g^-1 (p < 0.05), whereas in the pH-stat group CBF decreased from 28 +/- 2 to 9 +/- 1 mL • min^-1 • 100 g^-1 (p < 0.05) and CMRO₂ decreased from 1.63 +/- 0.07 to 0.31 +/- 0.09 mL • min^-1 • 100 g^-1 (p < 0.05). Hypercapnic vascular reactivity during hypothermic CPB was abolished during alpha-stat management (0.065 +/- 0.013 [normothermic CPB] to -0.010 +/- 0.049 mm Hg • mL^-1 • min^-1 • 100 g^-1 • mm Hg CO₂^-1 [hypothermic CPB]; p = not significant), but was preserved by pH-stat management (0.057 +/- 0.009 to 0.113 +/- 0.006 mm Hg • mL^-1 • min^-1 • 100 g^-1 • mm Hg CO₂^-1) (p < 0.05). After CPB, there was full recovery of normocapnic CBF, CMRO₂, and hypercapnic reactivity in all groups. We conclude that in this model of the immature animal on CPB (1) hypothermic CPB causes a profound decrease in CBF and CMRO₂, (2) cerebrovascular reactivity to CO₂ is decreased during hypothermic CPB with alpha-stat but not pH-stat management of arterial blood gases, and (3) regardless of method of blood gas management during CPB, CBF, CMRO₂, and hypercapnic reactivity are restored to pre-CPB values after CPB.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Neurologic dysfunction continues to be a perplexing complication after cardiac operations, affecting up to 50% of patients undergoing cardiac operations with cardiopulmonary bypass (CPB) [1, 2]. The cause of this dysfunction is multifactorial and may include embolization of air or particulate debris to the cerebral circulation, global or regional hypoperfusion, deleterious effects of hypothermia, and disordered autoregulation of cerebral blood flow (CBF) [1, 3, 4]. One important feature of cerebral homeostasis is the capacity of the cerebral circulation to vasodilate in response to hypoxia, hypercapnia, and low cerebral perfusion pressure [5]. This vasodilatory capacity has been used as an index of cerebral ``well-being'' and adequacy of perfusion. In adults undergoing CPB, CBF increases in response to hypercapnia when blood gases are managed by the alpha-stat method (blood gases measured at 37°C regardless of body temperature) [6, 7]. In children, CBF also increases in response to hypercapnia during alpha-stat management, but reactivity is less in very young children when compared with older children [8]. In several mature animal models of hypothermic CPB, hypercapnic CBF reactivity (change in blood flow or vascular resistance for each millimeter of mercury change in arterial partial pressure of carbon dioxide [PaCO₂]) is maintained when temperature correction is used for blood gas monitoring (pH-stat) but is reduced when blood gases are managed by alpha-stat technique [9]. However, relatively few investigators have evaluated whether the method of blood gas management affects hypercapnic reactivity in a pediatric model of hypothermic CPB.

We measured the effect of hypercapnia on CBF and cerebral oxygen consumption (CMRO₂) before, during, and after hypothermic and normothermic CPB in infant pigs, and examined whether blood gas management techniques (alpha-stat versus pH-stat) affects CBF response to hypercapnia in the immature brain. This model parallels a common clinical scenario in pediatric cardiac surgery.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Animal Preparation
All piglets in this study received humane care in compliance with the ``Principles of Laboratory Animal Care'' formulated by the National Society for Medical Research and the ``Guide for the Care and Use of Laboratory Animals'' prepared by the Institute of Laboratory Animal Resources and published by the National Institutes of Health (NIH publication 85-23, revised 1985). Eighteen mixed-breed piglets 4 to 6 weeks old, each weighing 6 to 12 kg, were studied. After intramuscular ketamine administration (20 mg/kg), the animals were anesthetized with intravenous pentobarbital sodium (20 mg/kg). Anesthesia was maintained with intermittent doses of pentobarbital sodium (2 mg/kg intravenously), and muscle relaxation was achieved with pancuronium bromide (0.1 mg/kg intravenously) 15 minutes before each CBF measurement and as necessary to prevent shivering. Extensive experience with this anesthetic regimen in piglets in our laboratory has revealed little influence of barbiturates on hypercapnic reactivity in these doses [10, 11]; indeed, all experimental groups received similar doses. Tracheostomy was performed and ventilation was controlled to maintain normocapnia (PaCO₂, 33 to 38 mm Hg). Supplemental oxygen was administered to maintain arterial partial pressure of oxygen greater than 100 mm Hg during surgical preparation. Vascular access was obtained using 5F pediatric feeding tubes placed into the femoral artery, femoral vein, and brachiocephalic artery. The superior sagittal sinus was catheterized (Tygon microbore tubing, 0.4 mm inner diameter, 0.7 mm outer diameter; Fisher Scientific Co, Pittsburgh, PA) 1.5 cm proximal to the confluence of the sinuses. Rectal and epidural thermistors (Yellow Springs telethermometer, Yellow Springs, OH) were placed, the latter through a skull burr hole. The chest was opened through a median sternotomy, and a 5F pediatric feeding tube was placed in the left atrium for microsphere injection.

