Management Issues for the Neonatal Patient

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MANAGEMENT ISSUES NEONATAL PATIENT Frank W. Bowen, MD

The primary purpose of the immediate management of the neonatal patient is to preserve function and physiology during the transition from the fetal to the neonatal state. The second purpose is to stabilize and assess systems that have sustained injury and to create a management plan and environment that allow continued organ system support. Specifically, our objective is to assist the transition from fetal to adult type circulation, stabilize organ systems, assess function, and establish a therapeutic environment that is effective in a managed care system. The health care system and our function within it are in such transition now that discussions that relate to physiology and function must include factors of resource use and management process. Methods and techniques that are not amenable to data processing are being replaced by sophisticated new models. Clinical observations require biochemical justification. This article reviews areas of physiology as they relate to concepts of perinatal asphyxia, resuscitation, and stabilization. It looks into the need for new assessment techniques and how those would relate to emerging psychosocial and legal issues. The whole healthcare system is changing, and we must grasp this opportunity for change. All components of the system are affected. The central theme is that our capability of processing at multiple levels has expanded in the realm of medical informatics. Now relationships will be as important as specifics.

From the Department of Pediatrics and Obstetrics, Thomas Jefferson University College of Medicine, and Newborn Pediatrics, Pennsylvania Hospital, Philadelphia, Pennsylvania

CLINICS IN PERINATOLOGY VOLUME 23 •NUMBER 1•MARCH1996

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FACTORS RELATED TO BIRTHING

Humans have had almost 4.5 million years to perfect the birthing process. 155 By this time, it seems logical to assume that the normal human fetus is designed to withstand a normal labor and delivery and result in a healthy mother-infant pair in the vast majority of instances. The premise of this introduction is that the biologic processes exist to allow for the variability of gestation and the labor process to proceed in a normal manner. In other words, a need for resuscitation equates to pathology in the mother, the infant, the placenta, the labor, or a combination of those factors. To define this process in terms of physiology, it is necessary to understand gas transport across the placenta and the physiology of that transport. The factors involved are those that are primarily maternal, those that are placental/ fetal, and those that are related to the labor process.

MATERNAL-FETAL GAS TRANSPORT

The mother and fetus are unique in physiology because their gas transport depends on a blood-blood interface in the placenta. The current theory of intervillous placental blood flow allows a maximum interface of maternal and fetal blood as well as the time necessary for effective equilibration of partial pressure of oxygen (Po2), partial pressure of carbon dioxide (Pco2 ), and pH.11 8 , 134 The maternal compensated respiratory alkalosis of pregnancy allows a net flow of C02 from the fetus to the mother, which maintains fetal Pco2 values in the 35 to 40 mm Hg range. C02 transfer across the placenta largely is based on the difference between maternal and fetal arterial partial pressure of carbon dioxide (Paco2 ) values. The rapidity of transport allows the process to be flow independent. 159 The transfer of 0 2 from mother to fetus depends on the transfer of 0 2 from maternal hemoglobin to fetal hemoglobin. This process is relatively slow and therefore is sensitive to flow differences. The other major factor affecting maternal-fetal 0 2 transfer is the magnitude of the affinity difference between the maternal and fetal oxygen half-saturation pressure of hemoglobin (P-50) values (d P-50). Shifts in the dissociation curves relative to each other affect the d P-50 and therefore the amount of 0 2 available for transport. 96 The normal d P-50 in vivo-approximately 6 mm Hg-is caused by differences in active maternal and fetal red blood cell 2,3-diphosphoglycerate (2,3-DPG). The lower level of 2,3-DPG found in fetal red blood cells results in increased fetal hemoglobin 0 2 affinity. This increased affinity effectively moves the fetal hemoglobin dissociation curve to

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the left of the mother's, thereby allowing 0 2 transport from maternal hemoglobin to fetal hemoglobin at any given Po2 . 10• 153 The Haldane and Bohr effects further increase the Li P-50 at the placental interface. The Haldane effect involves the release of C02 from fetal blood, shifting the fetal P-50 to the left, increasing its 0 2 affinity, while the simultaneous uptake of C02 and hydrogen (H+) by maternal hemoglobin shifts that P-50 to the right (Bohr effect). The net effect is a widening of the P-50 gradient to as high as 10 to 12 mm Hg, which enhances 0 2 release from maternal to fetal hemoglobin and results in highly saturated fetal hemoglobin at low Po2 values (20-30 mg Hg) (Fig. 1).79, 107 This increase in Li P-50 allows a larger quantity of 0 2 to be transferred at low gradient levels. Such a shift is important because a P-50 of 6 mm Hg is insufficient for 0 2 transport that would allow fetal hemoglobin saturation at levels high enough to meet fetal 0 2 needs. It, therefore, is the combination of Haldane and Bohr effects that permits efficient gas exchange between maternal and fetal blood by causing P-50 shifts at the interface that result in an increased distance between the respective hemoglobin dissociation curves. 11 The 2,3 DPG gradient is the baseline on which the Bohr and

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0 2 Transfer capability with Bohr/Haldane at interface

P50

Shift due to Maternal C02 uptake Hemoglobin Saturation

Figure 1. Bohr and Halden effects at interface.

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Haldane effects enhance gas transport and maintain a significant P-50 gradient despite changes in maternal and fetal Pco2 and pH values. If the fetus and maternal P-50s move in the same direction, the ~ P-50 remains constant and 0 2 transport therefore is maintained. This concept of maternal-fetal (M-F) P-50 movement is significant because the position of the hemoglobin dissociation curve (P-50) is significantly affected by pH and Pco2 changes. The first stage of labor is associated with both the development of progressive maternal metabolic acidosis and maternal hyperventilation, with Pco2 decreasing to 20 to 30 mm Hg. The acidosis develops rapidly because it is superimposed on a low bicarbonate (Hco3 -) reserve because of chronic compensation for the respiratory alkalosis of gestation. The combined effect in the first stage of labor results in a decrease in pH in the mother. Fetal pH also decreases in the first stage of labor, presumably because of decreased placental perfusion secondary to uterine contractions. The M-F P-50 gradient is maintained, however, because both dissociation curves are displaced to the right in a parallel fashion. 5 The second stage of labor results in an increase in maternal Pco2 and a consequent decrease in maternal pH that is associated with a continuing fetal acidosis because of the obligate fetal Pco2 increase as well as continuing inhibition of placental perfusion. The M-F dissociation curves, therefore continue to shift in parallel so the P-50 gradient and, therefore, 0 2 transport is preserved (Fig. 2).5 • 47• 82• 115 At the same time, maternal and fetal Pco2 are rising, creating the fetal ventilatory drive soon to be needed. The use of analgesia in labor abolishes the maternal metabolic acidosis without decreasing fetal acidosis. Normalization of maternal pH at this stage of labor should allow M-F P-50 curves to approach each other. The maternal pH will increase because of hyperventilation (P-50 shift to the left) and the fetal pH should decrease because of fetal metabolic acidosis (P-50 shift to the right). The resultant decrease in the M-F P-50 gradient could decrease 0 2 transport to the fetus. 47• 142 We studied this potential issue as a single-masked, prospective controlled study. Pregnant women in labor following a normal full-term (38-40 weeks) pregnancy had a maternal venous blood specimen drawn within 1 minute of delivery. An umbilical cord venous blood specimen was drawn from a doubly clamped cord within 1 minute of delivery. Patients either received or did not receive analgesia according to the obstetric plan. The patients were placed in the analgesia group if they received analgesia within 2 hours of onset of the second stage of labor and passed an effectiveness test. The specimens were collected by one of the investigators and were coded and processed by an independent laboratory technologist who determined paired values of hemoglobin, hematocrit, Pco2, pH, Hco3 - , Po2 , and P-50. The results were withheld

