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Coronary flow reserve in the newborn lamb: An intracoronary Doppler guide wire study

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Coronary flow reserve in the newborn lamb: An intracoronary Doppler guide wire study
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  Coronary Flow Reserve in the Newborn Lamb:An Intracoronary Doppler Guide Wire Study GYLFI ÓSKARSSON, ERKKI PESONEN, SÆMUNDUR GUDMUNDSSON, JÓNAS INGIMARSSON,STAFFAN SANDSTRÖM, AND OLOF WERNER  Department of Pediatrics [G.Ó, E.P.], Division of Pediatric Cardiology, University Hospital of Lund,SE-221 85 Lund, Sweden; Department of Obstetric and Gynecology [S.G.], University Hospital Malmoe,SE-205 02 Malmoe, Sweden; Department of Anesthesia [J.I.], University Hospital Malmoe, SE-205 02 Malmoe, Sweden; Department of Diagnostic Radiology [S.S.], University Hospital of Lund, SE-221 85 Lund,Sweden; and Department of Anesthesia [O.W.], University Hospital of Lund, SE-221 85 Lund, Sweden Recent studies indicate a severely reduced coronary flowreserve (CFR) in neonates with congenital heart disease. Thesignificance of these studies remains debatable, as the ability of the anatomically normal neonatal heart to increase coronary flowis currently unknown. This study was designed to establishnormal values for CFR in newborns after administration of adenosine [pharmacologic CFR (pCFR)] and as induced by acutehypoxemia (reactive CFR). Thirteen mechanically ventilatednewborn lambs were studied. Coronary flow velocities weremeasured in the proximal left anterior descending coronaryartery before and after adenosine injection (140 and 280   g/kgi.v.) using an intracoronary 0.014-in Doppler flow-wire. Mea-surements were made at normal oxygen saturation (Sa O 2 ) andduring progressive hypoxemia induced by lowering the fractionof inspired oxygen. CFR was defined as the ratio of hyperemic tobasal average peak flow velocity. In a hemodynamically stablesituation with normal Sa O 2 , pCFR was 3.0    0.5. pCFR de-creased with increasing hypoxemia. Regression analysis showeda linear relation between Sa O 2  and pCFR (  R  0.86,  p  0.0001).Reactive CFR obtained at severe hypoxemia (Sa O 2   30%) was4.2    0.8, and no significant further increase in coronary flowvelocity occurred by administration of adenosine. Newbornlambs have a similar capacity to increase coronary flow inresponse to both pharmacologic and reactive stimuli as oldersubjects. Administration of adenosine does not reveal the fullcapacity of the newborn coronary circulation to increase flow,however, as the flow increase caused by severe hypoxemia issignificantly more pronounced.  (  Pediatr Res  55: 205–210, 2004)AbbreviationsAPV,  average peak flow velocity CFR,  coronary flow reserve F IO 2 ,  fraction of inspired oxygen IDGW,  intracoronary Doppler guide wire LAD,  left anterior descending coronary artery Pa CO 2 ,  arterial pressure of carbon dioxide pCFR,  pharmacologic coronary flow reserve PET,  positron emission tomography PFVd,  diastolic peak flow velocity PFVs,  systolic peak flow velocity rCFR,  reactive coronary flow reserve Sa O 2 ,  oxygen saturation Hemodynamic problems in the neonatal period, often relatedto congenital heart defects, may affect coronary blood flow(1–3). The coronary physiology in newborns has become of greater importance as cardiac surgery for congenital heartdefects is increasingly performed in the neonatal period. Cor-onary flow reserve (CFR) has been found to be useful inevaluating the effects of cardiac disease and pathologic hemo-dynamic conditions on coronary flow dynamics in adults (4–6). CFR is defined as the ratio of maximal coronary blood flow,as induced by reactive hyperemia or administration of vasodi-lators, divided by resting flow (4).Recent studies performed with positron emission tomogra-phy (PET) have shown low CFR in neonates and infants withcongenital heart disease (1, 7). The significance of these studiesremains debatable, as the ability of the anatomically normalneonatal heart to increase coronary flow is currently unknown(1, 7). The objective of this study was to provide normal valuesfor CFR in the normal neonatal heart by administration of adenosine [pharmacologic CFR (pCFR)] and by inducing