Cardiopulmonary Bypass
A bubble oxygenator (Bentley 10 Plus; American Bentley, Irvine, CA) was primed with homologous blood and Hespan (6% hetastarch in 0.9% sodium chloride solution; Du Pont Pharmaceuticals, Wilmington, DE). A 40-µm arterial line filter (AF-1040C; Bentley) was included in the bypass circuit as a bubble trap. A single 22F venous cannula drained the right atrium. Blood was returned by a nonpulsatile roller pump (Sarns, Inc, Ann Arbor, MI) to the ascending aorta, proximal to the origin of the brachiocephalic artery. The aortic cannula tip was positioned carefully to avoid preferential streaming of blood into arch vessels; this position was confirmed at autopsy.

Temperature Management
Before and after CPB, all animals were maintained at core and brain temperatures of 37°C. Surface and perfusion cooling were employed to obtain a rectal temperature of 18°C in animals undergoing hypothermic CPB. The cooling rate on CPB was approximately 0.5°C/minute and perfusion flow rate was maintained between 75 and 100 mL • kg^-1 • min^-1 during normothermia and reduced to 40 to 60 mL • kg^-1 • min^-1 during hypothermia.

Physiologic Measurements
Systemic arterial and sagittal sinus pressures, both referenced to heart level, were monitored and recorded continuously (Hewlett Packard 7745B; Hewlett Packard Co, Palo Alto, CA). Brachial artery and sagittal sinus blood gases were withdrawn into 1-mL heparinized syringes and analyzed with a Radiometer ABL30 blood gas analyzer (Radiometer, Copenhagen, Denmark). Hemoglobin and O₂ saturation were measured with an OSM2 Hemoximeter (Radiometer).

Regional CBF was measured by means of the reference sample radiolabeled microsphere technique [12]. Briefly, 16 +/- 0.5 µm (mean +/- standard error of the mean) diameter microspheres (Dupont-New England Nuclear Products, Boston, MA) were injected into the left atrium, and a reference sample was withdrawn through a femoral arterial catheter. For each CBF measurement, approximately 1.5 x 10⁶ microspheres were injected into the left atrium (pre-CPB and post-CPB measurements) or 50 cm upstream from the tip of the arterial perfusion cannula (CPB measurements) over 30 seconds for complete mixing with the arterial blood. The catheter then was flushed with saline solution (10 mL). Six isotopes (gadolinium 153, indium 114m, tin 113, ruthenium 103, niobium 95, and scandium 46) were used in each piglet and were injected in random sequence. The microsphere injection did not affect mean arterial blood pressure (MABP). The arterial reference samples were withdrawn at a rate of 4.94 mL/min beginning 30 seconds before and ending 4 minutes after microsphere injection. At completion of the experiment, each piglet was killed with pentobarbital overdose and the brain removed and fixed in buffered formalin. Each brain was dissected to determine blood flow to cerebrum. The tissue was weighed and placed in 15-mL poly Q vials for analysis in an autogamma scintillation spectrometer (Packard Minaxi Auto-Gamma 5000 series, Downers Grove, IL). The energy windows were set at 68 to 170 keV for ¹⁵³Gd, 174 to 230 keV for ^114mIn, 360 to 440 keV for ¹¹³Sn, 450 to 560 keV for ¹⁰³Ru, 690 to 820 keV for ⁹⁵Nb, and 830 to 1200 keV for ⁴⁶Sc. The overlap of activity from high-energy isotopes into low-energy windows was corrected by differential spectroscopy. Blood flow was calculated by the reference sample technique [12]; samples were taken from both sides of the brain and more than 400 counts verified in each sample. Blood flows were expressed as milliliters per minute per 100 g tissue by normalizing for tissue weight. Cerebrovascular resistance (CVR = [MABP - sagittal sinus pressure]/CBF) and CMRO₂ (CBF x [arterial - cerebral venous O₂ content]) were calculated for each CBF measurement.

