Physiology of the Newborn

Question 1

What is the estimated blood volume of a newborn?

Answer 1

80-85 ml/kg

Medscape: Samir Gupta, 12/18/2020

Question 2

The approximate degree of intravascular volume depletion in clinical shock?

Answer 2

Compensated shock: 25%

Uncompensated shock: 25-40%

Irreversible shock: >40%

(Medscape: Samir Gupta, 12/18/2020)

Question 3

What are appropriate general supportive measures for a newborn in shock?

Answer 3

Secure the airway.

Supplemental oxygen and positive-pressure ventilation
Intravascular or intraosseous access.

10mL/kg colloid or crystalloid (if secondary to hemorrhage– blood should be instituted.)

Careful monitoring of coagulation profiles and management with FFP, platelets, cryoprecipitate (suspect DIC).

(Medscape: Samir Gupta, 12/18/2020)

Question 4

What is shock?

Answer 4

Acute state of oxygen deficiency at the cellular level.

Shock is a state in which the cardiac output is insufficient to deliver adequate oxygen to meet metabolic demands of the tissues. Cardiovascular function is determined by preload, cardiac contractility, heart rate, and afterload. Shock may be classified broadly as hypovolemic, cardiogenic, or distributive (systemic inflammatory response syndrome [SIRS]—septic or neurogenic).

| Holcomb & Ashcraft

Pediatric Surgery Secrets

Question 5

What physical signs are associated with shock?

Answer 5

Tachycardia
Peripheral vasoconstriction (leading to delayed capillary refill, diminished pulses, decreased skin temperature
Hypotension
Tachypnea
Decreased urine output

(Pediatric Surgery Secrets)

Question 6

What is MODS?

Answer 6

Multiple Organ Dysfunction Syndrome. It may be associated with shock of any etiology.

Acute respiratory failure, renal failure, hepatic dysfunction, and endocrine and metabolic abnormalities may result from inadequate tissue oxygenation.

The diagnosis of MODS indicates organ dysfunction to the degree that homeostasis cannot be maintained without intervention. Older textbooks may use the acronym MOSF (multiple organ system failure).

(Pediatric Surgery Secrets)

Question 7

What is SIRS?

Answer 7

SIRS, an acronym for systemic inflammatory response syndrome, is defined as a major inflammatory response to a variety of severe clinical insults such as sepsis, trauma and burns.

It results in activation of common pathogenic pathways, both the molecular and cellular, with common clinical manifestations. It is diagnosed by the presence of two or more of the following:

• Temperature <36C or >38C
• Heart rate > 90 beats/min (adults; variable increase in children)
• Respiratory rate > 20 breaths/min (adults) or partial pressure of carbon dioxide in arterial blood < 32mmHg
• WBC >12,000, <4,000, >10% bands

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Question 8

What is ARDS?

Answer 8

Acute Respiratory Distress Syndrome is acute respiratory failure due to injury to the alveolar capillary unit.

It results in increased permeability and pulmonary edema.

ARDS may be associated with a variety of insults but most frequently is associated with shock, sepsis, near-drowning, massive transfusions, or aspiration.

Clinical sequelae include metabolic acidosis, multiple organ dysfunction syndrome, disseminated intravascular coagulation, and death.

(Pediatric Surgery Secrets)

Question 9

When and how is the metabolic acidosis from shock treated?

Answer 9

Metabolic acidosis in shock results from inadequate tissue perfusion, which causes cellular hypoxia. Hypoxia results in the accumulation of acid products of anaerobic metabolism (lactic acidosis).

It usually resolves as oxygenation of tissues and renal function improve.

However, correction with sodium bicarbonate (in addition to volume resuscitation is indicated when the arterial blood pH is less than 7.2.

To avoid over-correction, aggressive correction of the acidosis should stop when the pH is greater than 7.3.

The reason for quickly correcting the acidosis is to alleviate the myocardial depression and increased systemic and pulmonary vascular resistance that undermine resuscitative efforts in patients with shock.

(Pediatric Surgery Secrets)

Question 10

What are four determinants of oxygen delivery (DO2)?

Answer 10

Heart rate (HR)
Stroke volume (SV)
Hemoglobin (Hgb)
Arterial oxygen saturation (SaO2)

Indicated by the following equations:
1) DO2 (O2 delivery) = CO (cardiac output) x CaO2 (arterial O2 content)

2) CO = HR x SV

3) CaO2 = (SaO2 x Hgb x 1.34) (Hgb x 1.39 x SaO2) + (0.003 x PaO2), where PaO2 = partial pressure of oxygen

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Question 11

What is SvO2? How is it helpful in monitoring the patient in shock?

Answer 11

SvO2 refers to mixed venous oxygen saturation in a sample taken from the right atrium. It is determined by the following equation:

SvO2 = 1 - VO2/DO2

where VO2 = volume of oxygen utilization. The determinants of SvO2 are oxygen consumption, hemoglobin, cardiac output, and oxygen saturation.

Other than oxygen consumption, these factors can be manipulated during resuscitation to maximize oxygen delivery to the tissues.

Monitoring of SvO2 allows minute to minute assessment of interventions in cardiorespiratory support and resuscitation.

SvO2 is affected by increasing Hgb with transfusions; support of cardiac output with volume, vasopressors, or cardiotropic drugs; and increased oxygen delivery.

(Pediatric Surgery Secrets)

Question 12

What type of shock is encountered most frequently in children?

Answer 12

Hypovolemic shock.

It is defined as a clinical state characterized by decreased venous return to the heart and subsequent diminished left ventricle filling (decreased stroke volume), resulting in insufficient oxygen delivery to the tissues.

(Pediatric Surgery Secrets)

Question 13

Initial order for resuscitation of patients with hypovolemic shock?

Answer 13

20mL/kg bolus

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Question 14

What percent of body weight must be lost as a result of dehydration before an average healthy child becomes hypotensive?

Answer 14

Decreased blood pressure usually is not seen until about 15% body weight is lost.

(Pediatric Surgery Secrets)

Question 15

Calculate the fluid deficit for a child who is hypovolemic and now weighs 18kg, given that the previous weight was 20kg.

Answer 15

The patient has lost 2kg, and is therefore 10% dehydrated (2kg of 20kg).

One liter is 1kg. Therefore, a 2kg weight loss translates to a 2000mL deficit.

(Pediatric Surgery Secrets)

Question 16

How should the fluids be administered to resuscitate the previous patient (2000mL deficit), assuming no ongoing losses?

Answer 16

The patient should be resuscitated over 24h. The usual rule of thumb for replacement of losses is one half of the deficit over the first 8 hours, and the other half over the next 16 hours.