acutehypoxemia [reactive CFR (rCFR)]. For this purpose, an intra-coronary Doppler guide wire (IDGW) technique was used inthe newborn lamb model. Received October 22, 2002; accepted July 22, 2003.Correspondence: Gylfi Óskarsson, M.D., Ph.D., Department of Pediatric Cardiology,Lund University Hospital, S-221 85 Lund, Sweden; e-mail: oggylfi@hn.isSupported by grants from the Swedish Heart Lung Foundation, Stockholm; TheCrafoord Foundation, Lund; the Swedish Medical Research Council, Stockholm; TheSwedish Heart-Children’s Association, Stockholm; the University Hospital of Lund; andthe Medical Faculty of Lund University. DOI: 10.1203/01.PDR.0000103932.09752.D6 0031-3998/04/5502-0205PEDIATRIC RESEARCH Vol. 55, No. 2, 2004Copyright © 2004 International Pediatric Research Foundation, Inc.  Printed in U.S.A. ABSTRACT 205  METHODS  Animals.  Thirteen near-term lambs of mixed breed and sexwere studied during the first day of life. Their gestational agecalculated from the conception date was 132–134 d (term145 d), and mean (range) weight was 3.7 kg (2.8–4.7 kg). Thestudy was approved by The Animal Ethics Research Commit-tee, Lund University. Surgical procedures.  The pregnant ewes were premedicatedwith xylazine, 6–8 mg i.m., before transportation to the labo-ratory. After sedation with ketamine, 35 mg i.v., anesthesiawas induced with thiopental, 650–800 mg i.v., and maintainedwith isoflurane in nitrous oxide/oxygen after intubation of thetrachea. The lungs were ventilated with a Servo Ventilator 900B (Siemens-Elema, Solna, Sweden). End-tidal P CO 2  was kept at4.5–6.0 kPa. Maintenance fluid with a balanced glucose/saltsolution was given. Arterial pressure was monitored through anindwelling arterial cannula, and systolic blood pressure wasmaintained between 90 and 110 mm Hg by adjusting theisoflurane concentration and infusing Ringer’s acetate asneeded.The lambs were delivered by cesarean section. The head wasexteriorized, and a 3.5- or 4.0-mm inner diameter tracheal tubewas inserted through an incision in the trachea, so the tip waslocated well above the carina. The tube was secured withligatures around the trachea, which prevented any air leak.Catheters were inserted into the right jugular vein, and a 4-Fintroducer was placed in the right carotid artery. The lamb wasthen given 8 mg of ketamine and 0.4 mg of pancuronium i.v.,and the umbilical cord was divided.The lamb was weighed, towel dried, placed in an openincubator, and covered with thin plastic sheets to reduce evap-orative heat loss. Esophageal temperature was kept at 38–39°Cwith radiant heat lamps as needed. The tracheal tube wasconnected to a Servo Ventilator (model 900C; Siemens-Elema)in the pressure control mode. The initial ventilator settingswere; inspiratory pressure 29 cm H 2 O (25 cm H 2 O  positiveend expiratory pressure of 4 cm H 2 O), ventilatory rate 50/min;inspiratory time 50% of the cycle and the fraction of inspiredoxygen (F IO 2 ) 0.5. The ventilator settings were subsequentlyadjusted to maintain initial Pa O 2  at 6–8 kPa, and arterialpressure of carbon dioxide (Pa CO 2 ) at 5–6 kPa.An additional arterial catheter was placed in the umbilicalartery. Adequate catheter positions were confirmed using flu-oroscopy. The arterial catheters in the carotid and umbilicalarteries were used to draw blood samples used for measure-ment of arterial blood gases and Hb and for continuous arterialblood pressure monitoring. When mean arterial blood pressurewas  40 mm Hg, blood was taken from the ewe and 10 mL/kgwas given to the lamb, unless the lamb’s Hb simultaneouslyexceeded 150 g/L, in which case Ringer’s acetate was usedinstead for volume expansion. Blood was likewise given (10mL/kg) when Hb was   130 g/L. A total of 1 mmol/kg of sodium bicarbonate was given when the pH was   7.25 andbase deficit was   5 mmol/L. Ketamine, 1 mg/mL in 5%glucose, was infused at a rate of 4 mL · kg  1 · h  1 , andpancuronium was administered i.v. as needed to maintainparalysis. Sedation and analgesia after delivery were obtainedwith an initial i.v. bolus dose of 20  g/kg of Fentanyl, followedby a continuous infusion of 10   g · kg  1 · h  1 .The lamb was allowed to stabilize for at least 2 h afterdelivery. A left lateral thoracotomy was then performed in thefourth intercostal