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P50

Hemoglobin Saturation

P,02

Figure 2. Maternal-fetal P-50 shift in normal labor.

from the investigators until the study conclusion (total n = 20 in each group). P-50 was measured on a hemox-analyzer. Four samples, all in the analgesia group, were inadequate for analysis, leaving 16 patients in the analgesia group and 20 patients in the control (no analgesia) group. The analgesia group received the following medications: 11 epidural, one spinal, two pudendal, two narcotic (neperidine). There were no differences between the groups for gestational age, 1- or 5-minute APGAR scores, gender, weight, maternal factors (age, parity, race, socioeconomic status), or neonatal outcome (discharge diagnosis). The results of the laboratory analyses of the two groups are presented in Table 1. Chi-squared analysis revealed that there were no differences between groups regarding maternal venous C02, fetal umbilical vein C02 , and fetal umbilical vein P-50. We found significant decreases in maternal pH in the no analgesia group, fetal pH in the analgesia group, maternal P-50 in the analgesia group, and the M-F gradient in the analgesia group. The expected occurrence in the nonanalgesic group was a parallel movement of the M-F curves, with preservation of the baseline reported in vitro /J,. P-50 of approximately 6 mm Hg. By abolishing the maternal

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Table 1. RESULTS OF LABORATORY ANALYSES OF TWO GROUPS

No Analgesia

n = Gestational age 1-min Apgar Maternal pH Maternal Pvco2 Fetal pH Fetal UV Pco2 Maternal P-50 Fetal P-50 Delta P-50

39 8.2 7.37 34 7.33 37 24.3 19.7 4.61

16 ± ± ± ± ± ± ± ± ±

0.16 0.3 0.07 2.7 0.04 3.1 0.08 0.05 0.61

Analgesia

Significance

20 ± ± ± ± ± ± ± ± ±

NS NS NS p <0.01 NS P<0.01 NS p <0.05 NS p <0.01

39 8.1 7.31 31 7.38 39 26.7 20.2 6.42

0.4 0.5 0.06 1.7 0.04 2.6 0.06 0.03 0.41

NS = No statistical difference; Pvco, = venous carbon dioxide pressure; UV Pco, = umbilical vein partial pressure of carbon dioxide; P-50 = oxygen half-saturation pressure of hemoglobin.

acidosis and fixing the position of the maternal curve in the analgesia group, a narrowing of baseline d P-50 was observed because of the obligate acidosis of the fetus in labor. The baseline on which 0 2 transport is dependent therefore is observed to be significantly decreased in this clinical situation. The observed decrease ind P-50 may have decreased 0 2 transport from mother to fetus, which could account for the lower fetal pH (metabolic acidosis) seen in the analgesia group. If so, these data would support a hypothesis that the maternal acidosis of labor is a physiologic protective mechanism that assures adequate 0 2 transport to the fetus across a blood-blood interface when one of those blood volumes (the fetal) is subjected to an obligate acidosis. The lack of clinical correlate (neonatal asphyxia) in the analgesia group probably is related to the study design, which preselected a population of healthy mothers with term pregnancies and normal prenatal fetal test results; basically, a fetal-placental unit with physiologic reserve. A study of complicated pregnancies, especially those with uteroplacental insufficiency, is in process. This study allowed us to conclude that analgesia in the first stage of labor decreases the metabolic acidosis of labor in the mother; that the position of P-50 of the maternal hemoglobin dissociation curve is affected by maternal acid-base status in the first stage of labor; and that there is a significant decrease in the M-F P-50 gradient when maternal acidosis is abolished in the first stage of labor. Of greater import is the understanding that C0 2 and 0 2 transport between mother and fetus is controlled by placental and maternal fetal blood flow factors prior to the onset of labor. Abnormalities in fetal oxygenation prior to labor should be centered around factors that affect maternal placental perfusion, placental health, and the matching of fetal and maternal blood flow at the intervillous interface. Any factor that

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decreases the matching of fetal and maternal flow at interface will result in a physiologic shunt. The result will be a transient decrease in oxygen transport with subsequent compensation; the reserve of the whole system is decreased, however. In a chronic situation, the reserve continues to be decreased until critical levels are reached. The point of expression depends on the stress imposed on the system. Once labor stress begins, the factors controlling gas transport are related to those that influence the Bohr and Haldane effects on M-F P50 values at interface. In other words, those factors that influence maternal pH and Paco2 and those that influence fetal pH and Pco 2 become the key factors. Our study showed that there can be an effect on gas transport in healthy pregnancy without an acute clinical correlate. This finding supports a reserve, in that the hemoglobin saturation exceeds the basal needs of the fetus and an acute decrease in oxygenation that does not descend below basal needs is not associated with signs. The obvious hypothesis is that a similar insult in a compromised fetus may result in a clinical correlate. The concept fits the observation that asphyxia becomes apparent in only an already compromised fetal-placental unit in the absence of markedly abnormal labor. That signs of asphyxia appear, relates to the fact that the compromise has had the opportunity to become symptomatic (measurable and observable) under a stress that would not injure an intact fetal unit.

Metabolism and Asphyxia Another explanation is available that may compliment these observations: Except in the extreme setting, it is not the oxygen decrease but, rather, the results of that decrease that cause damage. This hypothesis relates the concept of oxyradical generation and oxyradical-mediated injury. Extremely premature ( <32 weeks' gestation) infants are susceptible to several illnesses related to increased oxyradical (OH-) production. These include retinopathy of prematurity (ROP), necrotizing enterocolitis (NEC), respiratory distress syndrome (RDS), bronchopulmonary dysplasia, intracranial hemorrhage (ICH), and sepsis. 78 Furthermore, there is increasing evidence that the central nervous system damage related to "perinatal asphyxia" is an oxyradical-mediated event. 83, 156 These illnesses frequently occur as temporal clusters in the same patient and, together, account for approximately 90% of the morbidity and mortality related to prematurity. They are, however, quite unusual in the term infant without signs of perinatal asphyxia. OH- are extremely reactive molecules produced naturally by all

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humans through several well-recognized reactions. 34, 35, 61 In the fetalneonatal patient, the most potent OH- producer is the xanthine oxidase reaction, which requires a combination of hypoxemia and reoxygenation to occur (reaction 1; Fig, 3). 124 The result of this reaction is the generation of OH- radicals that interact with lipid membranes of cells, resulting in a biomechanical injury that interferes with normal membrane kinetics. The damage is manifest by loss of membrane active transport and cellular death or, as in the case of the vascular system, a loss of integrity. 61 This mechanism of injury results in differing clinical lesions in each affected organ system, In the immature retina, the damage is manifest as increased gap junctions, resulting in inhibition of normal vasoproliferation and the clinical disease ROP. Some stage of ROP occurs in 90% of infants of fewer than 28 weeks' gestation. 70 In the gastrointestinal system, the damage results in cell death, which may not result in clinical findings. In the intestine, however, cellular injury may cause loss of the intraluminal barrier and subsequent bacterial invasion, The resultant interstitial infection and edema may cause necrosis (NEC) either directly because of endotoxins or secondarily because of pressure effects. 42, rns, 140, 144 The pulmonary, intracranial (ICH), cardiac and septic results are all related to the unique metabolically active capillary vasculature of the preterm infant. Highly metabolic cells produce large quantities of adenosine triphosphate and, therefore, have the greatest substrate adenosine monophosphate; for the xanthine oxidase system following a period of relative hypoxemia. Paradoxically, these highly active cells are most susceptible to possible OH- radical production and damage. 44, 61 , 67, n, 83 Damage to the vascular system in these critical areas results in the clinical syndromes of RDS and ICH. Sepsis is lethal through the mecha-

Xanthine

deh~fle Xanthine

oxidase

Hypoxanthine ~--~~-~ OH"+

Uric Acid

(

02 ----Reperfusion ____..