The patient’s calculated deficit is 2000mL. In addition, the patient has a maintenance requirement of 60mL/h.

Every patient receives an initial bolus of 20mL/kg (=400mL). Therefore, the deficit to be replaced over the next 24 hours is now 1600mL.

The rate in mL/hour for the first 8 hours is 800mL/8 hours = 100mL/hr + maintenance = 160mL/hr.

The rate for the next 16 hours is 800mL/16 hours = 50 mL/h + maintenance = 110mL/hr.

Electrolyte composition after intravenous flush is determined and adjusted according to the results of serum electrolytes and laboratory tests.

(Pediatric Surgery Secrets)

Question 17

What is the estimated blood volume for a term infant?

Answer 17

EBV for a Term infant: 90mL/kg

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Question 18

What is the estimated blood volume for a child?

Answer 18

EBV for a child: 80mL/kg

Pediatric Surgery Secrets

Question 19

What are the clinical symptoms and signs of cardiogenic shock?

Answer 19

Symptoms:
Tachycardia
Diaphoresis
Oliguria
Acidosis
Hypotension

Signs:
Hepatomegaly
Jugular venous distension
Rales
Peripheral edema
Decreased cardiac output
Elevated CVP, PAWP, SVR

(Pediatric Surgery Secrets)

Question 20

What are the clinical signs of cardiac tamponade?

Answer 20

Low cardiac output
Pulsus paradoxus
Jugular venous distension
Narrowed pulse pressure
Muffled heart tones

(Pediatric Surgery Secrets)

Question 21

What diagnostic testing should be done in a patient suspected of having cardiogenic shock?

Answer 21

Chest radiograph
Electrocardiogram
Echocardiogram
CVP determination
Urine output

(Pediatric Surgery Secrets)

Question 22

What pathogens most often cause septic shock in neonates?

Answer 22

Neonates:
Group B Beta-hemolytic streptococci
Enterobacteriaceae
Listeria monocytogenes
Staphylococcus aureus
Herpes simplex

(Pediatric Surgery Secrets)

Question 23

What pathogens most often cause septic shock in infants?

Answer 23

Infants:
Haemophilus influenzae
Streptococcus pneumoniae
S. aureus

(Pediatric Surgery Secrets)

Question 24

What pathogens most often cause septic shock in children?

Answer 24

S. pneumoniae
Neisseria meningitidis
S. aureus
Enterobacteriaceae
H. influenzae

Question 25

What pathogens most often cause septic shock in immunocompromised patients?

Answer 25

Enterobacteriaceae
S. aureus
Pseudomonadaceae
Candida albicans

Question 26

How are newborns classified based on gestational age?

Answer 26

Preterm: <37 weeks AOG
Term: 37-42 weeks AOG
Post-term: >42 weeks AOG

Question 27

How are newborns classified based on weight?

Answer 27

SGA: <10th percentile for age
AGA: Between SGA and LGA
LGA: at or >90th percentile for age

Question 28

How are premature infants classified based on weight?

Answer 28

Moderately low BW: 1501-2500g
Very low BW: 1001-1500g
Extremely low BW: <1000g

Question 29

Physiologic characteristics of SGA infants?

Answer 29

Due to intrauterine malnutrition, body fat levels are frequently below 1% of total body weight.

Lack of body fat increases risk of hypothermia.

Hypoglycemia is the most common metabolic problem for neonates, which develops earlier for SGA infants (higher metabolic activity and reduced glycogen stores).

RBC volume and total blood volume are much higher In SGA infants, leading to polycythemia, and an associated rise In blood viscosity.

Due to adequate length of gestation, the SGA infant has a pulmonary function approaching that of the AGA or full term infant.

Question 30

Special problems of the premature infant include?

Answer 30

Weak suck reflex
Inadequate GI absorption
Hyaline membrane disease
Intraventricular hemorrhage
Hypothermia
Patent ductus arteriosus
Apnea
Hyperbilirubinemia
Necrotizing enterocolitis (NEC)

Question 31

Why are neonates prone to hypoglycemia?

Answer 31

The fetus maintains a blood glucose value of 70-80% of maternal levels by facilitated diffusion across the placenta.

There is a build up of glycogen stores in the liver, skeleton, and cardiac muscles during the later stages of fetal development, but little gluconeogenesis. The newborn must depend on glycolysis until exogenous glucose is supplied.

After delivery, the baby depletes his or her hepatic glycogen stores within 2-3h.

The newborn is severely limited in his/her ability to use fat and protein as substrates to synthesize glucose.

When TPN is needed, the glucose infusion rate should be initiated at:
4-6 mg/kg/min and advanced 1-2mg/kg/min with a goal of 12mg/kg/min.

Question 32

What are the most common manifestations of severe hypoglycemia?

Answer 32

Seizure and coma

Question 33

What is the defined value for neonatal hypoglycemia?

Answer 33

Neonatal hypoglycemia is generally defined as a glucose level lower than 50mg/dL.

Infants at high risk include:
Premature
SGA
Born to mother with gestational DM, severe preeclampsia, HELLP (hemolysis, elevated liver enzymes, low platelet count).
Newborns requiring surgical procedures (hence a 10% glucose infusion is typically started on admission to the hospital).

Question 34

How is newborn hypoglycemia treated?

Answer 34

Infusion of 1-2mL/kg (4-8mg/kg/min) of 10% glucose

If an emergency operation is required, concentrations of up to 25% glucose may be used. Consider central venous access for infusions exceeding 12.5%.

During the first 36-48h after a major operation, it is common to see wide variations In serum glucose levels.

Question 35

What is the usual clinical picture of a neonate with hyperglycemia?

Answer 35

Hyperglycemia is a common problem associated with the use of parenteral nutrition in very immature infants born at <30 weeks AOG, and birth weight of <1.1kg.

Historically, neonatal hyperglycemia has also been linked to intraventricular hemorrhage, dehydration, and electrolyte losses; however, a causal relationship has not been established.

Congenital hyperinsulinism refers to an inherited disorder that is the most common cause of recurrent hypoglycemia in infants.

Question 36

Why are premature infants prone to hypocalcemia?

Answer 36

Hypocalcemia is defined as an ionized calcium level of less than 1.22 mmol/L (4.9 mg/dL).

Calcium is actively transported across the placenta. Of the total amount of calcium transferred across the placenta, 75% is observed after 28 weeks’ gestation, which partially accounts for the high incidence of hypocalcemia in preterm infants.

Neonates are predisposed to hypocalcemia due to limited calcium stores, renal immaturity, and relative hypoparathyroidism secondary to suppression by high fetal calcium levels.