space. The lung was retracted, the pericar-dium was opened, and the arterial duct and ascending aortawere identified. The arterial duct was ligated. A precalibratedultrasonic blood flow transducer of proper size (Transonic R orS series) was applied around the ascending aorta to measurecardiac output and was connected to Transonic T101 flowmeter. ECG electrodes were sutured on the chest wall subcu-taneously for continuous ECG monitoring, and a pulse-oximeter was placed on the tail for continuous monitoring of oxygen saturation (Sa O 2 ). Hemodynamic stabilization of 30–60 min was allowed before intracoronary measurements of coronary flow velocities were performed.  Experimental procedure.  A 4-F right coronary angiographycatheter (Judkins) was advanced through the introducer in theright carotid artery to the aortic root. After identification of theleft coronary artery by contrast injection (Omnipaque 240),selective left coronary angiography was performed. The IDGWwas then advanced into the proximal left anterior descendingcoronary artery (LAD) through the coronary catheter, theposition of the tip of the IDGW in the proximal LAD wasconfirmed by fluoroscopy, and the coronary catheter was thenwithdrawn to the ostium of the left coronary artery. Theposition of the IDGW was kept as constant as possible bysecuring it tightly within the coronary catheter and repeatedlyconforming its position by fluoroscopy.Measurements were made at Sa O 2   90%, and the level of oxygenation was confirmed with blood gas analysis and pulse-oxymetry. In seven of the lambs, the F IO 2  was then graduallylowered to reduce the Sa O 2 , while all other ventilatory param-eters were kept constant. The aim was to lower Sa O 2  stepwiseand register hemodynamic and coronary flow variables at asmany different levels of Sa O 2  as possible. When reduction of F IO 2  to room air levels was inadequate to produce desiredreduction in Sa O 2 , nitrogen was added to inspired air and F IO 2 was lowered further as needed (lowest F IO 2  used, 0.09). Beforeeach hemodynamic and coronary flow velocity measurement,the Sa O 2  was kept stabile for 2–3 min before measurementswere performed. Sa O 2  was measured by pulse-oximeter andconfirmed by simultaneous blood gas analysis at every secondto third measurement. There was excellent correlation betweenthe Sa O 2  registered with pulse-oximeter and Sa O 2  measuredwith blood gas analysis when simultaneous analysis was per-formed. The hemodynamic variables measured at each stagewere heart rate, blood pressure, cardiac output, and LAD flowvelocities before and after a bolus injection of adenosine. Thelambs were killed with thiopental overdose when the experi-mental protocol had been completed.  Measurements of coronary flow velocities and coronary  flow reserve.  Coronary flow velocities were measured with a0.014-in-diameter (0.36 mm) IDGW (Flowire, Cardiometrics,Inc, Mountain View, CA, U.S.A.). It is equipped with a15-MHz piezoelectric ultrasound transducer at its tip thatpermits velocity acquisition with a high pulse repetition fre-quency (up to 90 kHz) from a sampling depth of 5 mm. This 206  ÓSKARSSON  ET AL.  forward-directed ultrasound beam with a 25° divergent anglesamples a large proportion of the coronary flow profile. Bloodflow velocities are determined from the Doppler frequencyshift based on the difference between the transmitted andreturning signals, calculated from the Doppler equation. Thevelocity data are processed by on-line fast Fouriertransformation.After IDGW was placed in the proximal LAD, baseline flowvelocity data were obtained at this position once a stableDoppler signal was achieved (Fig. 1). This was accomplishedby means of torque adjustment with attention to the amplitudedisplay until a high-quality signal had been attained.Continuous flow velocity profiles and audio signals alongwith simultaneous ECG were displayed and recorded on vid-eocassette. Doppler flow velocity spectra were analyzed on-line to determine average peak velocity (APV), where APV isthe time average value of the instantaneous peak velocitysamples over the last two cardiac cycles. Diastolic peak flowvelocity (PFVd) and systolic peak flow velocity (PFVs) weremeasured off-line and averaged over three cardiac cycles.Once baseline