The foramen ovale (FO) accounts for the majority of fetal left ventricular (LV) output. Increased right ventricular afterload can cause a redistribution of combined cardiac output between the ventricles. To understand the capability of the FO to increase its volume blood flow and thus LV output, we mechanically occluded the main pulmonary artery in seven chronically instrumented near-term sheep fetuses. We hypothesized that FO volume blood flow and LV output would increase during main pulmonary artery occlusion. Fetal cardiac function and haemodynamics were assessed by pulsed and tissue Doppler at baseline, 15 and 60 min after occlusion of the main pulmonary artery and 15 min after occlusion was released. Fetal ascending aorta and central venous pressures and blood gas values were monitored. Main pulmonary artery occlusion initially increased fetal heart rate (P < 0.05) from [mean (SD)] 158 (7) to 188 (23) beats min(-1) and LV cardiac output (P < 0.0001) from 629 (198) to 776 (283) ml min(-1). Combined cardiac output fell (P < 0.0001) from 1524 (341) to 720 (273) ml min(-1). During main pulmonary artery occlusion, FO volume blood flow increased (P < 0.001) from 507 (181) to 776 (283) ml min(-1). This increase was related to fetal tachycardia, because LV stroke volume did not change. Fetal ascending aortic blood pressure remained stable. Central venous pressure was higher (P < 0.05) during the occlusion than after it was released. During the occlusion, fetal pH decreased and PCO2 increased. Left ventricular systolic dysfunction developed while LV diastolic function was preserved. Right ventricular systolic and diastolic function deteriorated after the occlusion. In conclusion, the FO has a limited capacity to increase its volume blood flow at near-term gestation.

New Findings What is the central question of this study? The fetal aortic isthmus has an important physiological role, allowing communication between the left and right ventricular outputs, which are arranged in parallel. Can the aortic isthmus provide unrestrictive communication between the left and right ventricular circulations during occlusion of the ascending aorta? What is the main finding and its importance? During occlusion of the ascending aorta, fetal carotid artery perfusion pressure fell significantly, showing that the aortic isthmus failed to redirect blood flow and pressure from the ductus arteriosus to the aortic arch. This suggests that the aortic isthmus cannot provide unrestrictive communication between left and right ventricular circulations. The fetal aortic isthmus (AoI) allows communication between left (LV) and right ventricular (RV) outputs and represents an arterial watershed between the brachiocephalic (brain) and subdiaphragmatic (placenta) circulations. To understand the capability of the AoI to maintain the balance between the upper and lower body circulations, we performed a complete occlusion of the fetal ascending aorta in nine chronically instrumented sheep at near term gestation. We hypothesized that the occlusion would significantly decrease LV output and concomitantly increase RV output in order to maintain adequate systemic cardiac output and perfusion pressure to the fetal brain circulation through retrograde filling of the AoI. Fetal cardiac function and haemodynamics were assessed by pulsed and tissue Doppler at baseline, 15 and 60 min after occlusion of the ascending aorta and 15 min after occlusion was released. Carotid artery and jugular vein pressures were monitored. Occlusion of the ascending aorta increased (P < 0.002) RV output from [mean (SD)] 684 (369) to 907 (414) ml min−1 and decreased (P < 0.0001) LV output from 440 (136) to 40 (16) ml min−1. Combined cardiac output decreased (P < 0.02) from 1125 (494) to 946 (417) ml min−1. During occlusion, carotid artery mean pressure decreased from 32 (7) to 12 (7) mmHg (P < 0.0001). Systemic venous pressure was unaffected. Left ventricular systolic and diastolic function deteriorated during occlusion. Right ventricular systolic function improved, while diastolic dysfunction developed. Fetal carotid artery perfusion pressure decreased significantly during occlusion of the ascending aorta, demonstrating that AoI failed to redirect blood flow and pressure from the ductus arteriosus to the aortic arch. Our finding suggests that at near term gestation the aortic AoI cannot provide unrestrictive communication between LV and RV circulations.