Some infants are at further risk for neonatal calcium disturbances owing to the presence of genetic defects, pathologic intrauterine conditions, or birth trauma.

At greatest risk for hypocalcemia are preterm infants, newborn surgical patients, and infants born to mothers with complicated pregnancies, such as those with diabetes or those receiving bicarbonate infusions.

Calcitonin, which inhibits calcium mobilization from the bone, is increased in premature and asphyxiated infants.

Question 37

What are signs and symptoms of hypocalcemia in neonates?

Answer 37

Similar to hypoglycemia:
Jitteriness
Seizures
Cyanosis
Vomiting
Myocardial arrhythmias

Increased muscle tone (not found in hypoglycemia)

Question 38

How is symptomatic hypocalcemia treated?

Answer 38

10% calcium gluconate administered intravenously at a dosage of 1-2ml/kg (100-200mg/kg) over 30 minutes, while monitoring ECG for bradycardia.

If possible, parenteral calcium should be given through a central venous line, as skin and soft tissue necrosis may occur should the peripheral IV infiltrate.

Question 39

How is asymptomatic hypocalcemia treated?

Answer 39

Calcium gluconate in a dose of 50mg of elemental calcium/kg/day added to the maintenance fluid: 1mL of 10% calcium gluconate contains 9mg of elemental calcium.

Question 40

What percentage of body weight is the total body water content of a fetus in utero?

Answer 40

12 weeks AOG: 94% of body weight
32 weeks AOG: 80% of body weight
Term: 78% of body weight

A further 3–5% reduction in total body water content occurs in the first 3–5 days of life.

Body water continues to decline and reaches adult levels (approximately 60% of body weight) by 1½ years of age.

Extracellular water also declines by 1–3 years of age.

Premature delivery requires the newborn to complete both fetal and term water unloading tasks.

Surprisingly, the premature infant can complete fetal water unloading by 1 week following birth.

Postnatal reduction in extracellular fluid volume has such a high physiologic priority that it occurs even in the presence of relatively large variations of fluid intake.

Question 41

How is hypomagnesemia diagnosed and treated?

Answer 41

Magnesium is actively transported across the placenta. Half of total body magnesium is in the plasma and soft tissues.

Hypomagnesemia is observed with growth retardation, maternal diabetes, after exchange transfusions, and with hypoparathyroidism.

Although the mechanisms by which magnesium and calcium interact are not clearly defined, they appear to be interrelated.

The same infants at risk for hypocalcemia are also at risk for hypomagnesemia.

Magnesium deficiency should be suspected and confirmed in an infant who has seizures that do not respond to calcium therapy.

Emergent treatment consists of magnesium sulfate 25–50 mg/kg IV every 6 hours until normal levels are obtained.

Question 42

How is total blood volume computed in neonates?

Answer 42

Total RBC volume is at its highest point at delivery.

By about 3 months of age, total blood volume per kilogram is nearly equal to adult levels as infants recover from their postpartum physiologic nadir.

The newborn blood volume is affected by shifts of blood between the placenta and the baby before clamping the cord. Infants with delayed cord clamping (typically defined as greater than 1 minute after birth) have higher hemoglobin levels.

A hematocrit greater than 50% suggests placental transfusion has occurred. Although this effect on hemoglobin levels does not persist, iron stores are positively impacted up to 6 months of age by delayed cord clamping.

Question 43

What factors decrease the affinity of hemoglobin for oxygen (ie, facilitating the unloading of O2 from arterial blood?

Answer 43

Increases in:
PCO2
Temperature
2,3-DPG
Hydrogen ion concentration

Causes of a shift to the left are mirror images of those that cause a shift to the right: decreases in temperature, 2,3-DPG, and hydrogen ion concentration.

Question 44

What is polycythemia?

Answer 44

A central venous hemoglobin level greater than 22 g/dL or a hematocrit value greater than 65% during the first week of life is defined as polycythemia.

After the central venous hematocrit value reaches 65%, further increases result in rapid exponential increases in blood viscosity.

Neonatal polycythemia occurs in infants of diabetic mothers, infants of mothers with toxemia of pregnancy, or SGA infants.

Polycythemia is treated using a partial exchange of the infant’s blood with fresh whole blood or 5% albumin. This is frequently done for hematocrit values greater than 65%.

Question 45

What are the causes of anemia at birth?

Answer 45

1) Hemolysis

Hemolytic anemia is most often a result of placental transfer of maternal antibodies that are destroying the infant’s erythrocytes. This can be determined by the direct Coombs test.

The most common severe anemia is Rh incompatibility.

Hemolytic disease in the newborn produces jaundice, pallor, and hepatosplenomegaly. The most severely affected fetuses manifest hydrops. This massive edema is not strictly related to the hemoglobin level of the infant. ABO incompatibility frequently results in hyperbilirubinemia, but rarely causes anemia.

Congenital infections, hemoglobinopathies (sickle cell disease), and thalassemias produce hemolytic anemia.

In a severely affected infant with a positive-reacting direct Coombs test result, a cord hemoglobin level less than 10.5 g/ dL, or a cord bilirubin level greater than 4.5 mg/dL, immediate exchange transfusion is indicated.

For less severely affected infants, exchange transfusion is indicated when the total indirect bilirubin level is greater than 20 mg/dL.

2) Blood Loss

Significant anemia can develop from hemorrhage that occurs during placental abruption.

Internal bleeding (intraventricular, subgaleal, mediastinal, intra-abdominal) in infants can also often lead to severe anemia.

Usually, hemorrhage occurs acutely during delivery, with the baby occasionally requiring a transfusion.

Twintwin transfusion reactions can produce polycythemia in one baby and profound anemia in the other.

Severe cases can lead to death in the donor and hydrops in the recipient.

3) Decreased Erythrocyte Production

Decreased RBC production frequently contributes to anemia of prematurity.

Erythropoietin is not released until a gestational age of 30–34 weeks has been reached.

These preterm infants have large numbers of erythropoietin-sensitive RBC progenitors.

Research has focused on the role of recombinant erythropoietin (epoetin alpha) in treating anemia in preterm infants.

Successful increases in hematocrit levels using epoetin may obviate the need for blood transfusions and reduce the risk of blood borne infections and reactions.

Studies suggest that routine use of epoetin is probably helpful for very low birth weight infants (<750 g), but its regular use for other preterm infants is not likely to significantly reduce the transfusion rate.

Question 46

What are causes of prolonged indirect hyperbilirubinemia?

Answer 46

Breast milk jaundice
Hemolytic disease
Hypothyroidism
Pyloric stenosis
Crigler–Najjar syndrome
Extravascular blood

Question 47

When should jaundice be investigated in the neonate?