Figure 3. Reaction 1.

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nism of vascular also secondary to OH- radical because of the direct effect of lysosome release that follows the loss of membrane integrity. There are three defense mechanisms against OH-. These defenses are enzymatic, physiologic, and biochemical. The enzymatic system consists of the intracellular enzymes superoxide dismutase (SOD) and glutathione peroxidase, as well as the extracellular enzyme catalyase. The physiologic defense consists largely of the ability to preferentially shift blood flow to areas of hypoxemia (diving seal reflex) to maintain cerebral flow in the face of systemic hypotension (autoregulation). The biochemical system consists of a complex system of OH- scavengers that have differing sites of action. The most significant of these seem to be the vitamins E and A, the amino acid taurine, and the natural metabolite bilirubin. 34, 35, 49, 72 The fetus is in a constant oxic steady state in utero, with little oxyradical production. The extremely premature infant is relatively deficient in all three defenses compared with the full-term infant. SOD, glutathione peroxidase, and catalase are decreased to absent in all infants in proportion to their level of maturity. Autoregulation of blood flow (especially cerebral) and the diving seal reflex are diminished similarly. Data show that there is a rapid development of the antioxidant enzyme systems in the last 10% of gestation (36+ weeks). 49 Vitamins E, A, and C and taurine levels are normal but tissue stores are extremely low, resulting in rapid depletion following birth. Taurine is supplied through colostrum and breast milk, where it is found in high concentrations. Bilirubin is low but rises rapidly following birth, reaching peak levels at 3 to 5 days in the absence of significant asphyxial process. 93 In such instances, the consumption of bilirubin is increased. 12 The birth process, however, is characterized by an obligate hypoxemic episode (labor and delivery) followed by reperfusion (resuscitation or onset of ventilation). 107 This sequence triggers the xanthine oxidase system and the production of large quantities of OH- .114 In the term fetus, the combined defenses usually are sufficient to scavenge these reactive particles. Because the extremely preterm infant lacks such defenses, he or she is especially susceptible to biophysical OH- damage and the consequent disease processes. Recent data have demonstrated that early use of the antioxidants vitamin E and taurine have decreased the incidence and severity of the oxidant-related disease, ROP. 75 Currently, there are no methods available to induce enzymatic or physiologic maturation. There also exists a large quantity of experimental data in animals and humans concerning the ability to medically block OH- production. Allopurinol competes with hypoxanthine (reaction l; see Fig. 3) in the xanthine oxidase to inhibit uric acid and OH- production. 34• 35• 61 • 70 This

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medication has been used for many years in the treatment of gout, malignancy, and renal failure. 14 Allopurinol also is part of the treatment of pre-eclampsia or malignancy in the second and third trimesters of pregnancy. 39, 99, 121 Several studies have not shown any deleterious effects on the fetus. 20 , 53, s4, no, 13o, 148, 149 There are anecdotal data documenting normal growth and development of progeny for 22 years following maternal allopurinol treatment in the second and third trimesters of pregnancy (Rainey NB, personal communication, 1994). Data based on use of allopurinal to treat preterm infants with RDS have shown a statistically significant reduction in both mortality and duration of ventilator need. There were no adverse side effects in the more than 150 infants who received allopurinol. 17- 19 The unifying concept presented here is that 0 2 transport from mother to fetus is a physiologically controlled process designed to be maintained in the presence of blood gas and pH changes that are present in normal labor. Second, the generation of an oxyradical surge is a normal accompaniment of the birthing process and that the intact term fetus is designed to be antioxidant sufficient. The natural hypothesis is to study the antioxidant sufficiency of infants who are most susceptible to an asphyxia! injury. These approaches are in process at several centers and hold forth a potential for detecting the injured fetus, providing a therapeutic intervention prior to labor and delivery, and, finally, allowing for a treatment modality that is based on the causative process.

ADVERSE BIRTH OUTCOMES

The outcome that every delivering person (either parent or health care provider) dreads is one that results in a severely brain-injured infant. This result is what all the fetal assessment, all the monitoring, and the high cesarean rate is all about. This dreaded outcome is the factor all try to prevent. The specific lesion is termed hypoxic-ischemic encephalopathy. 106 The term implies a combined cause involving a decrease in both 0 2 availability and perfusion. The extent and type of lesion, the signs of impairment, and the outcome pattern vary greatly with gestational age, cause, and complicating issues. 147, 150 The more preterm the infant, the greater the frequency of intraventricular/periventricular hemorrhage. Both preterm and term infants share focal neuronal necrosis and periventricular leukomalacia. Ischemic brain necrosis and parasagittal injury are seen almost exclusively in term and post-term infants. It is virtually impossible to see tissue hypoxia without some ischemia in a clinical situation. Indeed, it seems that hypoxemia alone (as seen in congenital heart disease) does not produce a specific brain lesion.

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Ischemia, however, cannot exist without distal tissue The two therefore are thought of as etiologic partners, with ischemia being the more prominent of the two. This is particularly true in the term infant and is defined as the watershed phenomenon. This situation is particularly prominent in the neonate because of decreased numbers of anastomoses in the brain, allowing for a "distal drying" to occur in the presence of significant hypotension. 88• 89 The currently accepted pattern of events begins with an event or events that produce hypoxia, hypercarbia, acidosis, and hypotension. Because the fetus and neonate have a decreased autoregulatory response to hypotension, the decreased pressure results in decreased brain blood flow. If this loss of flow is significant, then an ischemic area may occur. 88• 89 Damage may be sustained either directly or indirectly at this time. Direct damage may be caused by cell death; indirect damage may be caused by an oxyradical surge following a reperfusion event The type of lesion may be focal, general, or related to subsequent bleeding into an area of necrosis. In any event, the resolution phase begins with edema followed by healing, in the form of either scar formation or cystic change. The lost neurologic elements are not replaced. Neuronal loss also initially may equate with connection loss. Connection loss, however, has a greater potential for recovery. 46• 89 Several factors must be considered in this scenario. First, the insult must be of sufficient depth or duration to overcome compensatory or autoregulatory mechanisms. In other words, the hypoxemia must have a sufficient combination of time and severity to produce subsequent ischemia. 46 Second, the biochemical lesions generated must be capable of causing cellular injury and overcoming biochemical defense mechanisms. These lesions include the areas of oxyradicals, psychoactive amine production, intercellular toxins, or lack of compensatory defenders. Finally, the susceptibility of various cell types and their connectors must be considered. The process of injury is complex and much remains to be discovered. One can appreciate that a simple equation of decreased oxygen for a few moments equaling brain damage represents naive thinking. 56• 90• 92 Finally, the degree of damage may not be evident at the time of initial examination. The damage signs may be quite remote to the injury event and may be dependent on the proper environmental circumstances. This concept means that timing an event that presents at birth may be virtually impossible-it may have occurred acutely, may have occurred over multiple episodes of time, or may have been remote and not manifest until the relative stress of labor allows visualization of signs. 9o, 128 The clinical syndrome of hypoxic-ischemic encephalopathy is a