Historically, the primary marker of quality for congenital cardiac surgery has been postoperative mortality. The purpose of this study was to determine whether additional markers (10 surgical metrics) independently predict length of stay (LOS), thereby providing specific targets for quality improvement. Ten metrics (unplanned ECMO, unplanned cardiac catheterization, revision of primary repair, delayed closure, mediastinitis, reexploration for bleeding, complete heart block, vocal cord paralysis, diaphragm paralysis, and change in preoperative diagnosis) were defined in 2008 and subsequently collected from 1024 consecutive index congenital cardiac cases, yielding 990 cases. Four patient characteristics and 22 case characteristics were used for risk adjustment. Univariate and multivariable analyses were used to determine independent associations between each metric and postoperative LOS. Increased LOS was independently associated with revision of the primary repair (p = 0.014), postoperative complete heart block requiring a permanent pacemaker (p = 0.001), diaphragm paralysis requiring plication (p < 0.001), and unplanned postoperative cardiac catheterization (p < 0.001). Compared with patients without each metric, LOS was 1.6 (95 % CI 1.1-2.2, p = 0.014), 1.7 (95 % CI 1.2-2.3, p = 0.001), 1.8 (95 % CI 1.4-2.3, p < 0.001), and 2.0 (95 % CI 1.7-2.4, p < 0.001) times as long, respectively. These effects equated to an additional 4.5-7.8 days in hospital, depending on the metric. The other 6 metrics were not independently associated with increased LOS. The quality of surgery during repair of congenital heart disease affects outcomes. Reducing the incidence of these 4 specific surgical metrics may significantly decrease LOS in this population.

Despite advances in neonatal intensive care, survivors of premature birth remain highly susceptible to unique patterns of developmental brain injury that manifest as cerebral palsy and cognitive-learning disabilities. Whereas preterm infants were previously at high risk for destructive brain lesions that resulted in cystic white matter injury and secondary cortical and subcortical gray matter degeneration, contemporary cohorts of preterm survivors commonly display less severe injury that does not appear to involve pronounced glial or neuronal loss. Cerebral development in fetal sheep shares many anatomical and physiological similarities with human. Thus, the fetal sheep has provided unique experimental access to the complex pathophysiological processes that contribute to injury to the human brain during successive periods in development. Recent refinements have resulted in models that replicate major features of acute and chronic human cerebral injury and which have provided access to complex clinically relevant studies of cerebral blood flow and neuro-imaging that are not feasible in smaller laboratory animals. We focus here on emerging insights and methodologies from studies in fetal sheep that have begun to define cellular and vascular factors that contribute to preterm white and gray matter injury. Despite the higher costs and technical challenges of instrumented preterm fetal sheep models, they provide powerful access to clinically relevant studies that provide a more integrated analysis of the spectrum of insults that appear to contribute to cerebral injury in human preterm infants.

Preterm fetal sheep preparations provide unique experimental access to the complex pathophysiological processes that contribute to injury to the human brain during successive periods in development. Recent refinements have resulted in preparations that offer a number of significant advantages to model key aspects of human preterm cerebral injury. We describe a global cerebral ischemia preparation that replicates major features of acute and chronic human cerebral injury and which has provided access to complex clinically relevant studies of cerebral blood flow and neuro-imaging that are not feasible in smaller laboratory animals. Despite the higher costs and technical challenges of instrumented preterm fetal sheep models, they allow an integrated analysis of the spectrum of insults that appear to contribute to cerebral injury in human preterm infants.

We investigated the effect of fetal sheep ductus arteriosus occlusion (DO) on the distribution of cardiac output and left and right ventricular function by tissue and pulsed Doppler at baseline; after 15 and 60 min of DO induced with a vascular occluder; and 15 min after release of DO. Ductal occlusion decreased fetal pO2. Mean left ventricular output increased (p < 0.001) from 725 to 1013 mL/min, and right ventricular (1185 mL/min vs. 552 mL/min) and systemic (1757 mL/min vs. 1013 mL/min) cardiac outputs fell (p < 0.001) after 15 min of DO, compared with baseline. Pulmonary vascular impedance decreased and volume blood flow increased more than threefold during DO, whereas foramen ovale volume blood flow remained unchanged. Left ventricular systolic function was unaffected, whereas isovolumic relaxation velocity deceleration decreased. Right ventricular functional indices remained unchanged. We conclude that DO increased pulmonary volume blood flow, not foramen ovale volume blood flow. Left ventricular output increased, although not as much as right ventricular output fell, resulting in decreased systemic cardiac output. During DO, left ventricular function exhibited diminished relaxation.