Answer 47

In the hepatocyte, bilirubin created by hemolysis is conjugated to glucuronic acid and rendered water soluble. Conjugated (also known as direct) bilirubin is excreted in bile.

Unconjugated bilirubin interferes with cellular respiration and is toxic to neural cells. Subsequent neural damage is termed kernicterus and produces athetoid cerebral palsy, seizures, sensorineural hearing loss, and, rarely, death.

The newborn’s liver has a metabolic excretory capacity for bilirubin that is not equal to its task. Even healthy full-term infants usually have an elevated unconjugated bilirubin level. This peaks about the third day of life at approximately 6.5–7.0 mg/dL and does not return to normal until the tenth day of life.

A total bilirubin level:

greater than 7 mg/dL in the first 24 hours or
greater than 13 mg/dL at any time in full-term newborns

often prompts an investigation for the cause.

Breast-fed infants usually have serum bilirubin levels 1–2 mg/dL greater than formula-fed babies. Various factors have been associated with breast milk jaundice including substances in breast milk (e.g., steroids, fats, cytokines, βglucuronidase, and epidermal growth factor), difficulties with breast-feeding, and infant weight loss. However, new studies also implicate differences in extrahepatic UDPglucuronosyltransferase 1A1.

Pathologic jaundice within the first 36 hours of life is usually due to excessive production of bilirubin.

Hyperbilirubinemia is managed based on the infant’s weight. Although specific cutoffs defining the need for therapy have not been universally accepted, the following recommendations are consistent with most practice patterns.

Phototherapy is initiated for newborns:
(1) less than 1500 g, when the serum bilirubin level reaches 5 mg/dL;

(2) 1500–2000 g, when the serum bilirubin level reaches 8 mg/dL; or

(3) 2000–2500 g, when the serum bilirubin level reaches 10 mg/dL.

Formulafed term infants without hemolytic disease are treated by phototherapy when levels reach 13 mg/dL.

For hemolytic-related hyperbilirubinemia, phototherapy is recommended when the serum bilirubin level exceeds:

1) 10 mg/dL by 12 hours of life,
2) 12 mg/dL by 18 hours,
3) 14 mg/dL by 24 hours, or
4) 15 mg/dL by 36 hours.

An absolute bilirubin level that triggers exchange transfusion is still not established, but most exchange transfusion decisions are based on the serum bilirubin level and its rate of rise.

Question 48

What are risk factors for retinopathy of prematurity?

Answer 48

Retinopathy of prematurity (ROP) develops during the active phases of retinal vascular development from the 16th week of gestation.

In full-term infants the retina is fully developed and ROP cannot occur.

The exact causes are unknown, but oxygen exposure (greater than 93–95%), low birth weight, and extreme prematurity are risk factors that have been demonstrated.

The risk and extent of ROP are probably related to the degree of vascular immaturity and abnormal retinal angiogenesis mediated to a large extent through vascular endothelial growth factor in response to hypoxia.

In the United States, ROP is found in 0.17% of all live births and 1.9% of premature infants in large neonatal units.

Retrolental fibroplasia (RLF) is the pathologic change observed in the retina and overlying vitreous after the acute phases of ROP subsides.

Treatment of ROP with laser photocoagulation has been shown to have the added benefit of superior visual acuity and less myopia when compared with cryotherapy in long-term follow-up studies.

The American Academy of Pediatrics’ guidelines recommend a screening examination for all infants who received oxygen therapy who weigh less than 1500 g and were born at less than 32 weeks’ gestation, and selected infants with a birth weight between 1500 and 2000 g or gestational age of more than 32 weeks with an unstable clinical course, including those requiring cardiorespiratory support.

Question 49

Why are neonates prone to hypothermia?

Answer 49

Newborns have difficulty maintaining body temperature due to their relatively large surface area, poor thermal regulation, and small mass to act as a heat sink.

Heat loss may occur as a result of:

(1) evaporation (wet newborn);

(2) conduction (skin contact with cool surface);

(3) convection (air currents blowing over newborn); and

(4) radiation (non-contact loss of heat to cooler surface, which is the most difficult factor to control).

Thermoneutrality is the range of ambient temperatures at which the newborn can maintain a normal body temperature with a minimal metabolic rate by vasomotor control.

The critical temperature is the temperature that requires adaptive metabolic responses to the cold in an effort to replace lost heat.

Infants produce heat by increasing metabolic activity by shivering like an adult, nonshivering thermogenesis, and futile cycling of ions in skeletal muscle.

Brown adipose tissue (BAT) may be involved in thermoregulatory feeding and sleep cycles in the infant, with an increase in body temperature signaling an increase in metabolic demand.

The uncoupling of mitochondrial respiration that occurs in BAT, where energy is not conserved in ATP but rather is released as heat, may be rendered inactive by vasopressors, anesthetic agents, and nutritional depletion.

Failure to maintain thermoneutrality leads to serious metabolic and physiologic consequences.

Double-walled incubators offer the best thermoneutral environment, whereas radiant warmers cannot prevent convection heat loss and lead to higher insensible water loss.

In the operating room, special care must be exercised to maintain the neonate’s body temperature in the normal range.

Question 50

How does transition from fetal to neonatal circulation happen?

Answer 50

In the first moments of extrauterine life, the transition from fetal to neonatal circulation begins. An appreciation of this transition is imperative to the care of neonates.

The changes occur primarily through shifts in vascular resistance and increased partial pressure of oxygen in the arterial blood (PaO2 ).

With the neonate’s first breath, the lungs begin inflating. Simultaneously, the relatively low fetal PaO2 (maximum of 30–35 mmHg from the umbilical vein) rises with the switch from placental to pulmonary gas exchange.

The combination of these changes causes a substantial decrease in pulmonary vascular resistance.

In addition, with the removal of the placenta from circulation, systemic vascular resistance increases.

Fetal circulation is marked by three prominent structures: the foramen ovale, ductus arteriosus, and ductus venosus.

The foramen ovale shunts blood from the right atrium into the left atrium, largely bypassing the pulmonary circulation. With an increase in blood flow from the pulmonary system returning to the left atrium after birth, the flap of the foramen ovale functionally closes in most infants by 3 months of age.

The ductus arteriosus serves as a conduit from the pulmonary artery to the descending aorta. Flow is reversed after birth due to higher systemic vascular resistance and lower pulmonary vascular resistance. The ductus arteriosus closes within 24 hours after birth primarily because of vasoconstriction secondary to higher PaO2 as well as the absence of placental prostaglandins.

The ductus venosus connects the umbilical vein to the inferior vein cava and serves as a route to divert approximately half of the blood flow away from the fetal liver. With increased oxygenation after delivery, the ductus venosus occludes and closes.