flow velocity data had been obtained, a bolusof i.v. adenosine 140  g/kg was injected into the catheter in theright jugular vein. Flow velocity spectra were registered for60 s after each bolus (Fig. 2). pCFR was defined as the ratio of the highest registered APV after administration of adenosine tobaseline APV. For ensuring that true maximal coronary flowvelocity was obtained by adenosine, a double dose of adeno-sine (280  g/kg) was given at the initial measurements in eachlamb. This did not result in any significant increase in LADflow velocity compared with the 140-  g/kg dose. rCFR wasdefined as the ratio of the highest registered APV at severehypoxemia (mean Sa O 2 , 11.4%) to baseline APV at normaloxygen saturation (mean Sa O 2 , 94.7%.)  Measurements and calculations.  Arterial pressures weremeasured with pressure transducers referenced to atmosphericpressure with zero obtained at the midchest position. Thesignal was averaged electronically to obtain mean pressures.Heart rate was obtained from continues ECG monitoring.Blood gas tensions, pH, Sa O 2 , and Hb were measured with aRadiometer OSM 3 blood gas analyzer (Radiometer, Copen-hagen, Denmark). Sa O 2  was additionally continuously moni-tored by OXImeter pulse-oximeter (Radiometer). Statistical analysis.  Results are presented as mean (SD).Hemodynamic values, arterial blood gases, and coronary flowparameters were analyzed using ANOVA for repeated mea-sures. When significant differences were found, they werefurther tested for significance by  post hoc  tests. Linear andlogarithmic regression analysis was used to calculate correla-tion coefficients (r). P  0.05 was considered significant. RESULTS  Blood gases and general hemodynamics.  Sa O 2 , blood gases,heart rate, blood pressure, cardiac output, and stroke volume atdifferent stages of the experimental protocol are presented inTable 1. The administration of adenosine did not result in anysignificant changes in heart rate or blood pressure. During thehypoxemia part of the experiment, no significant changes wereobserved in pH, base excess, P CO 2 , cardiac output, or strokevolume. Heart rate and blood pressure did not change signifi-cantly with moderate hypoxemia (Sa O 2 , 60–90%). With morepronounced hypoxemia (Sa O 2 , 30–60%) heart rate increasedsignificantly and blood pressure was reduced. At extremehypoxemia (Sa O 2  30%), blood pressure increased again (Ta-ble 1). Coronary flow dynamics.  Hemodynamic and coronary flowdata in the newborn lambs at normal oxygen saturation areshown in Tables 1 and 2. With progressive hypoxemia, theAPV increased significantly as illustrated in Figure 3, andregression analysis showed an inverse linear correlation be-tween log(Sa O 2 ) and APV (  R    0.90,  R 2   0.81,  F    274.0,  p    0.0001). PFVd also increased with progressivehypoxemia as illustrated in Figure 4, and an analogue inverselinear correlation was found between log(Sa O 2 ) and PFVd (  R  0.79,  R 2  0.62,  F   99.7,  p  0.0001). PFVs increasedwith progressive hypoxemia but not as consistently as PFVd.Regression analysis showed a significant negative linear cor-relation between Sa O 2  and PFVs (  R  0.66,  R 2  0.44,  F   44.5,  p  0.0001). The changes in coronary flow velocitiesat different levels of Sa O 2  are shown in Table 2. CFR and maximal coronary flow.  The pCFR at normal Sa O 2 was 3.0 (0.5). With progressive hypoxemia, the pCFR was Figure 1.  Intracoronary Doppler tracing in the left anterior descendingcoronary artery, showing basal flow at normal Sa O 2 . Figure 2.  CFR measurement in the LAD at normal Sa O 2 . The bottom of figureshows the coronary flow profile before (left) and after (right) administration of adenosine. The APV before administration of adenosine was 9.1 cm/s, and themaximal APV after administration of adenosine was 30.0 cm/s, which gives aCFR of 3.3. 