BACKGROUND:Platelet dysfunction resulting from abnormal fluid shear stress has been reported in adults with aortic stenosis. Blood flowing through a congenital heart defect at greater than normal velocity is subjected to increased shear stress. The primary aim was to determine whether peak flow velocity through congenital cardiac lesions predicts preoperative platelet dysfunction. METHODS:The charts of 402 patients who underwent cardiopulmonary bypass and had preoperative platelet function analysis were evaluated. Platelet dysfunction was measured as a prolonged closure time (CT) in seconds with a platelet function analyzer. Echocardiography was used to determine peak velocity. The relationship between peak velocity and CT was analyzed using linear regression and Kaplan-Meier estimation. RESULTS:The distribution of peak velocity was bimodal. The mean velocity of the lower group was 1.9 m/second and the higher group was 4.2 m/second. Univariate analysis showed age, weight, peak velocity, hematocrit, and Risk Adjustment for Congenital Heart Surgery score to be associated with prolonged CT. Using multivariable analysis, prolonged CT was significantly associated with peak velocity (p < 0.001). For each 1m/second increase in peak velocity the CT increased by over 9 seconds (p < 0.001). In addition, a median CT increase of more than 6 seconds was also associated with a 5 percentage point drop in hematocrit (p = 0.04). CONCLUSIONS:Platelet dysfunction is associated with high blood flow velocity through congenital cardiac lesions. Lower preoperative hematocrit was associated with prolonged CT, which may suggest subclinical bleeding secondary to platelet dysfunction.

OBJECTIVES:Excessive bleeding can be a problem during or after cardiac surgery. While cardiopulmonary bypass-associated platelet dysfunction is an important inducer of coagulopathy, preoperative platelet dysfunction can also contribute to this bleeding. We investigated the relationship between preoperative platelet dysfunction and transfusion of blood products given to children undergoing cardiac surgery.METHODS:The platelet function analyser test measures platelet function in vitro by aspirating blood through a small standard hole (creating high shear) in a collagen membrane infused with a platelet agonist. The time taken to form a platelet plug is known as closure time and prolonged closure time (CT) indicates platelet dysfunction. Three hundred and thirty-eight children who had undergone surgery with cardiopulmonary bypass between 2008 and 2012 were included. The volume of red blood cells and fresh-frozen plasma transfused was recorded. The relationship between closure time and transfusion requirements was analysed using linear and logistic regression.RESULTS:Patients with prolonged closure time had greater odds of getting red blood cells and fresh-frozen plasma transfusions compared with patients with normal closure time (P <0.01). On univariate analysis, age, weight, haematocrit, cardiopulmonary bypass time, Risk Adjustment for Congenital Heart Surgery score and closure time were associated with increased odds of red blood cells and fresh-frozen plasma transfusion in the operation theatre (P <0.05). However, when logistic multivariable regression analysis was applied, only age, cardiopulmonary bypass time and closure time remained as significant predictive factors for transfusion.CONCLUSIONS:In children who have undergone cardiac surgery, when age and cardiopulmonary bypass time are accounted for, a prolonged preoperative closure time is significantly associated with increased odds of red blood cells and fresh-frozen plasma transfusion in the operation theatre. This may have implications for planning and utilization of blood products.

Foramen ovale (FO) is an opening between the right and left atrium, and FO volume blood flow makes up a significant proportion of left ventricular cardiac output (LVCO). However, it is unknown whether FO volume blood flow can be further increased. We hypothesized that during acute fetal pulmonary artery (PA) occlusion FO volume blood flow increases, in order to maintain adequate systemic cardiac output. Seven ewes underwent surgery at 120-126 gestational days (term 145 days) for the placement of a vascular occluder around fetal PA. Fetal carotid artery and jugular vein were cannulated. After a 5-day recovery, fetal heart rate (FHR), right (RVSV) and left (LVSV) ventricular stroke volumes, and right (RVCO) and left ventricular cardiac outputs were measured by ultrasonography. Combined cardiac output (CCO) was calculated (RVCO+LVCO) at baseline, 15 and 60 minutes after PA occlusion, and 15 minutes after release of PA occlusion. Fetal mean arterial (mABP) and central venous (CVP) pressures, and blood gas values were monitored. All the data are presented as means (SD).* p<0.05, compared with baseline. In fetal sheep, acute PA occlusion leads to increased LVCO, however CCO decreases. The rise in LVCO is caused by increased FHR with no change in LVSV. Fetal CVP increases. These findings suggest that fetal FO has a limited capacity to increase its volume blood flow, at least in response to acutely increased right ventricular afterload.Tabled 1 Open table in a new tab