Of note, congenital cardiac defects and prematurity can lead to alterations in the normal circulatory transition.

Question 51

What are the periods of lung maturation?

Answer 51

Maturation of the lungs is generally divided into five periods (EPCSA)

1) Embryonic phase (begins week 3)

Pulmonary development begins in the third week (embryonic phase) when a ventral diverticulum develops off the foregut (laryngotracheal groove), initiating tracheal development.

2) Pseudoglandular phase (5-17 weeks)

During the pseudoglandular phase, all of the major elements of the lung form except those involved in gas exchange. The dichotomous branching of the bronchial tree that develops during the fourth week from the primitive trachea is usually completed by 17 weeks’ gestation. Fetuses born during this phase are unable to survive because respiration is not possible.

3) Canalicular phase (16-25 weeks)

In the canalicular phase, respiration is made possible because thin-walled terminal sacs (primordial alveoli) have developed at the ends of the respiratory bronchioles and the lung tissue is well vascularized.

No actual alveoli are seen until 24–26 weeks’ gestation, during the terminal saccular phase. The air–blood surface area for gas diffusion is limited should the fetus be delivered at this age.

4) Terminal saccular phase (24 weeks to full term birth)

The terminal saccular phase is defined by the establishment of the blood–air barrier that allows gas exchange for the survival of the fetus should it be born prematurely.

Between 24 and 28 weeks, the cuboidal and columnar cells flatten and differentiate into type I (lining cells) and/or type II (granular) pneumocytes.

Between 26 and 32 weeks of gestation, terminal air sacs begin to give way to air spaces.

At the same time, the phospholipids that constitute pulmonary surfactant begin to line the terminal lung air spaces.

Surfactant is produced by type II pneumocytes and is extremely important in maintaining alveolar stability.

5) Alveolar phase (late fetal phase to childhood)

During the alveolar phase, further budding of these air spaces occurs and alveoli become numerous, a process that continues postnatally until the age of 3–8 years.

Question 52

How is fetal lung maturity assessed?

Answer 52

The change in the ratio of the amniotic phospholipids (lecithin: sphingomyelin) is used to assess fetal lung maturity.

A ratio greater than 2 is considered compatible with mature lung function.

Absence of adequate surfactant leads to HMD or respiratory distress syndrome (RDS).

HMD is present in 10% of premature infants.

Other conditions associated with pulmonary distress in the newborn include delayed fetal lung absorption, meconium aspiration syndrome, intrapartum pneumonia, and developmental structural anomalies (e.g., CDH and congenital lobar emphysema).

In all of these conditions, endotracheal intubation and mechanical ventilation may be required for hypoxia, CO2 retention, or apnea.

To accelerate fetal lung maturity, a maternal dose of corticosteroids is the standard of care of threatened preterm delivery. This therapy reduces the incidence of perinatal death as well as RDS.

Proposed pathways for the effect of corticosteroids on lung maturity include stimulation of surfactant production through enzymatic induction, increasing pulmonary blood flow, and increasing air space volume by decreasing perialveolar tissue volume.

Studies are ongoing to investigate concerns regarding the short- and long-term effects of antenatal corticosteroid administration as well as the consequences of repeated doses.

Question 53

What is the major cause of hyaline membrane disease?

Answer 53

Surfactant deficiency is the major cause of HMD.

Surfactant replacement therapy reduces the surface tension on the inner surface of the alveoli, preventing the alveoli from collapsing during expiration and thereby improving air exchange.

Three exogenous surfactants are available:
(1) surfactant derived from bovine or porcine lung,
(2) synthetic surfactant without protein components, and
(3) synthetic surfactant containing protein components.

A human-derived surfactant has been tested but is not currently in use.

The most efficacious administration method is currently under investigation. The standard approach is to instill aliquots into an endotracheal tube.

Question 54

What are indications for surfactant use?

Answer 54

The indications for the use of surfactant include:

(1) intubated infants with RDS,

(2) intubated infants with meconium aspiration syndrome requiring more than 50% oxygen,

(3) intubated infants with pneumonia and an oxygen index great than 15, and

(4) intubated infants with pulmonary hemorrhage who have clinically deteriorated.

Its efficacy is uncertain in neonates with pulmonary hemorrhage and pneumonia. Worse outcomes are associated when surfactant is used in CDH.

The acute pulmonary effects of surfactant therapy are improved lung function and alveolar expansion leading to improved oxygenation, which results in a reduction in the need for mechanical ventilation and extracorporeal oxygenation.

Two meta-analyses support the use of surfactant therapy in infants with RDS to reduce air leak syndromes, pneumothorax, bronchopulmonary dysplasia (BPD), pulmonary interstitial emphysema, and mortality.

The INSURE (INtubate, SURfactant, Extubate) technique consists of administration of surfactant followed by extubation within 1 hour to nasal continuous positive airway pressure (nCPAP).

Another randomized trial demonstrated the reduced mortality and air leaks for infants assigned to early surfactant treatment versus nCPAP alone.

In large trials that reflect the current practice of treating infants at risk for the development of RDS (administration of maternal steroids and the routine stabilization on nCPAP), the selective use of surfactant in infants with established RDS demonstrates a decreased risk of chronic lung disease or death when compared with infants who are more aggressively treated with prophylactic administration of surfactant.

Several adverse outcomes have been associated with the use of surfactant. Intraventricular hemorrhage is one of the most worrisome potential side effects. However, meta-analyses of multiple trials have not shown a statistically significant increase in this risk.

Question 55

How are arterial blood gases used for monitoring neonates?

Answer 55

Arterial oxygen tension (PaO2 ) is measured most commonly by obtaining an arterial blood sample and by measuring the partial pressure of oxygen with a polarographic electrode.

In the term newborn, the general definition for hypoxia is a PaO2 less than 55 mmHg, whereas hyperoxia is greater than 80 mmHg.

Capillary blood samples are “arterialized” by topical vasodilators or heat to increase blood flow to a peripheral site.

Blood flowing sluggishly and exposed to atmospheric oxygen falsely raises the PaO2 from a capillary sample, especially in the 40–60 mmHg range.

Capillary blood pH and carbon dioxide tension (PCO2 ) correlate well with arterial samples, unless perfusion is poor.

PaO2 is least reliable when determined by capillary blood gas. In patients receiving oxygen therapy in which arterial PaO2 exceeds 60mmHg, the capillary PaO2 correlates poorly with the arterial measurement.

In newborns, umbilical artery catheterization provides arterial access. The catheter tip should rest at the level of the diaphragm or below L3.