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balance between the extent of the lesion and the compensatory ability of the infant. When the lesion is extensive, the signs progress rather rapidly over the first hours following birth. The resuscitation usually requires extensive intervention and the infant's assessment reveals a comatose or poorly responsive infant. Brainstem function usually is intact. This comatose time is followed by increased alertness usually characterized by abnormalities in state change and habituation. The next, and often definitive, sign is the onset of seizures, which may begin subtly, as apnea or irritability. Seizures are thought to be coincident with cerebral edema and an effect rather than a cause of damage. The seizures usually remit but may be quite resistant to anticonvulsant agents in their acute phase. Over the next several days, specific neurologic deficits occur, usually in cranial nerve function and muscle tone. These signs probably will evolve and be replaced buy other specific (hearing, sight) and nonspecific (spasticity, cerebral palsy syndrome) signs as the infant ages. Less extensive lesions result in a moderation of this described course, even to the extent of being so subtle as to be missed. This problem may be more significant in these days of rapid discharge and decreased observation time. 89

Management There is no definitive treatment that can prevent or reverse the damage seen in hypoxic-ischemic encephalopathy. Current therapy is supportive of compromised organ systems, careful fluid management, and symptomatic support. Phenobarbital and indocin may have efficacy in decreasing the incidence of intracranial hemorrhage. 32' 101 Oxyradical research seems to offer the most promising direction for prevention and treatment for the future.

ACUTE MANAGEMENT ISSUES REGARDING DELIVERY

Resuscitation Immediate neonatal management issues include resuscitation and stabilization efforts. The results of resuscitation lead to the process of stabilization, which leads to the process of assessment. The assessment process is a definitive part of the ongoing management of the neonate, in either the well infant or delivery room setting. Resuscitation is the process that converts the infant from fetal to adult type circulation. The mechanics of the resuscitative process are

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based on the physiology of the fetal circulation and the factors necessary to accomplish the conversion to adult-type circulation. The mechanics of resuscitation are well defined in the American Academy of Pediatrics/ American Heart Association neonatal resuscitation manual and certification course, to which the reader is referred. 16 The fetus must maintain fetal circulation to survive and to use the placenta as an organ of gas exchange. Fetal circulation is defined as a circulatory system that shunts blood away from the lungs and to the placenta. The fetal vessels needed for this process are the umbilical/ placental vessels and the ductus arteriosus, in conjunction with the foramen ovale and the ductus venosus. The circulatory system must be maintained despite changes that may occur in blood gas, pH, and pressure status. The circulatory dynamics therefore must include factors that depend on both flow and resistance. Furthermore, these factors must be reversible within minutes of delivery in a manner that could not (or only rarely) occur in utero. 134 Oxygenated blood returning from the placenta and lower body of the fetus is preferentially shunted across the foramen ovale to the systemic circulation. Blood returning from the fetal head crosses the tricuspid valve and is pumped out the pulmonary artery (PA), where 90% of the right heart output crosses the patent ductus arteriosis and enters the systemic circulation. Only 10% of cardiac output enters the pulmonary circulation. The cause of this right-to-left shunt is an elevated pulmonary resistance caused by alveolar capillary vasoconstriction and pulmonary arteriolar vasoconstriction. The two sites are sensitive to different physiologic parameters. The arteriolar circulation is sensitive to pulmonary artery oxygen pressure (PPao)z, PPaco2 , and pH; the capillary bed is sensitive to Pao 2 • This critical juncture, therefore, is doubly protected from change in utero. Even if PPao 2 , PPaco 2, or pH changed sufficiently to decrease PA pressure, the capillary backup system would remain intact. 134 The aortic circulatory pressure is lower than the pulmonary pressure, allowing a pulmonary-to-aorta flow across the ductus because the PA resistance is elevated and the aortic resistance is decreased. The aortic resistance is low because it includes the umbilical circulation. The placental lakes represent a huge cross-sectional area of very low resistance. Furthermore, the umbilical arteries are not catecholamine, Pao 2, Paco 2, or pH sensitive. The epinephrine surges accompanying labor contractions therefore do not result in increased aortic resistance and a change in ductal shunting. Not surprisingly, the umbilical arteries (not the veins) are sensitive to light and cold. The low pulmonary blood flow results in a decrease in left atrial (LA) return and low left atrial pressure. The right atrium (RA), however,

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receives return from the placenta and the entire fetal body. The RA flow and pressure therefore exceed the LA flow and pressure and the foramen ovale, which opens into the LA, remains open. It is not until flow changes occur that the pressure changes can result in foramen closure. The fetal circulat!on, therefore, is perfectly positioned to remain fetal throughout pregnancy and the changes of labor. It takes air in the lungs and blood gas changes to allow a decrease in pulmonary resistance, and delivery of the cord to allow an elevation in aortic resistance. Finally, the atrial pressures are flow dependent and cannot change without changes in aortic and pulmonary blood flow. The change from fetal to adult type circulation depends on decreasing pulmonary pressure and raising aortic pressure, which result in increased pulmonary blood flow and increased LA pressure, with closure of the foramen ovale. The coordination of resistance dependent events and flow dependent events allows the criteria of preservation of the fetal circulation in the face of physiologic flux and the rapid changes needed at the time of delivery. With this understanding, the process of resuscitation becomes clear. Resuscitation begins with the delivery of the cord and the contracture of the umbilical arteries. These events decrease placental blood flow and raise aortic pressure. The pulmonary squeeze accompanying the delivery of the chest allows the evacuation of pulmonary fluid and the elastic recoil stimulates stretch receptors, allowing the filling of alveoli within two to three breaths. The abrupt rise in PAo2 results in capillary dilation and filling with an abrupt decrease in pulmonary resistance. The decrease in PA pressure results in increased pulmonary circulation and a reversal of the ductus shunt, allowing blood with a high Pao2 to perfuse the pulmonary arterioles, resulting in a further drop in PA pressure and a second increase in pulmonary blood flow and subsequent LA flow. The increased LA flow and pressure reaffirms foramen ovale closure. The circulation, within a minute or two, has converted from fetal to adult. Most of the time, the fetus can accomplish this event without our assistance. 2 • 67 Occasionally, some help from a friend is needed. The key to the establishment of this cascade is the filling of alveoli with air. 67 This process is called ventilation. The establishment of ventilation is essential to the conversion to adult circulation. The entire resuscitative effort, therefore, is geared toward the establishment of ventilation. 67 Because neonates have a paradoxical Head's reflex (raising pharyngeal pressure causes a gasp response), they tend to respond well to bag and mask ventilation. If, however, there is significant central nervous system depression, then intubation and direct positive pressure ventilation are indicated. The measure of the effectiveness of ventilation is the maintenance of a normal heart rate and the characteristic pink flush of the conversion from fetal to adult circulation.