Objective: Although the spectrum of white matter injury (WMI) in preterm infants is shifting from cystic necrotic lesions to milder forms, the factors that contribute to this changing spectrum are unclear. We hypothesized that recurrent hypoxiaischemia (rHI) will exacerbate the spectrum of WMI defined by markers of inflammation and molecules related to the extracellular matrix (hyaluronan (HA) and the PH20 hyaluronidase) that regulate maturation of the oligodendrocyte (OL) lineage after WMI.Methods: We employed a preterm fetal sheep model of in utero moderate hypoxemia and global severe but not complete cerebral ischemia that reproduces the spectrum of human WMI. The response to rHI was compared against corresponding early or later single episodes of HI. An ordinal rating scale of WMI was compared against an unbiased quantitative image analysis protocol that provided continuous histo-pathological outcome measures for astrogliosis and microglial activation. Late oligodendrocyte progenitors (preOLs) were quantified by stereology. Analysis of hyaluronan and the hyaluronidase PH20 defined the progressive response of the extracellular matrix to WMI.Results: rHI resulted in a more severe spectrum of WMI with a greater burden of necrosis, but an expanded population of preOLs that displayed reduced susceptibility to cell death. WMI from single episodes of HI or rHI was accompanied by elevated HA levels and increased labeling for PH20. Expression of PH20 in fetal ovine WMI was confirmed by RT-PCR and RNA-sequencing.Conclusions: rHI is associated with an increased risk for more severe WMI with necrosis, but reduced risk for preOL degeneration compared to single episodes of HI. Expansion of the preOL pool may be linked to elevated hyaluronan and PH20.

Objective Recently, we reported that the neocortex displays impaired growth after transient cerebral hypoxia–ischemia (HI) at preterm gestation that is unrelated to neuronal death but is associated with decreased dendritic arbor complexity of cortical projection neurons. We hypothesized that these morphological changes constituted part of a more widespread neuronal dysmaturation response to HI in the caudate nucleus (CN), which contributes to motor and cognitive disability in preterm survivors. Methods Ex vivo magnetic resonance imaging (MRI), immunohistochemistry, and Golgi staining defined CN growth, cell death, proliferation, and dendritic maturation in preterm fetal sheep 4 weeks after HI. Patch‐clamp recording was used to analyze glutamatergic synaptic currents in CN neurons. Results MRI‐defined growth of the CN was reduced after ischemia compared to controls. However, no significant acute or delayed neuronal death was seen in the CN or white matter. Nor was there significant loss of calbindin‐positive medium spiny projection neurons (MSNs) or CN interneurons expressing somatostatin, calretinin, parvalbumin, or tyrosine hydroxylase. Morphologically, ischemic MSNs showed a markedly immature dendritic arbor, with fewer dendritic branches, nodes, endings, and spines. The magnitude and kinetics of synaptic currents, and the relative contribution of glutamate receptor subtypes in the CN were significantly altered. Interpretation The marked MSN dendritic and functional abnormalities after preterm cerebral HI, despite the marked resistance of immature CN neurons to cell death, are consistent with widespread susceptibility of projection neurons to HI‐induced dysmaturation. These global disturbances in dendritic maturation and glutamatergic synaptic transmission suggest a new mechanism for long‐term motor and behavioral disabilities in preterm survivors via widespread disruption of neuronal connectivity. Ann Neurol 2014;75:508–524

