Daniel Sidi

Developmental Changes in Myocardial Contractile Reserve in the Lamb

ABSTRACT: We have assessed serial changes in myocardial contractility and reserve in the normal lamb over the first month of life using an in vivo adaptation of the endsystolic pressure-volume relationship. Via a left thoracotomy, we insert a catheter tip pressure transducer into the left ventricle, affix an echo transducer onto the left ventricular epicardium, place an electromagnetic flow transducer around the pulmonary artery, and insert catheters for monitoring and infusions. We measure contractility by generating left ventricular wall stress-volume index (the cube of dimension) curves, at the same time increasing afterload by infusing phenylephrine. The slope of the endsystolic wall stress-volume index relationship is our index of contractility. Weekly studies were performed at rest and during isoproterenol infusion in 12 animals, and after propranolol administration in four. The data showed a progressive decrease in resting contractility but no change in maximal contractility during isoproterenol infusion over the 4 wk. Taking each week separately, the average increase in contractility during isoproterenol infusion was small at 1 wk (13%), moderate at 2 and 3 wk (24 and 26%, respectively), and large at 4 wk (79%). β-Adrenergic blockade with propranolol caused a significant decrease in contractility in three of four animals studied at 1 wk, in only one of four animals at 2 wk, and in none of four animals at 3 or 4 wk. Thus, the newborn lamb shows a limited reserve in contractility that increases progressively with age; the limited reserve appears secondary to a high resting β-adrenergic state.

Comparison of methods of measuring cardiac output in newborn lambs.

Summary: To define agreement between methods, we measured cardiac output (CO) in chronically instrumented lambs by four different methods. In 23 lambs we measured CO simultaneously by the Fick and microsphere methods and with an electromagnetic flowmeter over a wide range of CO (80–454 ml/kg/min) in different experimental conditions on 97 occasions. When the electromagnetic flowmeter was corrected for coronary flow (about 8% of CO) calculated from microspheres, the mean cardiac outputs were almost identical for these three methods (237, 235, and 236 ml/kg X min, respectively). Comparisons between any two of the methods showed a correlation coefficient greater than 0.89. In four lambs, 52 measurements of CO by Fick and thermodilution had a correlation coefficient of 0.94. We conclude that any of the four methods, if appropriately applied, adequately measures CO in a variety of circumstances and may be used with confidence for physiologic or other studies.Speculation: In newborn and young animals cardiac output can be measured with equal accuracy by any of four different techniques when appropriately applied. These methods can be used with confidence in future studies of the newborn circulation.

Effects of ambient temperature on oxygen consumption and the circulation in newborn lambs at rest and during hypoxemia.

Summary: To assess the effects of environmental temperature on responses to hypoxemia, we studied five unsedated lambs in the first week after birth. We catheterized the carotid artery and pulmonary artery (via the jugular vein). After recovery of at least 1 day, we measured pH, blood gases, arterial and mixed venous blood O2 content, oxygen consumption (VO2), heart rate, carotid and pulmonary arterial pressures, and cardiac output in both warm (25°C) and cool (17.4 ± 1.1°C) environments. In the cool environment, with no shivering, VO2 increased 40% (14.9 to 20.8 ml/kg/min). There were also increases of arteriovenous blood O2 content difference of 19%, cardiac output of 18%, and heart rate of 14%. In four lambs, we studied the same variables during hypoxemia (FiO2 = 0.09 for 1 h) at both temperatures. In the cool environment, hypoxemia produced a greater fall of VO2 (26% versus 6%) and arteriovenous oxygen differences (30% versus 19%) and a smaller increase of cardiac output (8% versus 14%) and heart rate (26% versus 43%). Also in the cool environment, core temperature decreased more (2.1 versus 0.4°C), but base deficit was the same (-6 versus −5 mEq/liter). Despite the greater fall in VO2 during hypoxemia in the cool environment, the lowest value achieved was still higher than the level during normoxemia in the warm environment. Similarly, cardiac output during hypoxemia was greater in the cool than in the warm environment. These findings may explain the variability in reported normal resting values and responses to hypoxemia. Contrary to previous reports, they also indicate that during severe hypoxemia neonates have a decreased reserve of metabolic and cardiovascular responses in a cool compared with a warm environment.