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Once ventilation has been accomplished, then the secondary factors that affect vascular resistance or flow may be addressed. The factors affecting vascular resistance relate to vascular integrity and the degree of oxyradical damage that has occurred; vascular responsiveness, again related to injury; and, finally, pump function. The factors that relate to flow primarily are volume factors. The umbilical vein does not contract as do the arteries on exposure to cold or light. 11 • 134 This vascular patency allows the flow of placental blood to the fetus until the central venous pressure of the fetus equals the column of fluid between the fetus and the placenta (about 10-15 cm in the normal human squat for birthing). The continuance of flow allows the filling of the previously empty pulmonary vascular space. In the absence of the placental transfusion, the fetus can use the increased interstitial fluid volume to provide a vascular fill that is sustaining, except in the face of oxyradical injury that results in vascular leakage. In such cases, specific fluid management is essential.

Stabilization

Once the conversion to adult type circulation has occurred, the next management step is designed to maintain that state. The circulatory changes are fragile. The anatomic closures of the ductus arteriosis and the foramen ovale have not yet occurred. The neonate is at risk for a resumption of fetal circulation if there is an increase in pulmonary resistance or pressure and decrease in aortic resistance or pressure. The process called stabilization occurs over the next several hours and is designed to assess and manage the factors that could result in a physiologic change that would allow a resumption of fetal circulation. The areas of concern include maintenance of blood gases (ventilation), intravascular volume, thermoneutrality, and fluid and electrolyte status, and infection control. Because the pulmonary vasculature is sensitive to blood gas changes, abnormalities in the pulmonary examination deserve high priority. The neonate whose lungs have been fluid-filled must establish a functional residual capacity, develop pulmonary mucus and a low airway resistance, and establish a ventilation/perfusion (V /Q) match. This transition time is a time of instability. 112 There can be significant changes in blood gases in response to irregular ventilation, and increased work of breathing and the mismatch of ventilation and perfusion. Observation systems should allow for rapid detection of abnormality. Compliance problems appear as grunting, rapid respirations. Neonates with increased airway resistance have slow, noisy respirations. V /Q mismatch most often is manifest by clinical central cyanosis.

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The vascular filling depends on whether placental transfusion was adequate or whether there is evidence of a significant vascular leak. The mode of delivery will speak to the absence or presence of a placental transfusion. Any situation that requires cord clamping before the onset of ventilation is without a transfusion. In the absence of other illness, these infants usually are able to call on reserves and will not need additional intravenous fluids. One should be cognizant, however, that the normal weight loss may not be accomplished without difficulty in this population of infants and they well may need supplemental fluid feeds in the first day or two following delivery. There may be a vascular leak in infants who have sustained significant asphyxia! injury. 40, 76 They frequently are symptomatic at the time of delivery, with apnea. Cord ligation after ventilation therefore, is not practical, so the compound problems of decreased vascular volume and leakage may present together. These infants need intensive management of vascular volume to prevent the development of blood gas and pH abnormalities that may trigger reversion to fetal circulation.116 Temperature regulation is a significant issue for the neonate, an obligate homeotherm. The newborn spends calories to maintain body temperature. Because the neonate's mass is small in comparison with its surface area, there is significant cold stress surrounding the time of delivery. Cold exposure triggers a release of norepinephrine, which releases brown fat for metabolism. This highly active substance consumes large quantities of 0 2 and results in acidic end products. The result of significant cold stress can be a metabolic acidosis that results in pulmonary vasoconstriction and a need to hyperventilate for compensation. If ventilation is compromised, then the inability to compensate may increase the acidosis and result in a cycle of pulmonary vasoconstriction, leading to ventilator compromise, leading to more acidosis, leading to more constriction and, eventually, to reversion to fetal circulation.116 Part of the resuscitation process therefore, is to create an environment conducive to temperature maintenance at minimal metabolic cost. Such environments include decreasing sources of heat loss such as evaporation (drying the infant), conduction (with warm blankets), convection (with air flow monitoring), and radiation (with warming apparatus ).116 The fetus has received all nutrients and fluids intravenously for 9 months. Birth is associated with an abrupt discontinuance of that intravenous flow. The infant now must regulate fluid balance, electrolytes, and glucose metabolism. The one of these that may result in significant illness is glucose metabolism. Infants who are predisposed to hypoglycemia usually are those who have had a hyperglycemic gestation, such as that seen in the diabetic syndromes or, increasingly, with the use of

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diabetogenic tocolytic agents. Hypoglycemia, if it occurs, will occur within 2 hours in over 80% of affected infants. Infants with low glycogen stores (growth-retarded or with metabolic diseases) may present days later, or after a significant feeding interval. Part of the stabilization process for infants at risk includes glucose surveillance. The infant with hypoglycemia and increased activity to seizures has an increased 0 2 requirement and, with apnea may have decreased delivery, leading to an acidotic state.11 6• 117 Additional significant attention must be paid to renal function and maintenance of urine output. The kidney is a target organ in perinatal asphyxia that has easily measured effects. Loss of renal function currently equals loss of the infant. 73 • 113 Finally, infection control is still a significant issue for the neonate. The infant is born in an immune-compromised state, primarily in the aspects of nonspecific humerol immunity. The chemotactic factors of complement are relatively deficient, so the neonate cannot confine infection well and generally develops sepsis as a manifestation of infection. Further, barrier antibody, immunoglobulin A, must be derived from breast milk, so exposure to bacteria that otherwise would not pass the barrier defense may occur in the infant who does not receive fresh, frequent breast milk feeds. This group, unfortunately, includes almost all severely compromised infants. 57• 58• 6s, 87 Attention to these parameters as part of the immediate management allows identification of the infant who needs additional attention. That attention should be rapid and specific. Sufficient stabilization can prevent illness that accompanies instability and create a more stable sick patient who is better able to be managed for specific illnesses. The presenting physiology will be that of a disease process rather than a nonstabilized infant.

Assessment

Assessment of neonatal status is a continuation of the stabilization process. The concept is to evaluate each organ system as to function and relative maturity. This assessment process begins with the birth event, with the Apgar assessment, and moves through the physical and neurologic evaluation, the gestational age assessment, and, finally, the emerging field of psychobiology. Further detailed predictive analysis needed to satisfy the requirements of care mapping and managed care plans has led to the development of combined scoring systems. Two are the Score for Neonatal Acute Physiology (SNAP) and the Clinical Risk Index for Babies (CRIB) assessments.11 9 The Apgar assessment, done at 1 and 5 minutes postbirth, has been

