003 1-3998/87/2205-0557$02.00/0 PEDIATRIC RESEARCH Vol. 22. No. 5. 1987 Copyright (c) 1987 International Pediatric Research Foundation. Inc. I'rin!ecl in C' S. .4. Effects of Birth-Related Events on Central Blood Flow Patterns DAVID F. TEITEL, HARRIET S. IWAMOTO, AND ABRAHAM M. RUDOLPH Cardiovascular Research Institute and the Depurrments of'Pediatrics, Physiology, and 0b.srelrics and Reproductive Sciences, Univer.riry ofCa1~fi)rnia.Sun Francisco, Cal/fornin94143 ABSTRACT. We determined the effects of three compo- uptake. The right ventricle ejects about 50% more blood than nents of the birth process on central blood flow patterns in the left ventricle in the sheep fetus (1). As part of the transition fetal sheep. We instrumented 16 fetal sheep at 133.0 f from fetal to neonatal life, these central blood flow patterns 1.2 days gestation, inserting various intravascular cathe- change abruptly. The right to left shunts through the foramen ters, intubating the trachea, and placing an inflatable ovale (2) and through the ductus arteriosus (3) cease rapidly, and balloon around the umbilical cord. After 2-3 days, we a transient left to right shunt occurs until the ductus arteriosus determined central blood flow patterns using radionuclide- closes fully within a few hours after birth (3,4). The two ventricles labeled microspheres under control conditions, during pos- eject the same volumes once the ductus arteriosus does close. itive pressure ventilation without oxygenation, during ven- Associated with the increased oxygen requirements after birth, tilation with 100% Oz, and after umbilical cord occlusion. left ventricular output increases 2- to 21/2-fold (5, 6). The foramen ovale right to left shunt was essentially The specific factors that cause this dramatic change in central abolished, decreasing from 102 f 48 to 66 f 40 ml/min/ blood flow patterns and their timing are not known, because kg with ventilation, and to only 13 f 10 ml/min/kg with birth involves several processes that occur almost simultaneously. oxygenation. The ductus arteriosus right to left shunt Labor, delivery, rhythmic gaseous expansion of the lung (venti- decreased progressively, from a control level of 224 2 64 lation), increased oxygenation, umbilical cord clamping, and to 6 f 10 ml/min/kg after umbilical cord occlusion. A decreased environmental temperature are all components of the ductus arteriosus left to right shunt appeared with oxygen- birth process and each may individually or in concert affect the ation (41 f 26 ml/min/kg) and increased to 65 f 43 ml/ circulation. Previous studies either have compared fetal meas- min/kg after cord occlusion. Left ventricular output in- urements with those obtained postnatally after the entire birth creased progressively as a percentage of combined ventric- process has been completed (6), or have been performed on ular output (from a control value of 34.8 to 59.5% after acutely exteriorized, open-chest sheep fetuses (2, 7-9), in which cord occlusion), and increased absolutely with ventilation cardiovascular responses may be greatly altered (10). A recent (from 134 f 44 to 211 f 87 ml/min/kg). However, right study has investigated the in zttero effects of oxygen ventilation ventricular output decreased (from a control value of 258 on left ventricular output in fetal sheep (I I), but the effects of f 75 to 144 f 36 ml/min/kg after cord occlusion) so that ventilation prior to oxygenation and of umbilical cord occlusion combined ventricular output did not change. Although the were not studied, nor were the changes in right ventricular output transition from the fetal to neonatal circulatory pattern and blood flow through the central shunts. was accomplished by simulating these three components We undertook the present study to determine the sequential of the birth process, none is alone responsible for the large effects of three important components of the birth process: increase in combined ventricular output normally seen at ventilation, oxygenation, and umbilical cord occlusion, on the birth. (Pediatr Res 22: 557-566, 1987) central blood flow patterns in the near-term sheep fetus. We studied chronically instrumented fetuses in ztfero so that the Abbreviation sequential effects of each component could be determined with- out the influence of anesthesia or exteriorization. We defined the CVO, combined ventricular output hemodynamic adjustments that are induced by each of these processes and the subsequent effects that these adjustments have on the central circulation. The adaptation of the fetus to extrauterine life involves nu- MATERIALS AND METHODS merous processes that occur rapidly. Paramount among these is the change in the pattern of circulation of blood. The fetal Animals. Sixteen fetal sheep between 133 and 137 days gesta- circulation is characterized by the presence of central shunts that tion (mean of 135.1 days) were studied 48-72 h after surgery was direct systemic venous return to the systemic arterial circulation completed (performed at 133.0 + 1.2 days gestation). The fetuses (Fig. 1): the foramen ovale directs the more highly oxygenated were of normal weight (3.55 & 0.56 kg) and had normal blood umbilical venous blood from the right atrium to the left heart to gases (Table I) and hemoglobin concentrations (10.9 + 1.6 g/dl) supply oxygen to the heart, brain, and other organs, and the at the onset of the study. ductus arteriosus directs the less oxygenated right ventricular Surgery. The ewe was fasted for 24 to 48 h prior to surgery. output via the descending aorta to the placenta for oxygen Spinal or low epidural anesthesia was achieved with 4 ml of 1 % tetracaine hvdrochloride (Pontacaine HCI. Breon Laboratories. Received September 10, 1986; accepted June 30, 1987. New York, NY), and poliviny~catheters wire inserted in a pedal Correspondence and reprint requests David F. Teitel, M.D.. Room MI327 Box artery and vein for blood sampling and infusion of dextrose 0130, University of California, San Francisco, San Francisco, CA 94143. Supported by an NIH Program Project Grant HL 24056 and NIH Research in 0.9% saline during the surgery. During surgery, 50-loO mg Grant HL 35842. ketamine hydrochloride (Vetalar, Parke-Davis, Moms Plains, 558 TEITEL ET AL. NJ) was administered intravenously to the ewe every 10- 15 min, fluid that may accumulate postoperatively and for drainage of a and 0.25% lidocaine hydrochloride (Xylocaine, Astra Pharma- potential left-sided pneumothorax during subsequent ventilation. ceutical Products Inc., Westborough, MA) was administered The chest was closed in layers. The fetal neck was then exposed locally to the fetus, for additional anesthesia. through the same uterine incision and the trachea was dissected. A midline incision was made in the ventral abdomen and the It was ligated proximally and a 4.5 mm ID tracheal tube was pregnant horn of the uterus was exposed. A fetal hindlimb was advanced just beyond the level of the clavicle. The tube was exposed through a small incision in the uterus, and polyvinyl attached to two 100-cm lengths of 12F polyvinyl tubing using a catheters were placed in the pedal artery and vein and advanced Y connector and all tubes were filled with 0.9% NaCl solution. to the descending aorta and abdominal inferior vena cava re- One tube was sealed to prevent loss of tracheal fluid, and the spectively. A 12F polyvinyl catheter was placed in the amniotic other was connected to the 12F tubing that was placed in the cavity and a multiple side-hole catheter was placed in the umbil- amniotic cavity, to allow tracheal fluid to drain into the amniotic ical vein after exposure ofthe allantoic sac. The skin and uterine cavity. The skin incision was closed. The umbilical cord was incisions were then closed. Through a separate uterine incision, then located at the umbilical ring and a silicone rubber cuff with the left chest of the fetus was exteriorized and a left lateral an inflatable balloon was placed around the cord just distal to thoracotomy was performed in the fourth intercostal space. the abdomen. Antibiotics (600 mg of kanamycin sulfate, Bristol Succinylcholine hydrochloride (Burroughs-Wellcome Co., Re- Laboratories, Syracuse NY, and 1 million U of penicillin G search Triangle Park, NC), in a single dose of 5 mg, was admin- potassium, E.R. Squibb &Sons Inc., Princeton, NJ) were instilled istered intravenously upon exposure of the upper body because, in the amniotic cavity and 0.9% warmed saline was added to despite the anesthesia, fetal breathing can occur when the face is replace loss of amniotic fluid. The uterine incision was closed. exposed to air: inspiration of any air into the alveoli may induce All vascular catheters were filled with heparin sodium (1000 U/ irreversible processes in the lungs that normally occur at birth ml, Organon Inc., West Orange, NJ) and sealed. All catheters and which would invalidate our subsequent study of ventilation. and tubing were exteriorized to the left flank of the ewe and A polyvinyl catheter was placed in the internal thoracic artery protected by a cloth pocket sutured to the skin. The abdominal and advanced to the ascending aorta or brachiocephalic trunk. incision was closed in layers and the ewe was allowed to recover. The pericardium was then opened and Teflon-tipped polyvinyl Antibiotics (600 mg of kanamycin sulfate and 1 million U of catheters were inserted in the left atrium and main pulmonary penicillin G potassium) were administered intravenously to the artery using a special needle-cannula assembly (12). An 8F ewe and into the amniotic cavity daily. polyvinyl catheter was placed in the pleural cavity to drain any Experimental protocol. Four conditions were studied in the following sequence: 1) control, 2) ventilation using a gas mixture with pOz and pCO2 levels equivalent to those in fetal arterial blood, to determine the effects of rhythmic gaseous distension of the lung without oxygenation, 3) ventilation with 100% oxygen (oxygenation), and 4) umbilical cord occlusion during ventilation with 100% oxygen.