Perinatal physiology Neonatal physiology and pharmacology

1. Perinatal physiology Neonatal physiology and pharmacology Dr. Poonam Patel University College of Medical Sciences & GTB Hospital, Delhi www.anaesthesia.co.in

2. Definitions Perinatal period: The perinatal period commences at 22 completed weeks (154 days) of gestation (the time when birth weight is normally 500 g), and ends seven completed days after birth. (WHO - World Health Organization). Neonate: 1-30 days old

3. Perinatal physiology • The circulatory system is the first to achieve a functional state in early gestation • The developing fetus outgrows its ability to obtain & distribute nutrients and O2 by diffusion from the placenta • The functioning heart grows & develops at the same time it is working to serve the growing fetus • At 2 months gestation the development of the heart and blood vessels is complete • In comparison, the development of the lung begins later & is not complete until the fetus is near term

4. Fetal Circulation Placenta • Gas exchange • Waste elimination • O2 saturation of ~65% in maternal blood, but ~80% in the fetal umbilical vein (UV) • Low affinity of fetal Hb for 2,3-DPG as compared with adult hemoglobin • Low concentration of 2,3-DPG in fetal blood • O2 & 2,3-DPG compete with HbF for binding, the reduced affinity of HbF for 2,3-DPG causes the HbF to bind to O2 tighter • Higher fetal O2 saturation

5. Fetal Circulation • P50 is 27mmHg for adult Hb, but only 20mmHg for fetal Hb • This causes a left shift in the O2 dissociation curve

6. Fetal Circulation

7. Fetal Circulatory Flow • Starts at the placenta with the umbilical vein • Carries essential nutrients & O2 from the placenta to the fetus (towards the fetal heart, but with O2 saturated blood) • The liver is the first major organ to receive blood from the UV • Essential substrates such as O2, glucose & amino acids are present for protein synthesis • 40-60% of the UV flow enters the hepatic microcirculation where it mixes with blood draining from the GI tract via the portal vein • The remaining 40-60% bypasses the liver and flows through the ductus venosus into the upper IVC to the right atrium (RA)

8. Fetal Circulatory Flow • The fetal heart does not distribute O2 uniformly • Essential organs receive blood that contains more oxygen than nonessential organs • This is accomplished by routing blood through preferred pathways • From the RA the blood is distributed in two directions: • 1. To the right ventricle (RV) • 2. To the left atrium (LA) • Approximately 1/3 of IVC flow deflects off the crista dividens & passes through the foramen ovale of the intraatrial septum to the LA

9. Flow then enters the LV & ascending aorta • This is where blood perfuses the coronary and cerebral arteries • The remaining 2/3 of the IVC flow joins the desaturated SVC (returning from the upper body) mixes in the RA and travels to the RV & main pulmonary artery • Blood then preferentially shunts from the right to the left across the ductus arteriosus from the main pulmonary artery to the descending aorta rather than traversing the pulmonary vascular bed • The ductus enters the descending aorta distal to the innominate and left carotid artery • It joins the small amount of LV blood that did not perfuse the heart, brain or upper extremities

10. The remaining blood (with the lowest sat of 55%) perfuses the abdominal viscera • The blood then returns to the placenta via the paired umbilical arteries that arise from the internal iliac arteries • Carries unsaturated blood from the fetal heart • The fetal heart is considered a “Parallel” circulation with each chamber contributing separately, but additively to the total ventricular output • Right side contributing 67% • Left side contributing 33% • The adult heart is considered “Serial”

13. Transitional & Neonatal Circulation • Successful transition from fetal to neonatal circulation requires 1. Foramen Ovale, ductus arteriosus & ductus venosus close to establish a heart whose chambers pump in series rather than parallel 2. Removal of placenta 3. Decrease in PVR: The principal force causing a change in the direction & path of blood flow in the newborn