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the classic assessment of newly born infants. The score has been related to asphyxia and prognostic data but currently is receiving a critical reevaluation.15, 74' 97 The predictive value, either as a measure of asphyxia! injury or as a predictor of poor neurologic outcome, has flaws of both a specificity and sensitivity nature. 122, 129 Salamalekis126 found that a normal nonstress test was of adequate specificity to predict an Apgar score greater than 7 but was insufficiently sensitive to be reliable as a correlate alone. Likewise, Manganaro 95 found the 1-minute Apgar score to be more specific for mode of delivery than for evidence of asphyxia. Socol136 found the complexity of the neonatal course as being more specific for poor neurologic outcome than the acid-base status of the Apgar score at birth. Marrin's review of pertinent literature of Apgar scores97 reveals that the score has poor specificity and sensitivity as a measurement of the degree of asphyxia! insult. These data should not be surprising. The Apgar score at 1 minute measures the clinical response to delivery, the ability of the central nervous system (CNS) to receive and send, and the biochemical integrity of the myocardium. Further, it tells the resuscitator the level of vigor needed in the resuscitative process. Apgars of less than 3 indicate a depressed CNS and a need for controlled ventilation, usually with bag and tube. Higher scores indicate a more intact CNS and the ability to respond to stimuli and have a responsive reflex system. The score is nonspecific, however, in that anything that can depress the CNS can produce a decrease in score.11 6 The 5-minute score is not sensitive because it can mean either that the infant is so depressed that response to resuscitation was not forthcoming, that depression was transient and resuscitative efforts were inadequate, that the depression is caused by some other factor that would be addressed as part of stabilization or assessment and not in the first 5 minutes following delivery, or, finally, that the cause of depression was totally unrelated to the APGAR and the resuscitative mechanism. Such an example was reported by Sakala and Henry,1 25 who found higher 5-minute Apgar scores when the father was present in the delivery room. Finally, the dilemma this assessment produces centers about whether it measures a depression caused by perinatal events or records that which was previously not seen because the measurement tools are too imprecise. Several investigators have found poor correlation between perinatal events, fetal testing, and low Apgar scores. In addition, low Apgar scores, in the absence of neonatal illness, do not seem to differentiate the neurologically handicapped. The prevailing data seem to indicate that fetuses who are compromised prior to labor tend to have symptoms at birth that are measurable in the immediate

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neonatal period. This concept has led to a more detailed method of measurement.7· 119• 120• 138 Scoring systems such as SNAP and CRIB have developed in parallel with computerized systems of medical informatics. Computerized systems have allowed the coordination of resource use and morbidity and mortality in a mathematically predictable manner.7· 119• 12°· 138 In addition, Bard7 has been able to develop a predictive model based on Baysean analysis that allows for detailed interhospital and interphysician management and outcome parameters. Stevens and Richardson,1 38 using similar analyses, have correlated predictive indices with clinical judgment. These concepts are integral to the process of cost-driven health care reform. The central care theme is care mapping or critical pathway development. Care mapping is a standardized method of approaching complex illness that allows for several branch therapies at critically predefined nodes. The nodal points are well defined and adapt to pointof-service multidisciplinary input. Further, these decision nodes lie on paths that define the domains and resources needed to pass from node to node. The probability of a given output, the resources needed, the health care input, and the efficacy of procedures or tests all can be subjected to Baysean risk/benefit analysis.3°. 31 · 43· 91. m. 146· 15s. 160 For care mapping to be a functional tool, there must be a consistent evaluative input point and standardized data collection analysis and decision making. The critical factors that relate to these performance spots are computer-assisted assessment, point-of-care service, empowerment of multidisciplinary team care models, and institutional medical informatics systems. This is a new area of medicine that is critical to the progress of neonatal care. Its detail is beyond the scope of this article, however, and the reader is urged to follow up with the cited textual material. 45 The emerging field of psychobiology assessment of the neonate is beginning to offer a new avenue of evaluation. 137 This field measures behavioral interaction as distinct from primitive reflex measurement, which is a hallmark of gestational assessment. These tests can define patterns of "normal" that vary across gestational ages and alertness states. These evaluations have grown out of the recognition of the neonatal alertness states of dream and nondream sleep, quiet, and active alert. The Brazelton evaluation looks at both stimulus-response and habituation and rate and degree of change between alertness states. 21 · 22 The concept of psychobiology defines these behaviors as learned responses superimposed on a developing central input-output system. The concept is that at term delivery, the neonate has multiple interconnections between brain processing centers. In essence, the baby can hear tastes, smell sights, and the like. This state originally leads to a general-

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ized stimulus-response cycle that, on repetition, begins to establish pathways of preference. The repetition leads to a specificity of behavior. The rapidity of this development, the factor of critical windows, the relation of this phenomenon to "learning," and the relation to environmental issues in neonatal care are fascinating. 60 This area clearly is one that will be receiving significant attention.

PSYCHOSOCIAL ISSUES SURROUNDING THE BIRTHING PROCESS

The birthing process has more emotion attached to it than most human endeavors. The psychological measurement of our personhood is tied to our ability to father and to birth a healthy child. The rituals of birth, the activities of the parents, and the management of the infant have origins in our most sacred and aged beliefs as humans. Yet, across centuries and cultures, mothers and infants behave and interact in remarkably similar fashions. 55, 152 The rules for birth have changed over the centuries. The birthing process used to be the domain of women. The father, siblings, and other family males were abolished from the environment and not welcomed back until the event was completed, and then for only a short time. The next 2 to 6 weeks were devoted to mother and child. The other family females cared for the mother, the household, the other children, and the father. The mother's time of confinement had come and her only task was to be a mother. During this time of bonding and attachment, certain rituals occurred, such as naming the child and circumcision.86 How we have changed. Now the birthing process is a family event. The process frequently is filmed lest we forget the happenings. Fully more than 20% of our deliveries are operative. The hospital confinement is a brief day. Legislation was required to allow a time of parenting to occur. There may or may not be other female support for the mother-more often the couple is encouraged to manage on their own. 109 The bottle has replaced the breast as a means of nourishment. The state wants our name before we leave the hospital. Circumcision routinely is done within hours of birth and for rather loose medical indications. 3 , 154 Attachment and bonding are parts of the birthing process and are critical to the health of a land. The birthing is characterized by a grief reaction over the loss of the mind's eye image-the imagined child. Bonding, a hormonally driven nonspecific process, prevails over the first few days; attachment, the more powerful specific psychological process, takes weeks. As the grief is processed through the stages of denial, shock, anger, and depression, the mother's needs are supported by her

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colleagues. The depressive time that requires detachment can be processed before the resolution and the new attachment occurs. 59• 135 Attachment is specific and lasting. It is the psychological antithesis of the detachment of the depressive phase of a grief reaction. If we do not create an environment that allows women to complete their grieving process, we create disorders of attachment. At the extreme, these are abuse and neglect. At the least, they may be parenting disorders. We must learn to include this important part of the birthing process as part of our immediate management.4· 27, 4s. s1, 63, so. 10s. 141

Issues

Several neonatologists surveyed revealed that over 70% of legal consultation cases were for so-called perinatal asphyxia. Lawyers advertise in journals and even on CompuServe and the internet for experts to review "bad baby" cases. 36 Understanding the causes of this litigation and the case law is important. Health care professionals may not have the power to reform of the tort system of the United States, but by understanding the dynamics of the legal system, we may be able to discourage suits that have little basis in science. 25 • 54• 161 Several publications point to poor doctor-parent communication as the leading cause of lawsuits. The nature of the poor communication often is the development of untrue expectations or unsolicited remarks in an emotionally charged atmosphere. If one accepts the two major psychological concepts of normal birthing-being central to one's personhood and the existence of a grief reaction in association with both normal and abnormal delivery-then the reasons for anger at communication or outcome become clear. 26· 66· 77 These unmet expectations may be especially true in these times of marketed "high-tech" saves. 123 If a baby is born damaged or sick and having a healthy infant is a measure of one's personhood, then fertile ground exists for the development of guilt and self blame on the part of the parent. Psychologically, the fetus and immediate newborn are part of the self. When the outcome is poor, therefore, the guilt is self-directed, something that is quite painful. In fact, we use defense mechanisms to lessen the pain of self guilt. Some defenses, like denial, are quite effective temporarily. Others, like reaction formation and projection, allow us to place the guilt somewhere other than on ourselves. Like many defense mechanisms, they are effective while reality processing is occurring. If, however, the dynamic of the grief reaction, blocked by the negative effect of guilt on attachment, stalls at the phase of anger I depression, then projection allows us to transfer the