The second most frequently used arterial site is the radial artery.

Complications of arterial blood sampling include repeated blood loss and anemia.

Distal extremity or organ ischemia from thrombosis or arterial injury is rare but can occur.

Changes in oxygenation are such that intermittent blood gas sampling may miss critical episodes of hypoxia or hyperoxia.

Due to the drawbacks of ex vivo monitoring, several in vivo monitoring systems have been used.

Question 56

How is pulse oximetry used for monitoring?

Answer 56

The noninvasive determination of oxygen saturation (SaO2) gives moment-to-moment information regarding the availability of O 2 to the tissues.

If the PaO2 is plotted against the oxygen saturation of hemoglobin, the S-shaped hemoglobin dissociation curve is obtained. From this curve, it is evident that hemoglobin is 50% saturated at 27 mmHg PaO2 and 90% saturated at 50 mmHg.

Pulse oximetry has a rapid (5–7 seconds) response time, requires no calibration, and may be left in place continuously.

Pulse oximetry is not possible if the patient is in shock, has peripheral vasospasm, or has vascular constriction due to hypothermia.

Inaccurate readings may occur in the presence of jaundice, direct high-intensity light, dark skin pigmentation, and greater than 80% fetal hemoglobin.

Oximetry is not a sensitive guide to gas exchange in patients with high PaO2 due to the shape of the oxygen dissociation curve. On the upper horizontal portion of the curve, large changes in PaO2 may occur with little change in SaO2 . For instance, an oximeter reading of 95% could represent a PaO2 between 60 and 160 mmHg.

A study comparing pulse oximetry with PaO2 from indwelling arterial catheters has shown that SaO2 greater than or equal to 85% corresponds to a PaO2 greater than 55 mmHg, and saturations less than or equal to 90% correspond with a PaO2 less than 80 mmHg.

Guidelines for monitoring infants using pulse oximetry have been suggested for the following three conditions:

1. In the infant with acute respiratory distress without direct arterial access, saturation limits of 85% (lower) and 92% (upper) should be set.
2. In the older infant with chronic respiratory distress who is at low risk for ROP, the upper saturation limit may be set at 95%; the lower limit should be set at 87% to avoid pulmonary vasoconstriction and pulmonary hypertension.
3. As the concentration of fetal hemoglobin in newborns affects the accuracy of pulse oximetry, infants with arterial access should have both PaO2 and SaO2 monitored closely.

A graph should be kept at the bedside, documenting the SaO2 each time the PaO2 is measured.

Limits for the SaO2 alarm can be changed because the characteristics of this relationship change.

Question 57

How is carbon dioxide tension used for monitoring?

Answer 57

Arterial carbon dioxide tension (PaCO2 ) is a direct reflection of gas exchange in the lungs and metabolic rate.

In most clinical situations, changes in PaCO2 are due to changes in ventilation.

For this reason, serial measurement of PaCO2 is a practical method to assess the adequacy of ventilation.

It is also possible to monitor PaCO2 and pH satisfactorily with venous or capillary blood samples.

Therefore, many infants with respiratory insufficiency no longer require arterial catheters for monitoring.

Question 58

How is end tidal CO2 used for monitoring?

Answer 58

Measuring expired CO2 by capnography provides a noninvasive means of continuously monitoring alveolar PCO2 .

Capnometry measures CO2 by an infrared sensor either placed in-line between the ventilator circuit and the endotracheal tube or off to the side of the air flow, both of which are applicable only to the intubated patient.

A comparative study of end-tidal carbon dioxide in critically ill neonates demonstrated that both sidestream and mainstream endtidal carbon dioxide measurements approximated PaCO2 .

When the mainstream sensor was inserted into the breathing circuit, the PaCO2 increased an average of 2mmHg.

Question 59

What are indications for central venous catheter placement?

Answer 59

Indications for central venous catheter placement include:

HITI
(1) hemodynamic monitoring,
(2) inability to establish other venous access,
(3) TPN, and
(4) infusion of inotropic drugs or other medications that cannot be given peripherally.

Measuring central venous pressure (CVP) to monitor volume status is frequently used in the resuscitation of a critically ill patient.

A catheter placed in the superior vena cava or right atrium measures the filling pressure of the right side of the heart, which usually reflects left atrial and filling pressure of the left ventricle.

Often, a wide discrepancy exists between left and right atrial pressure if pulmonary disease, overwhelming sepsis, or cardiac anomalies are present.

Positive-pressure ventilation, pneumothorax, abdominal distention, or pericardial tamponade all elevate CVP.

Question 60

How is pulmonary artery pressure used for monitoring?

Answer 60

The pulmonary artery pressure catheter has altered the care of the child with severe cardiopulmonary derangement by allowing direct measurement of cardiovascular variables at the bedside.

With this catheter, it is possible to monitor CVP, pulmonary artery pressure, pulmonary wedge pressure, and cardiac output.

The catheter is usually placed by percutaneous methods (as in the adult), except in the smallest pediatric patient in whom a cutdown is sometimes required.

When the tip of the catheter is in a distal pulmonary artery and the balloon is inflated, the resulting pressure is generally an accurate reflection of left atrial pressure because the pulmonary veins do not have valves.

This pulmonary “wedge” pressure represents left ventricular filling pressure, which is used as a reflection of preload.

The monitors display phasic pressures, but treatment decisions are made based on the electronically derived mean CVP.

A low pulmonary wedge pressure suggests that blood volume must be expanded.

A high or normal pulmonary wedge pressure in the presence of continued signs of shock suggests left ventricular dysfunction.

Cardiac output is usually measured in liters per minute.

Cardiac index represents the cardiac output divided by the body surface area. The normalized cardiac index allows the evaluation of cardiac performance without regard to body size.

The normal value for cardiac index is between 3.5 and 4.5 L/min/m2 .

The determination of cardiac output by the thermodilution technique is possible with a Swan–Ganz pulmonary artery catheter.

Accurate cardiac output determination depends on rapid injection, accurate measurement of the injectant temperatures and volume, and absence of shunting.

Because ventilation affects the flow into and out of the right ventricle, three injections should be made at a consistent point in the ventilatory cycle, typically at end-expiration.

Another study concluded that using right heart catheters in treating critically ill adult patients resulted in an increased mortality. However, a consensus committee report has documented the continued safety and efficacy of right heart catheters in the care of critically ill children.

A newer technique of deriving some of these data employs femoral arterial access and is gaining popularity in the pediatric intensive care unit: transcardiopulmonary thermodilution monitoring device (pulse contour cardiac output [PCCO]).