14. Transitional & Neonatal Circulation Changes that establish the newborn circulation are an “orchestrated” series of interrelated events • As soon as the infant is separated from the low resistance placenta & takes the initial breath creating a negative pressure (40-60cm H2O), expanding the lungs, a dramatic decrease in PVR occurs • Exposure of the vessels to alveolar O2 increases the pulmonary blood flow dramatically & oxygenation improves

15. Transitional & Neonatal Circulation • The pulmonary vasculature of the newborn can also respond to chemical mediators such as Histamine Acetylcholine Prostaglandins **All are vasodilators • Hypoxia and/or acidosis can reverse this causing severe pulmonary constriction

16. Transitional & Neonatal Circulation • PVR & PAP continue to fall at a moderate rate throughout the first 5-6 weeks of life then at a more gradual rate over the next 2-3 years • Most of the decrease in PVR (80%) occurs in the first 24 hours & the PAP usually falls below systemic pressure in normal infants • Babies delivered by C-section have a higher PVR than those born vaginally & it may take them up to 3 hours after birth to decrease to the normal range

18. Closure of the Ductus Arteriosus,Foramen Ovale & Ductus Venosus

19. Ductus Arteriosus • Closure occurs in two stages • Functional closure occurs 10-15 hours after birth • This is reversible in the presence of hypoxemia or hypovolemia • Permanent closure occurs in 2-3 weeks • Fibrous connective tissue forms & permanently seals the lumen • This becomes the ligamentum arteriosum

20. Foramen Ovale • Increased pulmonary blood flow & left atrial distention help to approximate the two margins of the foramen ovale • This is a flap like valve & eventually the opening seals closed • This hole also provides a potential right to left shunt • Crying, coughing & valsalva maneuver increases PVR which increases RA & RV pressure • A right to left atrial shunt may therefore readily occur in newborns & young infants

21. Foramen Ovale • Probe Patency • Is present in 50% of children < 5 years old & in more than 25% of adults • Therefore, the possibility of right to left atrial shunting exists throughout life & there is a potential avenue for air emboli to enter the systemic circulation • A patent FO may be beneficial in certain heart malformations where mixing of blood is essential for oxygenation to occur such as in transposition of the great vessels

22. Ductus Venosus • After the placenta is separated , blood passing through the ductus venosus is suddenly reduced causing passive closure over the next 3-7 days

23. Changes in the lung after delivery Fluid compressed from fetal lung during vaginal delivery establishing lung volume  first breath initiated centrally secondary to arousal from sound, temperature changes and touch central chemoreceptors stimulated by hypoxia and hypercarbia further increase respiratory drive  initial respiratory efforts generate large negative intrapleural pressure (-70 mm Hg)  recruitment of alveoli with assistance of surface tension lowering properties of surfactant alveolar fluid is cleared through upper airway  residual fluid cleared over 24- 72 hours by transcapillary and translymphatic route  initially expiration is active with pressures of 18-115 cm H2O generated forcing amniotic fluid from the bronchi.

24. Neonatal Physiology Nervous System: • Soft pliable cranium with two open fontanelles • Structurally complete brain but incompletely myelinated (till 2 years of age). • Predominant brain constituent in neonate is water. During infancy myelin and protein content increases. • Spinal cord ends at L4

25. Blood brain barrier is immature in the neonate till 6 months of age allowing easy access to large lipid soluble molecules like anaesthetic drugs and free bilirubin. • Brain increases in size by 3 times during first year of life, producing high metabolic demand. In neonate one third of cardiac output perfuses the brain as compared to one seventh in adult • Cerebral blood flow  neonate – 30- 40 ml/ 100gm / min Adult – 55 ml/100 gm / min Children – 65- 100 ml/ 100gm /min

26. Cerebral blood flow is autoregulated in neonate upto mean arterial pressure of 30 mmHg. • Autonomic responses better developed to protect against hypertension as parasympathetic system predominates. • Neonates have neural and neuroendocrine mechanisms for perception of noxious stimuli as early as 6 weeks after gestation.

27. Respiratory physiology Respiratory rhythm generated in ventrolateral medulla and modulated by central chemoreceptors in response to carbon dioxide, ph and oxygen content in the blood. Peripheral chemoreceptors are located in aortic and carotid bodies  functional at birth  initially silent because of high post delivery blood oxygen content  receptor adaptation occurs over 48 hours.