Chronic Hypoxemia in the Newborn Lamb: Cardiovascular, Hematopoietic, and Growth Adaptations

ABSTRACT.: We have created a model of chronic hypoxemia in the newborn lamb by decreasing pulmonary blood flow in the presence of an atrial septal defect. Via a left lateral thoracotomy, we place an inflatable balloon around the pulmonary artery and perform an atrial septostomy under direct vision. We also insert several vascular catheters and place an electromagnetic flow transducer around the ascending aorta. Three days after surgery, we inflated the balloon in 11 lambs such that arterial oxygen saturation decreased to 60 to 75%. Studies were performed on these lambs twice weekly and weekly on 12 normoxemic lambs. Growth decreased sharply (47 ± 123 versus 221 ± 82 g/day) at the onset of hypoxemia and remained low, although oxygen consumption followed the normal gradual decline. Heart rate remained elevated throughout the study. Arterial PCO2 levels decreased from 40 ± 5 to 35 ± 7 torr and remained low. Systemic blood flow decreased at balloon inflation but quickly returned to normal. Mixed venous saturation was low, but could decrease further with shivering. Systemic oxygen delivery decreased initially but returned to normal as Hb concentration rose (from 9.4 ± 1.5 to 12.5 ± 2.2 g/dl). P50 increased normally over the study period. Four of the 11 hypoxemic lambs died during the study. These data show that, in the chronically hypoxemic newborn, systemic oxygen delivery is maintained primarily by a rising Hb. Total body oxygen consumption is maintained at rest but is redistributed away from anabolic requirements and toward cardiorespiratory work. This signal to decrease growth occurs despite less than maximal oxygen extraction at rest.

Redistribution of regional blood flow and oxygen delivery in experimental cyanotic heart disease in newborn lambs.

ABSTRACT. Redistribution of regional blood flow is an important compensatory response to acute hypoxemia which preserves oxygen delivery to the most vital organs. It is not known if this change in blood flow persists when hypoxemia is prolonged, as occurs in cyanotic congenital heart disease. Chronic hypoxemia was produced in newborn lambs by creating pulmonary stenosis and an atrial septal defect. Oxygen saturation was maintained at 60- 70% of control for 2 wk. Distribution of cardiac output was then measured with radionuclide-labeled microspheres. As compared with control, chronic hypoxemia did not alter total cardiac output. Regional blood flow was redistributed, however, the pattern of this redistribution was different from that seen during acute hypoxemia. Myocardial and cerebral blood flows, which increase during acute hypoxemia, return to control levels during chronic hypoxemia. Renal, splenic, gastrointestinal, carcass, and skin blood flows remain decreased. Hemoglobin gradually increases so that after 2 wk of hypoxemia total systemic oxygen delivery returns toward control. However, oxygen delivery to all organs except the heart and brain is reduced. Thus, although cardiac output and total systemic oxygen delivery return toward normal during chronic hypoxemia, these measurements may not reflect important regional variations in blood flow and oxygen delivery. Decreased oxygen and substrate delivery to the gastrointestinal tract, liver, and carcass may account for the alterations of metabolism and growth seen in the newborn with cyanotic congenital heart disease.

Recovery of Cardiovascular Function in Newborn Lambs after Thoracotomy

Summary: Knowledge of the quality and speed of recovery after thoracotomy is crucial for studies of the early changes in cardiovascular function in the neonatal period. We studied the early recovery period after thoracotomy with pericardiotomy, but without ventriculotomy, in 21 lambs operated on between 2–24 days after birth. In 15 lambs, we measured resting pH, PaO2, PaCO2, O2 consumption, cardiac output, heart rate, and aortic and pulmonary arterial pressures, before and after thoracotomy, daily for 1 wk. We found that, except for PaO2 (82 versus 87 torr), all variables returned to normal by the third day after thoracotomy. Four lambs were exposed to hypoxia (FIO2 0.09 for 1 h) before and 3 days after thoracotomy; hypoxia-induced changes were not different at the two different periods. Six other lambs, undergoing thoracotomy within the first 3 days after birth and exposed to hypoxia on the third postoperative day, had hypoxia-induced responses similar to six age-matched nonthoracotomized lambs. These findings indicate recovery of cardiovascular function by 48–72 h after thoracotomy. We believe, therefore, that reliable studies of the circulation in lambs are possible as early as 3–4 days after birth, even if thoracotomy is required for making measurements.Speculation: Thoracotomy, often required for the study of cardiovascular function, has adverse effects for a certain period of time. In newborn and young animals this period is only 2-3 days, thereby permitting essentially uninterrupted longitudinal studies despite thoracotomy.