Background. Shear stress-induced platelet dysfunction (PD) is prevalent among adults with aortic stenosis. Our aim was to determine whether abnormal platelet function was associated with specific congenital cardiac lesions in children.Methods. The charts of 407 children who had undergone cardiopulmonary bypass and had preoperative platelet function analysis were evaluated. Patients were assigned to 1 of 11 different lesion categories. Platelet dysfunction (PD) was defined as prolonged closure time (CT) as measured with a platelet function analyzer. Odds ratio (OR) estimates for prolonged CT were calculated for each lesion category. Mean CTs were compared with Tukey-Kramer separated means testing. Analysis of variance modeling was used to determine association between hematocrit value and CT.Results. CT in patients with ventricular septal defects (VSD) and right ventricular outflow tract obstruction (RVOTO) lesions was prolonged. OR analysis found that patients with VSDs (OR, 2.46) or RVOTO (OR, 2.88) had at least a 95% probability of an abnormal CT. In contrast, patients with atrial septal defect (ASD), bidirectional Glenn procedure (BDG), and pulmonary insufficiency (PI) had a reduced probability of a prolonged CT (p < 0.05). A similar pattern was seen in parametric analysis comparing mean CTs across lesion categories. A lower preoperative hematocrit value was associated with prolonged CTs across all lesion types (p < 0.05).Conclusions. PD was common in children with congenital cardiac lesions involving systolic flow abnormalities and was uncommon among children with lesions having diastolic abnormalities. Lower preoperative hematocrit values were associated with prolonged CTs, suggesting subclinical bleeding secondary to excessive platelet shearing. (C) 2014 by The Society of Thoracic Surgeons

Background and Purpose: Although the spectrum of perinatal white matter injury (WMI) in preterm infants is shifting from cystic encephalomalacia to milder forms of WMI, the factors that contribute to this changing spectrum are unclear. We hypothesized that the variability in WMI quantified by immunohistochemical markers of inflammation could be correlated with the severity of impaired blood oxygen, glucose and lactate.Methods: We employed a preterm fetal sheep model of in utero moderate hypoxemia and global severe but not complete cerebral ischemia that reproduces the spectrum of human WMI. Since there is small but measurable residual brain blood flow during occlusion, we sought to determine if the metabolic state of the residual arterial blood was associated with severity of WMI. Near the conclusion of hypoxia-ischemia, we recorded cephalic arterial blood pressure, blood oxygen, glucose and lactate levels. To define the spectrum of WMI, an ordinal WMI rating scale was compared against an unbiased quantitative image analysis protocol that provided continuous histo-pathological outcome measures for astrogliosis and microgliosis derived from the entire white matter.Results: A spectrum of WMI was observed that ranged from diffuse non-necrotic lesions to more severe injury that comprised discrete foci of microscopic or macroscopic necrosis. Residual arterial pressure, oxygen content and blood glucose displayed a significant inverse association with WMI and lactate concentrations were directly related. Elevated glucose levels were the most significantly associated with less severe WMI.Conclusions: Our results suggest that under conditions of hypoxemia and severe cephalic hypotension, WMI severity measured using unbiased immunohistochemical measurements correlated with several physiologic parameters, including glucose, which may be a useful marker of fetal response to hypoxia or provide protection against energy failure and more severe WMI.

Children who survive preterm birth exhibit persistent unexplained disturbances in cerebral cortical growth with associated cognitive and learning disabilities. The mechanisms underlying these deficits remain elusive. We used ex vivo diffusion magnetic resonance imaging to demonstrate in a preterm large-animal model that cerebral ischemia impairs cortical growth and the normal maturational decline in cortical fractional anisotropy (FA). Analysis of pyramidal neurons revealed that cortical deficits were associated with impaired expansion of the dendritic arbor and reduced synaptic density. Together, these findings suggest a link between abnormal cortical FA and disturbances of neuronal morphological development. To experimentally investigate this possibility, we measured the orientation distribution of dendritic branches and observed that it corresponds with the theoretically predicted pattern of increased anisotropy within cases that exhibited elevated cortical FA after ischemia. We conclude that cortical growth impairments are associated with diffuse disturbances in the dendritic arbor and synapse formation of cortical neurons, which may underlie the cognitive and learning disabilities in survivors of preterm birth. Further, measurement of cortical FA may be useful for noninvasively detecting neurological disorders affecting cortical development.