207 CORONARY FLOW RESERVE IN NEWBORN LAMBS  reduced, and at severe hypoxemia (Sa O 2  30%), it was almostexhausted, with pCFR 1.1 (0.1). Regression analysis showed alinear relation between Sa O 2  and pCFR (  R  0.86,  R 2  0.74, F   135.6,  p  0.0001; Fig. 5).Severe hypoxemia (Sa O 2   30%) resulted in significantlyhigher (  p    0.0001) coronary flow velocities than what wasobtained by adenosine administration at normoxia (Fig. 6). TherCFR was 4.2 (0.8). At Sa O 2  between 30 and 100%, themaximal coronary flow velocities obtained after adenosineadministration were fairly constant. Administration of adeno-sine at severe hypoxemia (Sa O 2  30%) resulted in insignificantfurther increase in coronary flow velocities, as shown in Figure6, and as indicated by a CFR of 1.1 at Sa O 2  30%. DISCUSSION The main result of this study is the determination of pCFRin a normal neonatal heart in a stable hemodynamic condition.The results provide a reference interval for pCFR in thenewborn lamb model with possible applicability to humans.Measurements of CFR unavoidably involve exposure toradiation or administration of drugs with potential serious side Table 1.  Hemodynamic and metabolic changes during progressive hypoxemia Normoxia 60–90% 30–60% 0–30%Sa O 2  (%) 94.6 (2.9) 73.7 (8.2)† 47.7 (8.5)† 15.4 (4.8)†P O 2  (kPa) 7.67 (5.05) 2.84 (0.66)* 2.00 (0.67)* 0.84 (0.23)*O 2  content (mL/100 mL) 16.0 (2.2) 12.5 (2.6)† 7.7 (1.3)† 2.5 (0.7)†P CO 2  (kPa) 5.47 (1.77) 5.00 (1.84) 5.17 (1.90) 4.73 (0.38)Ph 7.40 (0.10) 7.41 (0.11) 7.42 (0.10) 7.43 (0.06)Base excess   1.1 (3.0)   0.5 (4.5)   0.1 (3.4) 0.1 (2.9)Heart rate (bpm) 151 (15) 155 (20) 171 (21)* 201 (38)†SBP (mm Hg) 57 (12) 57 (12) 49 (10)* 60 (9)DBP (mm Hg) 40 (11) 40 (10) 30 (7)* 35 (5)MAP (mm Hg) 47 (11) 46 (13) 37 (7)* 45 (6)Cardiac output (mL/min) 463 (212) 445 (222) 534 (264) 443 (221)Stroke volume (mL) 3.19 (1.47) 3.07 (1.53) 3.57 (1.54) 2.88 (2.00)All values are mean (SD). When the differences between the measured value and comparable value at normoxia are statistically significant, the values aremarked with * (  p  0.05) or † (  p  0.0001). Any other differences are not statistically significant. SBP, systolic blood pressure; DBP, diastolic blood pressure;MAP, mean arterial pressure. Table 2.  Summary of coronary flow data at different levelsof hypoxemia APV(cm/s)PFVd(cm/s)PFVs(cm/s) CFRNormoxia (  90%) 6.8 25.1 11.4 3.0O 2  61–90% 7.5 29.3 15.1* 2.2†O 2  31–60% 15.1† 47.6† 21.8† 1.3†O 2  0–30% 27.1† 72.5† 23.8† 1.1†Statistically significant differences between mean values and the mean atnormoxia are marked with * (  p  0.05) or † (  p  0.0001). Figure 3.  Regression plot showing a the relation between Sa O 2  and APV inthe left anterior descending coronary artery. Figure 4.  Regression plot showing the relation between Sa O 2  and PFVd in theLAD. Figure 5.  Linear regression plot showing the relation between CFR and Sa O 2 . 208  ÓSKARSSON  ET AL.  effects or both and therefore cannot be performed in healthyhuman neonates. As CFR studies in healthy neonates areentirely lacking and CFR measurements in healthy humanneonates with the currently available methods may proveunfeasible because of ethical restraints, we used an experimen-tal lamb model to determine CFR in the normal newborn heart.In this study, pCFR in the newborn lambs was similar orslightly lower than has been documented in children and adults(5, 8–11). A normal adult heart can increase coronary flow/ myocardial perfusion by maximally 2.5 to 4 times the restingvalue, but normal pCFR values for adults are somewhat dif-ferent for each method and vasodilator used (5, 6, 9, 12, 13).CFR can be measured with PET techniques, cine magneticresonance imaging, and Doppler ultrasound (1, 7, 9, 12, 13). Inthe newborn lamb, experimental studies using the radioactivemicrospheres method have shown a high myocardial perfusioncompared with older animals (14–16). High basal myocardialperfusion may be associated with reduced CFR; this has led tospeculations that CFR in the newborn is generally lower thanin older subjects (1, 16).CFR can be reduced if basal flow is increased as a result of myocardial hypertrophy or if maximal flow is reduced byfunctional disturbance of the microcirculation (6, 17). Severemyocardial hypertrophy, high ventricular pressures, and de-creased oxygen saturation commonly associated with congen-ital heart defects can affect both basal and maximal coronaryflow and therefore might reduce CFR (1, 7, 14, 18, 19). The PET technique has been used to measure CFR in humanneonates who are surgically treated for congenital heart dis-ease, and transthoracic Doppler has been used to describecoronary flow dynamics at rest in