Validation of Microsphere Technique
Uniformity of microsphere distribution within the arterial tree during perfusion line injection (on CPB) and left atrial injection (off CPB) was demonstrated in 6 additional piglets by simultaneous withdrawal of blood from the right axillary, left axillary, and right femoral arteries. Six microsphere injections were performed in random sequence in each animal. Microsphere counts in right versus left axillary and axillary versus femoral artery samples were compared for atrial and arterial reference line injections. Calculated blood flows from right and left brain structures were compared for the cerebral circulation. For each injection, microsphere shunt fraction across the cerebral circulation was computed from the ratio of raw counts in the arterial blood and simultaneously withdrawn sagittal sinus reference samples, after correction for differences in withdrawal rates.

Experimental Protocol
Three experimental groups of animals (n = 6) were examined. Conditions during CPB distinguished the groups: the normothermic group underwent normothermic CPB (37°C) for approximately 1 hour. The other two groups underwent hypothermic CPB at brain and core temperatures of 18°C for 3 hours. The alpha-stat subgroup was managed with arterial blood gas samples measured at 37°C (uncorrected for temperature); the pH-stat subgroup had samples measured at brain temperature (corrected). Each animal was studied before CPB, during CPB, and 1 hour after CPB. For each time period, physiologic variables and CBF were measured before and during a CO₂ challenge (PaCO₂ increased by 20 mm Hg). Thus, six CBF determinations were obtained in each animal.

Off CPB, changes in PaCO₂ were made by adjusting the ventilator rate. On CPB, changes in PaCO₂ were made by adjusting the ratio of CO₂ to O₂ in the gas supplied to the oxygenator. Throughout all experiments, cerebral perfusion pressure (calculated as MABP - sagittal sinus pressure) was maintained greater than 50 mm Hg by adjusting CPB flow rate (50 to 75 mL • kg^-1 • min^-1) or by administration of fluids off CPB. Arterial oxygen content and arterial hemoglobin concentration were kept constant with 100% O₂ and transfusion of homologous red blood cells. Marked hemodilution was avoided to eliminate it as a confounding variable. Base deficit was corrected with sodium bicarbonate. Adjustments in ventilatory rate, CO₂ in the gas mixture, or anesthetic plane were followed by 15 minutes of equilibration before CBF measurement.

Statistical Methods
All results are expressed as mean +/- standard error of the mean. Cerebral vascular CO₂ reactivity [(CVR_normocapnia - CVR_hypercapnia)/(PaCO_{2 hypercapnia} - PaCO_{2 normocapnia})] was calculated for each experimental condition. This ratio was used because we previously have demonstrated a linear correlation between CVR and PaCO₂ within this range [10]. Comparison between hypercapnia and normocapnia at each individual experimental condition was made using paired t tests and the Bonferroni correction. Comparisons between groups at a given point in time were made by one-way analysis of variance using Neuman-Keuls for post-hoc comparisons. Significance was determined at the p equal to or less than 0.05 level.

	Results

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Cardiopulmonary Bypass Duration and Flow
Cardiopulmonary bypass duration in the normothermic group was 80 +/- 6 minutes. Among hypothermic CPB groups, CPB duration was 187 +/- 10 and 204 +/- 10 minutes in the alpha-stat and pH-stat groups, respectively. At normothermic CPB, CPB flow was not different between groups (mL • kg^-1 • min^-1: normothermia, 82 +/- 3; alpha-stat, 83 +/- 5; pH-stat, 80 +/- 4). Cardiopulmonary bypass flow at 18°C was similar in the two hypothermic CPB groups (alpha-stat, 57 +/- 6 mL • kg^-1 • min^-1; pH-stat, 56 +/- 4 mL • kg^-1 • min^-1).

Physiologic Variables
Physiologic variables are shown in Table 1. There were no differences between groups in arterial oxygen tension or hemoglobin at each microsphere injection. Arterial pH was lower during CPB in the pH-stat group because CO₂ was added to the gas mixture of the oxygenator. Cerebral perfusion pressure was less during CPB than before or after CPB in all groups but remained greater than 50 mm Hg throughout the experiment. There were no significant differences in brain or body temperature among groups at normothermia. During hypothermic CPB, mean brain temperature was 17.5° +/- 0.6°C and 17.3° +/- 0.2°C for alpha-stat and pH-stat groups, respectively.

Cerebral Blood Flow
In the normothermic CPB group, normocapnic CBF was unchanged during and after CPB. Before CPB, a CO₂ challenge resulted in vasodilation (reactivity, 0.062 +/- 0.007 mm Hg • mL^-1 • min^-1 • 100 g^-1 • mm Hg CO₂^-1); this reactivity was not altered during or after CPB as long as normothermia was maintained (Fig 1).