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responsibility of guilt to hospitals, doctors, nurses, or any other individual who had a role in the birthing process. The reality processing and associated pain is postponed. Finally, the defense mechanism is reinforced by the legal system, which seeks to obtain retribution for the great wrong that has been inflicted.* The parents' real need is psychological assistance rather than legal assistance, but the legal system, designed as adversarial, is the perfect mechanism to play out the anger and projection. The process, fraught with argument, blame, and ritual, is the perfect stage. Unfortunately, when the process is resolved, regardless of the outcome, the original guilt remains, with the original anger. A new target is needed and the field has narrowed to the child and the spouse or significant other. The defense has become pathologic. The carnage of post-trial divorce, abuse, and violent action is quite astounding, but not unexpected under the circumstances. In addition, the damage of litigation is not confined to the patient/litigant but also significantly affects the delivery system and defendants.13, 94, 104, 127, 14s Medical practice law is defined by both state and federal regulation. The areas of significance are the Medical Practice Act of the state, the state criminal code, state regulatory agencies, federal statutory law, and federal regulatory agencies. Also involved are previous court decisions that impact legal interpretation, which are termed common law. The type of process used depends on the jurisdiction of the case or individual (federal, state, local), the venue or which court system is to be used (e.g., civil, criminal), and the choice of law (federal, state, statute, regulatory).100 With all these factors and the constantly changing face of the law, it is no wonder that the legal process must split hairs and demand definitions and the drawing of lines that at times seem obtuse and inappropriate. To the law, this is acceptable because, in the future, if the lines need redrawing, they can be redrawn in court to fit new logic and presumed ethics of that time and venue. Lawyers understand this flux and change process and base their practice on the interpretation of the constant change taking place. Physicians and scientists have a difficult time with such flux 102; we are used to the concept of scientific proof and empirical process. Malpractice litigation focuses on the tort system or the court designed to right an accidental wrong (accidental as being not consciously intentional). For a legitimate tort complaint to prevail, one must prove that there was an implied duty to act in a reasonable manner in the circumstances that were present, that the person did act differently from reasonable, that a injury did occur, and that the action/inaction did *References 9, 14, 37, 38, 41, 62, 65, 85, 103, 143, 151, 157.

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cause the injury. The big issues are those that define the standards of practice and determine causation. 100 The proof of those two factors often involves the testimony of experts. The court and state determine the definition of an expert. Our expert system has resulted in a large, lucrative practice of expert testimony that has little regulation from a scientific point of view. This situation offends physicians but is entirely consistent with the adversarial and common law context of tort thinking. 23, 28, 52, 64, 98, 131, 133, 139 Detractors argue that the tort system primarily rewards the attorneys, takes up to 40% of a plaintiff's settlement, is scientifically unresponsive, and is inappropriately adversarial. Shifting medical malpractice from tort to contract law has been proposed. To have a contractual complaint prevail, there must be a demonstrated contractual duty, a demonstrated breech of that duty, a demonstrated injury, and proof that the breech caused the injury. The system is similar to the tort process but contract law allows binding arbitration and does not depend on adversarial litigation. Such a concept of legal reform is based on the ethic that the patient and physician and health care organization have a contract regarding obligation to provide certain services for remuneration. Those who advocate this system point to the huge costs of litigation and "legal medical practice" that occurs. An arbitrative system would address the injury aspect and could refer any punitive professional issues to the appropriate forum. 1' 6, 8, 24, 5o, 81 The problem, of course, is that neither venue addresses the underlying psychological issue. Both methods purport to address the issue of poor medical practice but remove the discipline from the profession itself. Finally, tort procedures are considerably more lucrative for the legal profession (both plaintiff and defendant) than are contract procedures. Stay tuned, this issue is not yet resolved.

CONCLUSIONS AND THE FUTURE

The birthing process will continue to be an emotion-laden event with a unique physiology. Our ability to measure this physiology is increasing immensely. As we increase our knowledge of the medicine of cellular injury and apply methods to prevent circumstances from occurring, we hope to have a lessened need for treatment. The concepts of gas transport and oxyradical metabolism are important areas of investigation. Potential effects of psychobiology on the healing process and as a diagnostic tool are of immense importance. The obligation of other professions to move beyond the literal and punitive toward the curative is essential. Perhaps, though, one of the most significant changes is being caused

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by, as well as facilitated by, the computer. Medical informatics are changing what we can do and will do at an exponential pace. We now can manage huge cause-related studies with relational databases. Telemedicine for treatment or academics is a reality. Computer-driven use based on on-line expert systems is available. The integrated medical record is on the horizon. Use of the powerful new mathematic, CHAOS theory, holds great promise in the study of feedback systems from the molecular to the population level. We are developing the capability for integrated care systems that apply Baysean concepts to utilization and quality control. Our systems of care are allowing for a point-of-care multidisciplinary interaction through which we will be able to tune the care to individual needs by using sophisticated care mapping and domain analysis. The point is that all that has been written here today is on the threshold of magnificent change that will result in new abilities to provide excellence. Grasping this change as we continue to tackle the daily realities of birth is the challenge.