A proprietary PiCCO ® device has been developed and employs a standard central venous catheter and a proprietary thermistor-tipped arterial catheter to assess hemodynamic parameters via transpulmonary thermodilution. Manual calibration is required and must be performed frequently (every hour) for reasonably accurate data.

It is recommended to recalibrate the curve after interventions are performed. This device may give incorrect thermodilution measurements if blood is either extracted from or infused back into the cardiopulmonary circulation, as seen with an intracardiac shunt, aortic stenosis, lung embolism, and extracorporeal membrane oxygenation (ECMO).

Question 61

How is venous oximetry used for monitoring?

Answer 61

Mixed venous oxygen saturation (SvO2 ) is an indicator of the adequacy of oxygen supply and demand in perfused tissues. Oxygen consumption is defined as the amount of oxygen consumed by the tissue as calculated by the Fick equation:

O2 consumption = Cardiac output × (Arterial − venous oxygen content difference)

Reflectance spectrophotometry is currently used for continuous venous oximetry.

Multiple wavelengths of light are transmitted at a known intensity by means of fiber optic bundles in a special pulmonary artery or right atrial catheter.

The light is reflected by RBCs flowing past the tip of the catheter. The wavelengths of light are chosen so that both oxyhemoglobin and deoxyhemoglobin are measured to determine the fraction of hemoglobin saturated with oxygen.

The system requires either in vitro calibration by reflecting light from a standardized target that represents a known oxygen saturation or in vivo calibration by withdrawing blood from the pulmonary artery catheter and measuring the saturation by laboratory co-oximetry.

Mixed venous oxygen saturation values within the normal range (68–77%) indicate a normal balance between oxygen supply and demand, provided that vasoregulation is intact and distribution of peripheral blood flow is normal.

Values greater than 77% are most commonly associated with syndromes of vasoderegulation, such as sepsis.

Uncompensated changes in O2 saturation, hemoglobin level, or cardiac output lead to a decrease in SvO2.

A sustained decrease in SvO2 greater than 10% should lead to measuring SaO2 , hemoglobin level, and cardiac output to determine the cause of the decline.

The most common sources of error in measuring SvO2 are calibration and catheter malposition.

The most important concept in SvO2 monitoring is the advantage of continuous monitoring, which allows early warning of a developing problem.

Although most clinical experience has been with pulmonary artery catheters, right atrial catheters are more easily inserted and may thus provide better information to detect hemodynamic deterioration earlier and permit more rapid treatment of physiologic derangements.

A study has shown that, when oxygen consumption was monitored and maintained at a consistent level, the right atrial venous saturation was found to be an excellent monitor.

Question 62

What is the most common type of shock encountered in infants and children?

Answer 62

Hypovolemic shock

In infants and children, most shock situations are the result of reduced preload secondary to fluid loss, such as from diarrhea, vomiting, or blood loss from trauma.

Preload is predominantly a function of blood volume.

In most clinical situations, right atrial pressure or CVP is the index of cardiac preload.

In situations in which left ventricular or right ventricular compliance is abnormal or in certain forms of congenital heart disease, right atrial pressure may not correlate well with left atrial pressure.

Hypovolemia results in decreased venous return to the heart. Preload is reduced, cardiac output falls, and the overall result is a decrease in tissue perfusion.

The first step in treating all forms of shock is to correct existing fluid deficits.

Inotropic drugs should not be initiated until adequate intravascular fluid volume has been established.

The speed and volume of the infusate are determined by the patient’s responses, particularly changes in blood pressure, pulse rate, urine output, and CVP.

Shock resulting from acute hemorrhage is treated with the administration of 20mL/kg of Ringer’s lactate solution or normal saline as fluid boluses.

If the patient does not respond, a second bolus of crystalloid is given.

Type-specific or cross-matched blood is given to achieve an SvO2 of 70%.

In newborns with a coagulopathy, fresh frozen plasma or specific factors are provided as the resuscitation fluid.

The rate and volume of the resuscitation fluid are adjusted based on feedback data obtained from monitoring the effects of the initial resuscitation. After the initial volume is given, the adequacy of replacement is assessed by monitoring urine output, urine concentration, plasma acidosis, oxygenation, arterial pressure, CVP, and pulmonary wedge pressure, if indicated. When cardiac failure is present, continued vigorous delivery of large volumes of fluid not matched by cardiac output may cause further increases in preload to the failing myocardium and accelerate the downhill course. In this setting, inotropic agents are given while monitoring cardiac and pulmonary function, as previously discussed.

Question 63

What is the mechanism behind cardiogenic shock?

Answer 63

Myocardial contractility is usually expressed as the ejection fraction that indicates the proportion of left ventricular volume that is pumped.

Myocardial contractility is reduced with hypoxemia and acidosis.

Inotropic drugs increase cardiac contractility. Inotropes are most effective when hypoxemia and acidosis are corrected.

In cases of fluid-refractory shock and cardiogenic shock, inotropic drugs are necessary.

Traditionally, administration of inotropes requires the adjunct of central venous access. However, initial administration of pressors through peripheral IVs may be prudent.

Adrenergic receptors are important in regulating calcium flux, which, in turn, is important in controlling myocardial contractility. The α and β receptors are proteins present in the sarcolemma of myocardial and vascular smooth muscle cells.

The β 1 receptors are predominantly in the heart and, when stimulated, result in increased contractility of myocardium.

The β 2 receptors are predominately in respiratory and vascular smooth muscle. When stimulated, these receptors result in bronchodilation and vasodilation.

The α1 -adrenergic receptors are located on vascular smooth muscle and result in vascular constriction when stimulated.

The α 2 receptors are found mainly on prejunctional sympathetic nerve terminals.

The concept of dopaminergic receptors has also been used to account for the cardiovascular effects of dopamine not mediated through α or β receptors.

Activation of dopaminergic receptors results in decreased renal and mesenteric vascular resistance and, usually, increased blood flow.

Question 64

What vasoactive medications are usually used in the newborn?

Answer 64

Question 65

What is the effect of Epinephrine?

Answer 65

Epinephrine

Epinephrine is an endogenous catecholamine with α- and β-adrenergic effects.

At low doses, the β-adrenergic effect predominates. These effects include an increase in heart rate, cardiac contractility, cardiac output, and bronchiolar dilation.

Blood pressure rises, in part, not only due to increased cardiac output but also due to increased peripheral vascular resistance, which occurs with higher doses as the α-adrenergic effects become predominant.

Renal blood flow may increase slightly, remain unchanged, or decrease depending on the balance between greater cardiac output and changes in peripheral vascular resistance, which lead to regional redistribution of blood flow.

Cardiac arrhythmias can be seen with use of epinephrine, especially at higher doses.