View larger version (26K): [in this window] [in a new window]   Fig 1. . Blood flow (top panel) and cerebrovascular resistance (CVR) (bottom panel) in cerebrum before, during, and after cardiopulmonary bypass (CPB). Piglets were exposed to either normothermic (n = 6) or hypothermic CPB, with either alpha-stat or pH-stat (n = 6 each) control of arterial blood gases. Values for arterial partial pressure of carbon dioxide for normocapnia and hypercapnia during each experimental condition are in Table 1. Values are mean +/- standard error of the mean. (*p < 0.05 hypercapnia versus normocapnia for pre-CPB, CPB, or post-CPB period; +p < 0.05 versus value for normothermia group.)

In the pH-stat group, normocapnic CBF was decreased by hypothermia to an extent similar to the alpha stat group (p < 0.05), although alpha-stat animals had lower CBF during deep hypothermia than pH-stat animals (5 +/- 1 versus 9 +/- 1 mL • min^-1 • 100 g^-1, respectively; p < 0.05). In pH-stat animals before CPB, CO₂ challenge resulted in vasodilation (reactivity, 0.057 +/- 0.009 mm Hg • mL^-1 • min^-1 • 100 g^-1 • mm Hg CO₂^-1). During hypothermic CPB, vasodilation in response to CO₂ was preserved (reactivity, 0.113 +/- 0.006 mm Hg • mL^-1 • min^-1 • 100 g^-1 • mm Hg CO₂^-1), and returned to pre-CPB values after restoration of normothermia and separation from CPB (see Fig 1).

Cerebral Oxygen Consumption
The CMRO₂ was not affected by hypercapnia in any group, nor was CMRO₂ affected by normothermic CPB (Table 2). Cooling decreased CMRO₂ to a similar extent in pH-stat and alpha-stat groups; similarly, CMRO₂ returned to pre-CPB values with rewarming in both groups (see Table 2). The ratio of CBF to CMRO₂ (a crude index of cerebral metabolic supply/demand) was not affected by normothermic CPB (before CPB, 11.8 +/- 1.6; CPB, 13.6 +/- 0.7; p = not significant) or during alpha-stat hypothermic CPB (before CPB, 15.0 +/- 1.8; CPB, 22.8 +/- 3.5; p = not significant). However, the ratio of CBF to CMRO₂ increased during hypothermic CPB with pH-stat management (before CPB, 17.1 +/- 1.0; CPB, 28.3 +/- 2.0; p < 0.05). After CPB, the ratio of CBF to CMRO₂ was not different from pre-CPB values, regardless of blood gas management protocol.

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

The literature on CBF regulation is extensive, but only a small portion addresses the effect of profound hypothermia and nonpulsatile cardiopulmonary bypass on CBF regulation in a pediatric paradigm. Using pH-stat blood gas management, Henricksen [13] found a relationship between higher PaCO₂ and increased CBF in adult patients undergoing mildly hypothermic CPB. However, in that study CO₂ response was measured as the regression over the entire population rather than the blood flow response to an intentional increase in CO₂ for each patient. In a better controlled study of mildly hypothermic CPB in adults, Prough and associates [7] found that an increase in PaCO₂ results in increased CBF when alpha-stat management of blood gases was used. Although CBF increased in response to hypercapnia [7], Prough and associates did not determine whether reactivity was different from that observed before or after CPB. Similarly, McNeill and colleagues [14] found that CBF reactivity to PaCO₂ was present after CPB, but it was not compared with pre-CPB reactivity or reactivity during CPB. Johnsson and associates [15] found no effect of normothermic or mildly hypothermic CPB on CO₂ reactivity in adults during or after CPB when alpha-stat management of blood gases was used. Thus, there has been a shortage of studies with adequate controls, and most studies have been conducted in adults.

Because the cerebrovascular response to brain injury is different in young versus old animals [10], we specifically evaluated the effect of profound hypothermic CPB on CBF response to hypercapnia in young animals. Kern and co-workers [8] found that children respond to an increase in PaCO₂ with an increase in CBF during hypothermic CPB when alpha-stat protocols are used; they also found an attenuated CBF response in very young patients during profoundly hypothermic CPB. However, only 6 patients in their study were less than 1 year of age and reactivity was not compared with pre-CPB or post-CPB values. In our study of young pigs, we found that deeply hypothermic CPB was associated with decreased reactivity to hypercapnia when blood gases were controlled with alpha-stat management but not with pH-stat management. Regardless of the management during CPB, there was full recovery of reactivity after CPB. Although our study is controlled and incorporates the pediatric paradigm, one limitation is that the control group spent significantly less time on CPB than the alpha-stat and pH-stat groups. A better experimental design would have matched CPB duration of control animals to the two experimental groups prospectively; however, we still believe the conclusions of the study are valid, because CO₂ reactivity returned to pre-CPB levels, regardless of duration of CPB.