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16. Bloom RS, Crophy C: Textbook of Neonatal Resuscitation. American Heart Association, American Academy of Pediatrics, Chicago, 1990 17. Boda D: Role of hyperuricaemia in critically ill patients especially newborns. Acta Pediatr Hung 25:23, 1984 18. Boda D, Nemeth L: Effect of parenteral allopurinol treatment in critically ill children in need of intensive care. Acta Pediatr Hung 24:247, 1983 19. Boda D, Nemeth I, Hencz P, et al: Effect of allopurinol treatment in premature infants with idiopathic respiratory distress syndrome. Dev Pharmacol Ther 7:357, 1984 20. Bragonier RK, Roesby N, Carver MJ: Teratogenesis: Effects of substituted premises and the influence of 4-hydroxy pyrazolopyrimidine in the rat. PSEBM 116:685, 1964 21. Brazelton TB: Neonatal Behavioral Assessment Scale. Philadelphia, JB Lippincott, 1973 22. Brazelton TB: Infants and Mothers. New York, Dell Publishing, 1983 23. Brennan D: The role of the expert at trial. Br J Anaesth 73:98, 1994 24. Brennan TA: Practice guidelines and malpractice litigation: Collision or cohesion? J Health Polit Policy Law 16:67, 1991 25. Brown BS, Faulknier TE: Injured Infants Act: Study compares definition, newborn records. Va Med Q 116:114, 1989 26. Burstin HR, Johnson WG, Lipsitz SR, et al: Do the poor sue more? A case-control study of malpractice claims and socioeconomic status. JAMA 370:1697, 1993 27. Calkins SD, Fox NA: The relations among infant temperament, security of attachment, and behavioral inhibition at 24 months. Child Dev 63:1456, 1992 28. Capron AM: Facts, values, and expert testimony. Hastings Cent Rep 23:26, 1993 29. Carter BS, Haverkamp AD, Merenstein GB: The definition of acute perinatal asphyxia. Clin Perinatal 20:287, 1993 30. Cesta TG: The link between continuous quality improvement and case management. J Nurs Adm 23:55, 1993 31. Chen FG, Khoo ST: Critical care medicine-a review of the outcome prediction in critical care. Ann Acad Med Singapore 22:360, 1993 32. Chen HJ, Roloff DW: Routine administration of phenobarbital for the prevention of NH in premature infants: 5 years experience. J Perinatal 14:15, 1994 33. Clark DA, Hakanson DO: The inaccuracy of Apgar scoring. J Perinatol 8:203, 1988 34. Cohen G, Greenwald RA (eds): Oxyradicals and their Scavenger Systems: Cellular and Medical Aspects. New York, Elsevier Biomedical, 1983 35. Cohen G, Greenwald RA (eds): Oxyradicals and their Scavenger Systems, vol 1: Molecular Aspects. New York, Elsevier Biomedical, 1983 36. Compuserve: Legal forum, 1995 (Personal observation) 37. Condon JT: Medical litigation. The aetiological role of psychological and interpersonal factors. Med J Aust 157:768, 1992 38. Conner GK, Denson V: Expectant fathers' response to pregnancy: Review of literature and implications for research in high-risk pregnancy. J Perinat Neonatal Nurs 4:33, 1990 39. Connon AF, Wadsworth RJ: An evaluation of serum uric acid estimations in toxaemia of pregnancy. Aust J Obstet/Gynecol 8:97, 1968 40. Cornfield DN, Stevens T, McMurtry IF, et al: Acute hypoxia causes membrane depolarization and calcium influx in fetal pulmonary artery smooth muscle cells. Am J Physiol 266:469, 1994 41. Costello A, Gardner SL, Merenstein GB: Perinatal grief and loss. J Perinatal 8:361, 1988 42. Crissinger KD, Burney DL, Velasquez OR, et al: An animal model of necrotizing enterocolitis induced by infant formula and ischemia in developing piglets. Gastroenterology 106:215, 1994 43. Crummer MB, Carter V: Critical pathways-the pivotal tool. J Cardiovasc Nurs 7:30, 1993 44. Cutler RG: Aging and oxygen radicals. In Taylor AE, Matalon S, Ward PA (eds): Physiology of Oxygen Radicals. Bethesda, MD, American Physiological Society, 1986 45. Dubowitz LMS, Dubowitz V, Goldberg C: Clinical assessment of gestational age in the newborn infant. J Pediatr 77:1, 1970 46. Ellenberg J, Nelson KB: Cluster of perinatal events identifying infants at high risk of death or disability. J Pediatr 113:546, 1988

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47. Fleischer A, Schulman H, Jagani N, et al: The development of fetal acidosis in the presence of an abnormal fetal heart rate tracing. Am J Obstet Gynecol 141:55, 1982 48. Fox NA, Kimmerly NL, Schafer WD: Attachment to mother I attachment to father: A meta-analysis. Child Dev 62:210, 1991 49. Frank S, Sosenko IRS: Development of lung antioxidant enzyme system in late gestation: Possible implications for the prematurely born infant. J Pediatr 100:1, 1987 50. Freeman AD, Freeman JM: No-fault cerebral palsy insurance: An alternative to the obstetrical malpractice lottery. J Health Polit Policy Law 14:707, 1989 51. Freiberg S, Adelson E, Shapiro V: Ghosts in the nursery: A psycho analytic approach to the problems of impaired mother-infant relationships. J Am Acad Child Psychiatry, 1975 52. Frickleton J, Bartimus J: Antagonist: The trial lawyer's defense of the expert witness. J Lab Clin Med 124:157, 1994 53. Fujii T, Nishimura H: Comparison of teratogenic action of substances related to purine metabolism in mouse embryos. Jpn J Pharmacol 22:201, 1972 54. Giacoia GP: Low Apgar scores and birth asphyxia: Misconceptions that promote undeserved negligence suits. Postgrad Med 84:77, 1988 55. Giblin PT, Poland ML, Waller JB Jr, et al: Correlates of neonatal morbidity: Maternal characteristics and family resources. J Genet Psychol 149:527, 1988 56. Gilstrap LC III, Leveno KJ, Burris J, et al: Diagnosis of birth asphyxia on the basis of fetal pH, Apgar score, and newborn cerebral dysfunction. Am J Obstet Gynecol 161:825, 1989 57. Glezen WP: Epidemiological perspective of breastfeeding and acute respiratory illnesses in infants. Adv Exp Med Biol 310:235, 1991 58. Goldfarb J: Breast feeding. AIDS and other infectious diseases. Clin Perinatol 20:225, 1993 59. Grace JT: Development of maternal-fetal attachment during pregnancy. Nurs Res 38:228, 1989 60. Greenough WT: Experience effects on the Developing and Mature Brain: Dendriditic Branching and Synaptogenesis. In McGaugh JL, Fentress JC, Hegmann JP (eds): Perinatal Development: A Psychobiologic Perspective. New York, Academic Press, 1987 61. Grisham MB, McCord J: Chemistry and cytotoxicity of reactive oxygen metabolites. In Taylor AE, Matalon S, Ward PA (eds): Physiology of Oxygen Radicals. Bethesda, MD, American Physiological Society, 1986 62. Harr BD, Thistlethwaite JE: Creative intervention strategies in the management of perinatal loss. Matern Child Nurs J 19:135, 1990 63. Harris ES, Weston DR, Lieberman AF: Quality of mother-infant attachment and pediatric health care use. Pediatrics 84:248, 1989 64. Hull CJ: The expert report. Br J Anaesth 73:93, 1994 65. Hunfeld JA, Wladimiroff JW, Passchier J, et al: Reliability and validity of the Perinatal Grief Scale for women who experienced late pregnancy loss. Br J Med Psychol 66:295, 1993 66. Huycke LI, Huycke MM: Characteristics of potential plaintiffs in malpractice litigation. Ann Intern Med 120:792, 1994 67. Heinel LA, Rubin S, Rosenwasser RH, et al: Leukocyte involvement in cerebral infarct generation after ischemia and reperfusion. Brain Res Bull 34:137, 1994 68. Henson LA, Jalil F, Ashraf R, et al: Characteristics of human milk antibodies and their effect in relation to the epidemiology of breast feeding and infections in a developing country. Adv Exp Med Biol 310:1, 1991 69. Hill A, Volpe JJ: Perinatal asphyxia: Clinical aspects. Clin Perinatol 16:435, 1989 70. Hittner HM, Godio LB, Speer ME, et al: Retrolental fibroplasia: Further clinical evidence and ultrastructural support for efficacy of vitamin E in the preterm infant. Pediatrics 71:423, 1983 71. Hsu K, Wang D, Wu SY, et al: Ischemia-reperfusion lung injury attenuated by ATPMgC12 in rats. J Appl Physiol 76:545, 1994 72. Huxtable RJ: Physiological actions of taurine. Physiol Rev 72:101, 1992

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