28. Ventilatory response to carbon dioxide • CO2 levels   alveolar ventilation  response increases with gestational age and postnatal age. • Resting CO2 levels are lower than in adult • Ventilatory response to CO2 reaches adult value by 2 years

29. Ventilatory response to hypoxemia • During first 3 weeks  temperature dependant. • Hypothermia  hypoxemia decreases ventilation • normothermia  hypoxemia causes transient hyperventilation via peripheral chemoreceptors that is followed by a decrease in ventilation • At the end of first month  response is independent of temperature  hypoxemia increases alveolar ventilation

30. Breathing Patterns of Infants • Less than 6 months of age • Predominantly abdominal (diaphragmatic) and the rib cage (intercostal muscles) contribution to tidal volume is relatively small (20-40%) • In preterm neonate  periodic breathing pattern with occasional episodes of apnea (5-15 secs)  prolonged apneic episodes cause bradycardia and hypoxemia

31. Anatomic Differences in the Respiratory System • Upper Airway: the nasal airway is the primary pathway for normal breathing • During quiet breathing the resistance through the nasal passages accounts for more than 50% of the total airway resistance (twice that of mouth breathing) • Except when crying, the newborns are considered “obligate nose breathers” • This is because the epiglottis is positioned high in the pharynx and almost meets the soft palate, making oral ventilation difficult • If the nasal airway becomes occluded the infant may not rapidly or effectively convert to oral ventilation • Nasal obstruction usually can be relieved by causing the infant to cry

32. The Tongue: is large & occupies most of the cavity of the mouth & oropharynx • Pharyngeal Airway: is not supported by a rigid bony or cartilaginous structure • Is easily collapsed by: • The posterior displacement of the mandible during sleep • Flexion of the neck • Compression over the hyoid bone

33. Laryngeal Airway: this maintains the airway & functions as a valve to occlude & protect the lower airway • In the infant the larynx is located high (anterior & cephalad) opposite C-4 (adults is C-6) • The body of the hyoid bone is between C2-3 & in the adult is at C-4 • The high position of the epiglottis & larynx allows the infant to breathe & swallow simultaneously • The larynx descends with growth • Most of this descent occurs in the 1st year but the adult position is not reached until the 4th year • The vocal cords of the neonate are slanted so that the anterior portion is more cephalad anteriorly and rostral posteriorly

34. Narrowest area of the airway • Adult is between the vocal cords • Infant is in the cricoid region of the larynx (3-5mm diameter) • The cricoid is circular & cartilaginous and consequently not expansible • An endotracheal tube may pass easily through an infants vocal cords but be tight at the cricoid area. • This is also frequently the site of trauma during intubation • 1mm of edema on the cross sectional area at the level of the cricoid ring in a pediatric airway can decrease the opening 75% vs. 19% in an adult

36. Trachea • Infant: the alignment is directed caudally & posteriorly • Adult: it is directed caudally • Cricoid pressure is more effective in facilitating passage of the endotracheal tube in the infant • Newborn Trachea • Distance between the bifurcation of the trachea & the vocal cords is 4-5cm • Endotracheal tube (ETT) must be carefully positioned & fixed • Because of the large size of the infant’s head the tip of the tube can move about 2cm during flexion & extension of the head • It is extremely important to check the ETT placement every time the baby’s head is moved

37. Anatomical differences of chest and lower airway • ribs are horizontal , soft, non calcified & do not rise as much as an adult’s during inspiration • Intercostal muscles are poorly developed with fewer type1 oxidative fibers • The diaphragm is more important in ventilation & the consequences of abdominal distention are much greater • As the child grows (learns to stand) gravity pulls on the abdominal contents encouraging the chest wall to lengthen