Effect of |[beta]|-Adrenergic Receptor Blockade on Responses to Acute Hypoxemia in Lambs

ABSTRACT: We studied the effects of β-adrenergic receptor blockade on general circulatory and metabolic responses to moderate (FIO2 = 0.09) acute hypoxemia in newborn (protocol 1) and 3-wk-old (protocol 2) lambs, and on regional blood flow distribution in newborn lambs (protocol 1). Via a left thoracotomy we placed an electromagnetic flow transducer around the ascending aorta and inserted various vascular catheters. After 2 days of recovery, the lambs were studied. In protocol 1, we measured cardiovascular variables and regional blood flow distribution during control conditions, after 45 min of acute hypoxemia, and after 0.5 mg/kg of propranolol during acute hypoxemia. In protocol 2, we measured cardiovascular variables during control conditions and after 45 min of acute hypoxemia with and without propranolol pretreatment. In both groups, propranolol limited the increase in cardiac output and heart rate caused by hypoxemia, and thus decreased oxygen delivery. However, propranolol also decreased oxygen consumption so that pulmonary arterial pO2 was either higher (protocol 1) or the same (protocol 2) as during acute hypoxemia alone. Neither metabolic acidosis nor hypothermia ensued. In protocol 1, propranolol decreased renal, carcass, and most importantly, myocardial blood flows. However, myocardial O2 consumption also fell, coronary sinus pO2 increased, and blood was redistributed toward the subendocardium, suggesting that myocardial perfusion improved. Thus, β-adrenergic receptor blockade during acute moderate hypoxemia may have a beneficial effect by reducing total body and myocardial oxygen demand in excess of the reduction in oxygen delivery.

Experimental Cyanotic Heart Disease in the Newborn Lamb

Cyanotic congenital heart disease is the most common cause of chronic hypoxemia in infancy and young childhood. Many forms are complex and are not readily amenable to early surgical correction or alleviation of the hypoxernia. The aberrations of normal function caused by chronic hypoxemia must be understood so that we may attenuate its impact as the patient awaits surgical correction. It was our purpose to create a model of cyanotic heart disease in the newborn lamb and to describe its effects on cardiovascular function, hematopoiesis, and growth.

Regional Blood Flow Distribution Oxygen Delivery in Chronically Hypoxemic Newborn Lambs

Redistribution of blood flow is an important circulatory adjustment to acute hypoxemia. When arterial oxygen content is decreased, the subsequent increase in cardiac output is insufficient to maintain total body oxygen delivery. Redistribution of flow occurs mediated by local autoregulation, chemo- and pulmonary stretch receptor-mediated vasoconstriction, and central pressor mechanisms [1]. Oxygen delivery is thus preserved to the most metabolically active organs. Studies in the anesthetized adult dog have demonstrated both an increase in absolute flow and percent distribution of flow to the myocardium and brain and a decrease in flow to the gastrointestinal tract and renal and musculoskeletal beds during acute hypoxemia [2]. Others have demonstrated a similar pattern of flow redistribution in the nonanesthetized newborn lamb, and they have shown them to be independent of postnatal age (Figure 1) [3, 4].

1426 EFFECTS OF AMBIENT TEMPERATURE ON CIRCULATION AND O 2 CONSUMPTION (VO 2 ) IN NEWBORN LAMBS, AT REST AND DURING ACUTE HYPOXIA

To assess the effects of environmental temperature on the response to hypoxia in neonates, we studied 5 unsedated lambs in the first week after birth. We catheterized the carotid artery (CA) and pulmonary artery (PA) (via the jugular vein). After at least one day, we measured pH, blood gases, arterial and mixed venous O2 content, VO2, heart rate (HR), CA and PA pressures, and cardiac output (CO) in both warm (W) (25°C) and cool (C) (17.4 ± 1.1°C) environments. In C, with no shivering, VO2 increased 40% (14.9 to 20.8 ml/kg/min) and arteriovenous O2 content difference (A-V) 19%, CO 18%, and HR 14%. In 4 lambs, we studied the same variables during hypoxia (FIO2=0.09 for 1 hr) at both temperatures. In C, hypoxia produced a greater fall of VO2 (26% vs. 6%) and of A-V (30% vs. 19%) and a smaller increase of CO (8% vs. 14%) and of HR (26% vs. 43%); in C, core temperature decreased more (2.1° vs. 0.4°), but base deficit was the same (-6 vs. -4.5 meq). Despite the greater fall in VO2 during hypoxia in C, the lowest value achieved was still higher than that in W, even during normoxia. Similarly, CO during hypoxia was greater in C than in W. These findings may explain variabilities reported in normal resting values and responses to hypoxia. They also indicate that, contrary to previous reports, during severe hypoxia neonates have a decreased reserve of metabolic and cardiovascular responses in a cool compared with a warm environment. (Supported by NIH grant HL 23681.)