Despite advances in neonatal intensive care, survivors of premature birth remain highly susceptible to unique patterns of developmental brain injury that manifest as cerebral palsy and cognitive-learning disabilities. The developing brain is particularly susceptible to cerebral white matter injury related to hypoxia-ischemia. Cerebral white matter development in fetal sheep shares many anatomical and physiological similarities with humans. Thus, the fetal sheep has provided unique experimental access to the complex pathophysiological processes that contribute to injury to the human brain during successive periods in development. Recent refinements have resulted in models that replicate major features of acute and chronic human cerebral injury and have provided access to complex clinically relevant studies of cerebral blood flow and neuroimaging that are not feasible in smaller laboratory animals. Here, we focus on emerging insights and methodologies from studies in fetal sheep that have begun to define cellular and vascular factors that contribute to white matter injury. Recent advances include spatially defined measurements of cerebral blood flow in utero, the definition of cellular maturational factors that define the topography of injury and the application of high-field magnetic resonance imaging to define novel neuroimaging signatures for specific types of chronic white matter injury. Despite the higher costs and technical challenges of instrumented preterm fetal sheep models, they provide powerful access to clinically relevant studies that provide a more integrated analysis of the spectrum of insults that appear to contribute to cerebral injury in human preterm infants.

increased in chronically anemic fetal sheep Juulia Junno, Juha Rasanen, Jennifer Farwell, Roger Hohimer, Olli Vuolteenaho, Lowell Davis, Sonnet Jonker University of Oulu, Physiology, Oulu, Finland, Oregon Health and Science University, Obstetrics and Gynecology, Portland, OR, Kuopio University Hospital, Obstetrics and Gynecology, Kuopio, Finland, Oulu University Hospital, Obstetrics and Gynecology, Oulu, Finland OBJECTIVE: Chronically anemic fetuses increase cardiac output by 50%. Anemia-induced cardiac remodeling is associated with diminished isovolumic contraction velocity acceleration (IVCVacc) and isovolumic relaxation velocity deceleration (IVRVdec) in the left ventricle indicating reduced ventricular contractility and relaxation. We therefore sought to determine if there were changes in genes that affect ventricular function in chronically anemic fetuses. STUDY DESIGN: 7 fetal sheep with twin gestations had catheters placed surgically and 1 randomly selected twin was made anemic by daily isovolumic hemorrhage for 8 days. At 126 days gestation echocardiographic studies were performed under anesthesia and tissues from the right (RV) and left (LV) ventricles were obtained. Agilent’s 8x15K Sheep Gene Expression array with greater than 2 fold changes were selected for qRT-PCR. RESULTS: Hematocrit was reduced in anemic fetuses as compared to controls 13.1 (2.5) vs 34.9 (5.2)% means (SD) as well as oxygen content 2.3 (0.4) vs 8.4 (1.7) ml/dl. LV and RV IVCVacc and IVRVdec, and MRNA expression/18s are shown below. All the data are presented as means (SD).* p 0.05. CONCLUSION: Neither changes in -adrenergic receptor 1, phospholamban, nor troponin C account for the decrease in left ventricular contractility and relaxation in anemic fetuses. Increased Tachykinin 1 gene expression through substance P and neurokinin A may be important in mediating decreased ionotropy and lusitropy in chronic fetal anemia.

The fetal aortic isthmus (AoI) is the only arterial connection between the fetal right (RV) and left (LV) ventricles. In LV outflow obstruction, blood from the ductus arteriosus flows retrograde across the AoI to supply fetal brain. We hypothesized that in acute ascending aorta (AA) occlusion (AAO), RV cardiac output would increase and maintain normal arterial pressure in the carotid artery. Nine ewes underwent surgery at 115-135 gestational days (term 145 days) for the placement of a vascular occluder around fetal AA between the aortic valve and brachiocephalic artery. Fetal carotid artery (CA) and jugular vein, and descending aorta (DAo) via femoral artery were cannulated. After a 4-day recovery, fetal heart rate (FHR), right (RVCO) and left (LVCO) ventricular cardiac outputs were measured by ultrasonography. Pulmonary (Qp) volume blood flow and systemic CO (combined cardiac output-Qp) were calculated at baseline, 15 and 60 minutes after AAO, and 15 minutes after release of AAO. Mean arterial blood pressures (mABP) from CA and DAo, central venous (CVP) pressure, and CA pO2 were monitored. All the data are presented as means (SD).* p<0.05, compared with baseline. In fetal sheep, acute occlusion of AA leads to increased RV cardiac output and decreased LV and systemic cardiac outputs, and pulmonary volume blood flow. Fetal arterial blood pressure in the descending aorta is maintained. However, carotid artery blood pressure decreases during AA occlusion. Our results suggest that, at least in acute conditions, retrograde blood flow shunting across AoI is not able to maintain normal cerebral perfusion pressure.Tabled 1