38. Diaphragmatic & intercostal muscles of infants are more liable to fatigue than those of adults • This is due to a difference in muscle fiber type -Adult diaphragm has 60% of type I: slow twitch, high oxidative, fatigue resistant -Newborns diaphragm has 75% of type II: fast twitch, low oxidative, less energy efficient -The same pattern is seen in intercostal muscles • The newborn is more prone to respiratory fatigue & may not be able to cope when suffering from conditions that result in reduced lung compliance (RDS)

39. Differences in Lung volumes in neonate • Lung volumes in neonate are lesser than adult when adjusted for weight and even smaller when adjusted for metabolic differences • Total alveolar surface area for gas exchange in neonates is 50 times less than in adults even though metabolic rate in neonate is twice than that in adult. • FRC, TV and dead space is similar to adults when normalised for body weight

40. Pulmonary Function Values Neonate Adult Tidal volume (ml/kg) 6 7 Respiratory rate 35 15 Vital capacity (ml/kg) 35 70 Functional residual capacity (ml/kg) 30 35 Closing capacity (ml/kg) 35 23 Total lung capacity (ml/kg) 63 86 Alveolar ventilation (ml/kg/min) 130 60

41. Gas Exchange Values Neonate (3kg) Adult (70kg) O2 consumption 7 3.5 (ml/kg/min) CO2 production 6 3 (ml/kg/min)

42. Cardiovascular physiology There are gross structural differences & changes in the heart during infancy • At birth the right & left ventricles are essentially the same in size & wall thickness • During the 1st month volume load & afterload of the LV increases whereas there is minimal increase in volume load & decrease in afterload on the RV By four weeks the LV weighs more than the RV This continues through infancy & early childhood until the LV is twice as heavy as the RV as it is in the adult

43. Myocardial cell in neonate • The myocardial tissues contain a large number of nuclei & mitochondria with an extensive endoplasmic reticulum to support cell growth & protein synthesis during infancy • The amount of cellular mass dedicated to contractile protein in the neonate & infant is less than the adult • 30% vs. 60% • These differences in the organization, structure & contractile mass are partly responsible for the decreased functional capacity of the young heart • Both ventricles are relatively noncompliant

44. Circulation • The vasomotor reflex arcs are functional in the newborn as they are in adults • Baroreceptors of the carotid sinus lead to parasympathetic stimulation & sympathetic inhibition • There are less catecholamine stores & a blunted response to catecholamines. Therefore neonates & infants can show vascular volume depletion by hypotension without tachycardia

45. Cardiovascular Parameters • Parameters are much different for the infant than for the adult • Heart rate: higher Decreasing to adult levels at ~5 years old • Cardiac output: higher (200ml/kg/min) Especially when calculated according to body weight & it parallels O2 consumption • Cardiac index: constant Because of the infants high ratio of surface area to body weight • O2 consumption: depends heavily on temperature There is a 10-13% increase in O2 consumption for each degree rise in core temperature

46. Circulation Variables in Infants • Age (months) Sys/Dias mean • 1 85/65 50 • 3 90/65 50 • 6 90/65 50 • 9 90/65 55 • 12 90/65 55 Age (months) Sys/Dias mean 1 85/65 50 3 90/65 50 6 90/65 50 9 90/65 55 12 90/65 55

47. Autonomic Control of the Heart • Parasympathetic innervation has been shown to be complete at birth therefore we see an increased sensitivity to vagal stimulation • Sympathetic innervation of the heart is incomplete at birth with decreased cardiac catecholamine stores & it has an increased sensitivity to exogenous norepinephrine • It does not mature until 4-6 months of age

48. Autonomic Control of the Heart • The imbalance between sympathetic & parasympathetic tone predisposes the infant to bradycardia • Anything that activates the parasympathetic nervous system such as anesthetic overdose, hypoxia can lead to bradycardia

49. Body fluid composition

50. Changes in body fluid composition • First 12-24 hours of life urine output is limited to 0.5 ml/kg/hr due to poor renal perfusion (oliguric phase)  • Natriuresis phase  isotonic fluid lost from extracellular compartment  • 1-2% weight loss per day for first 5 days • Extracellular water becomes 30% of total body water