neonates (1–3, 7). Withfurther refinement of the noninvasive Doppler technique, it islikely that it can be used to measure CFR in neonates withcongenital heart defects (2, 3, 20). Available studies applying the PET technique to measure pCFR in neonates who undergosurgery for congenital heart defects have reported a CFR in therange 1.2–1.6 (1, 7). No healthy control subjects were in-cluded, but the CFR was low compared with what has beenmeasured by IDGW and PET on older healthy children andyoung adults (5, 10, 11, 21). One of the questions left unan-swered by these studies was whether the pCFR obtained in theneonates with surgically corrected congenital heart defects ispathologic, caused by the heart defect or recent surgery, or isa normal value for the neonatal heart. The results of our studypoint in the direction that neonates with surgically correctedcongenital heart defects may have pathologically low CFR andcould be at increased risk of myocardial ischemia during anysituation that increases myocardial oxygen demand (1, 7).The increase in LAD flow velocities in response to progres-sive hypoxemia in our study is in concordance with earlierstudies performed in the newborn lamb using the radioactivemicrospheres method to measure myocardial perfusion (14,22). These studies have shown an increase in myocardialperfusion with progressive hypoxemia and a maximal increaseup to 3.77 times the resting flow value when hypoxemia wassevere (14, 22). As coronary flow increases with hypoxemiaand pCFR is dependent on resting flow and maximal coronaryflow after administration of a vasodilator, we expected to findpCFR linearly reduced during hypoxemia as shown in Figure5.In the current study, the increase in coronary flow velocitywith progressive hypoxemia followed an exponential pattern,and at severe hypoxemia, coronary flow velocities significantlyexceeded what was obtained by administration of adenosinealone. The rCFR therefore was higher (4.2) than the pCFR(3.0) and slightly higher than the previous experimental lambstudies have indicated (14, 22). Our results are similar to thoseof Reller  et al.  (23), which showed that severe acute hypox-emia in the fetal lamb causes coronary flow to exceed what canbe obtained by administration of adenosine alone. In Reller’sstudy, nitric oxide was shown to be a modulator of the in-creased flow at severe hypoxemia, as the difference in flowvelocity obtained by severe hypoxemia and by administrationof adenosine was abolished by administration of nitric oxidesynthase inhibitor N-nitro- L -arginine (23). The mechanism forhypoxemia-induced increase in coronary flow is controversialand has not been studied in newborns. It may be explained byincreased coronary shear-stress that causes a release of endo-thelium-derived nitric oxide and vasodilatory prostaglandinsthat can increase coronary flow additionally by a mechanismdifferent from adenosine (23–25).  Methods and limitations.  Measurements of coronary flowvelocities and CFR with the IDGW have been validated ex-tensively both  in vitro  and  in vivo  (26, 27). The IDGWmeasures flow velocity, not volume flow, but a close linearcorrelation has been shown between coronary flow velocitymeasured by the IDGW and volume flow measured by elec-tromagnetic circumflex flow probes (26). The IDGW has beenshown to cause negligible flow disturbance in coronary arteriesas small as 1.2 mm in diameter, and even if our study wasperformed in small animals, the 0.014-in diameter wire isunlikely to have affected the coronary flow (26).Coronary flow becomes dependent on coronary perfusionpressure when the coronary bed is maximally dilated (4).Coronary perfusion pressure was not measured during thisexperiment but is closely related to mean arterial blood pres-sure. Mean blood pressure was not increased at severe hypox- Figure 6.  Data compare APV (mean and SE) in the LAD at rest (basal) andmaximal APV after administration of adenosine at severe hypoxemia (Sa O 2  30%) and after adenosine administration at severe hypoxemia. There is asignificant difference (  p    0.0001) between all values shown except hypox-emia (APV 27.1 cm/s) and hypoxemia  adenosine (APV 30.0 cm/s). 209 CORONARY FLOW RESERVE IN NEWBORN LAMBS
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