There exists extensive evidence of age-related differences in cerebrovascular control in both in vivo and in vitro preparations. For example, using in vitro preparations several authors have demonstrated age-related differences in cerebrovascular control in response to hypoxia [16], in cerebral endothelial response to a number of different agonists [17], and in cerebral artery composition [18]. In vivo preparations show a change in cerebral blood flow distribution with increasing age from birth to maturity [19]. In addition, as predicted by in vitro studies, there is a loss of responsiveness of cerebral arterioles to norepinephrine with increasing developmental age [20]. Directly relevant to the current study, we previously have demonstrated an age-related difference in cerebrovascular reactivity to carbon dioxide [21] and an age-related difference for the effect of ischemia on hypercapnic cerebral blood flow reactivity [10]. Therefore, we believe that studies of the effect of hypothermic and normothermic CPB on CBF in adults may not predict results in children.

In laboratory animals, there is a positive correlation between CMRO₂ and hypercapnic CBF reactivity [16, 21, 22], ie, decreased hypercapnic reactivity with decreased metabolism. This was observed in our study when blood gases were managed by alpha-stat protocol. Others have found that alpha-stat management preserves normal CBF autoregulation during moderate hypothermia [23–25], whereas in the setting of deep hypothermia, still others have found ``vasoparesis'' with pressure dependence of CBF with alpha-stat protocol [26, 27]. Our data also demonstrate vasoparesis with alpha-stat management; with pH-stat management, CBF response to hypercapnia was preserved.

Cerebral blood flow regulation is normally under multiple control mechanisms [5]. To study one aspect of CBF regulation, it is desirable to maintain other factors constant. This is difficult in clinical studies because adult patients have varying degrees of carotid atherosclerosis and other medical problems such as diabetes mellitus. Moreover, to assess cerebral vascular responsiveness to CO₂ before, during, and after CPB, multiple measurements are required in each patient; historical controls are fraught with error. In this study, we used radiolabeled microspheres to measure CBF in a piglet model of nonpulsatile CPB. Carbon dioxide reactivity was measured in each animal at three different times while cerebral perfusion pressure and arterial oxygen content were kept constant. We demonstrated decreased CBF with hypothermic CPB regardless of the method of blood gas management. Our data support the hypothesis that decreased CBF is due to decreased CMRO₂ (see Table 2), altered blood rheology associated with hypothermia [16], or both. We do not believe that the decreased CBF seen in hypothermia is due to CPB per se, because CBF did not decrease with normothermic CPB. Similarly, we do not believe that anesthetic management had a significant effect on CBF; indeed, the groups had identical anesthetic management. However, our data indicate that pH-stat management of blood gases, although providing possibly ``luxuriant'' CBF, may result in transient uncoupling of CBF and CMRO₂ during hypothermia. Whether this uncoupling is beneficial or detrimental is unclear. Coupling generally is thought to be important to match regional blood flow to metabolic demand. On the other hand, luxuriant flow may render the brain less vulnerable to microemboli, which are known to occur continuously during CPB. This mechanism may also explain the clinical findings of Jonas and associates [28], who observed better neurologic outcome in children undergoing deeply hypothermic CPB using pH-stat versus alpha-stat strategies [28].

In summary, in this model of hypothermic CPB in the immature subject, we demonstrated that (1) nonpulsatile normothermic CPB preserves CBF, CMRO₂, and vascular reactivity to hypercapnia, (2) hypothermic CPB decreases CBF and CMRO₂, (3) alpha-stat blood gas management during hypothermia causes a significant reduction in hypercapnic reactivity whereas pH-stat management preserves reactivity, and (4) recovery of normal hypercapnic reactivity occurs after CPB regardless of blood gas management protocol used during CPB. Although the optimal blood gas management strategy during deep hypothermic CPB in pediatric patients remains uncertain, this study provides additional insights into the behavior of CBF during the course of a congenital heart operation.

	Acknowledgments

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Supported in part by grant NS 20020 from the United States Public Health Service, National Institutes of Health, and Clinician Investigator Development Award NS 01225.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Address reprint requests to Dr Cameron, 600 N Wolfe St, Blalock, Baltimore, MD 21287.

	References

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Wen Cheng Duke E. Cameron Elaine M. Griffiths Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Cheng, W. Articles by Traystman, R. J. Search for Related Content PubMed PubMed Citation Articles by Cheng, W. Articles by Traystman, R. J.