Dosages for treating compromised cardiovascular function range from 0.05–1.0 μg/kg/min.

Excessive doses of epinephrine can cause worsening cardiac ischemia and dysfunction from increased myocardial oxygen demand.

Question 66

What is the effect of isoproterenol?

Answer 66

Isoproterenol is a β-adrenergic agonist.

It increases cardiac contractility and heart rate, with little change in systemic vascular resistance (SVR).

The peripheral vascular β-adrenergic effect and lack of a peripheral vascular α-adrenergic effect may allow reduction of left ventricular afterload.

The intense chronotropic effect of isoproterenol produces tachycardia, which can limit its usefulness.

Isoproterenol is administered IV at a dosage of 0.5–10.0 μg/ kg/min.

Question 67

What is the effect of Dopamine?

Answer 67

Dopamine is an endogenous catecholamine with β-adrenergic, α-adrenergic, and dopaminergic effects.

It is both a direct and an indirect β-adrenergic agonist.

Dopamine elicits positive inotropic and chronotropic responses by direct interaction with the β receptor (direct effect) and by stimulating the release of norepinephrine from the sympathetic nerve endings, which interacts with the β receptor (indirect effect).

At low dosages (<5 μg/kg/min), the dopaminergic effect of the drug predominates, resulting in reduced renal and mesenteric vascular resistance and further blood flow to these organs.

The β-adrenergic effects become more prominent at intermediate dosages (5–10 μg/kg/min), producing a higher cardiac output.

At relatively high dosages (10–20 μg/kg/min), the α-adrenergic effects become prominent with peripheral vasoconstriction.

Experience with the use of dopamine in pediatric patients suggests that it is effective in increasing blood pressure in neonates, infants, and children.

The precise dosages at which the desired hemodynamic effects are maximized are not known.

The effects of low dosages of dopamine on blood pressure, heart rate, and renal function were studied in 18 hypotensive, preterm infants. The blood pressure and diuretic effects were observed at 2, 4, and 8 μg/kg/min. Elevations in heart rate were seen only at 8 μg/kg/min. Further work is needed to better characterize the pharmacokinetics and pharmacodynamics of dopamine in children, especially in newborns.

Question 68

What is the effect of Dobutamine?

Answer 68

Dobutamine, a synthetic catecholamine, has predominantly β-adrenergic effects with minimal α-adrenergic effects.

The hemodynamic effect of dobutamine in infants and children with shock has been studied.

Dobutamine infusion significantly increased cardiac index, stroke index, and pulmonary capillary wedge pressure, and it decreased SVR.

The drug appears more efficacious in treating cardiogenic shock than septic shock.

The advantage of dobutamine over isoproterenol is its lesser chronotropic effect and its tendency to maintain systemic pressure.

The advantage over dopamine is dobutamine’s lesser peripheral vasoconstrictor effect.

The usual range of dosages for dobutamine is 1–10 μg/kg/min.

The combination of dopamine and dobutamine has been increasingly used; however, little information regarding their combined advantages or effectiveness in the neonate and infant has been published.

Question 69

What is the effect of Milrinone?

Answer 69

Milrinone, a phosphodiesterase inhibitor, is a potent positive inotrope and vasodilator (hence, also known as an ino-dilator) that has been shown to improve cardiac function in infants and children.

The proposed action is due, in part, to an increase in intracellular cyclic adenosine monophosphate and calcium transport secondary to inhibition of cardiac phosphodiesterase.

This effect is independent of β-agonist stimulation and, in fact, may act synergistically with the β agonist to improve cardiac performance.

Milrinone increases cardiac index and oxygen delivery without affecting heart rate, blood pressure, or pulmonary wedge pressure.

Milrinone is administered as a 75 μg/kg bolus followed by infusion of 0.75–1.0 g/kg/min.

Question 70

In which situations is distributive shock seen?

Answer 70

Distributive shock is caused by derangements in vascular tone from endothelial damage that lead to end-organ hypotension and is seen in the following clinical situations:

(1) septic shock,
(2) SIRS,
(3) anaphylaxis, and
(4) spinal cord trauma

Question 71

How does septic shock differ from other forms of shock?

Answer 71

Afterload represents the force against which the left ventricle must contract to eject blood. It is related to SVR and myocardial wall stress.

SVR is defined as the systemic mean arterial blood pressure minus right arterial pressure divided by cardiac output.

Cardiac contractility is affected by SVR and afterload.

In general, increases in afterload reduce cardiac contractility, and decreases in afterload increase cardiac contractility.

Septic shock is a distributive form of shock that differs from other forms of shock.

Cardiogenic and hypovolemic shock lead to increased SVR and decreased cardiac output.

Septic shock results from a severe decrease in SVR and a generalized maldistribution of blood and leads to a hyperdynamic state.

The pathophysiology of septic shock begins with a nidus of infection. Organisms may invade the blood stream, or they may proliferate at the infected site and release various mediators into the blood stream. Substances produced by microorganisms, such as lipopolysaccharide, endotoxin, exotoxin, lipid moieties, and other products can induce septic shock by stimulating host cells to release numerous cytokines, chemokines, leukotrienes, and endorphins.

Question 72

What is the role of endotoxin in septic shock?

Answer 72

Endotoxin is a lipopolysaccharide found in the outer membrane of Gram-negative bacteria.

Functionally, the molecule is divided into three parts:

(1) the highly variable O-specific polysaccharide side chain (conveys serotypic specificity to bacteria and can activate the alternate pathway of complement);
(2) the R-core region (less variable among different Gram-negative bacteria; antibodies to this region could be cross protective); and
(3) lipid-A (responsible for most of the toxicity of endotoxin).

Endotoxin stimulates tumor necrosis factor (TNF) and can directly activate the classic complement pathway in the absence of antibody.

Endotoxin has been implicated as an important factor in the pathogenesis of human septic shock and Gram-negative sepsis.

Therapy has focused on developing antibodies to endotoxin to treat septic shock.

Antibodies to endotoxin have been used in clinical trials of sepsis with variable results.

Question 73

What is the role of cytokines in septic shock?

Answer 73

Cytokines, especially TNF, play a dominant role in the host’s response.

Endotoxin and exotoxin both induce TNF release in vivo and produce many other toxic effects via this endogenous mediator.

TNF is released primarily from monocytes and macrophages. It is also released from natural killer cells, mast cells, and some activated T-lymphocytes.

Antibodies against TNF protect animals from exotoxin and bacterial challenge.

Other stimuli for its release include viruses, fungi, parasites, and interleukin-1 (IL-1).

In sepsis, the effects of TNF release may include cardiac dysfunction, disseminated intravascular coagulation, and cardiovascular collapse.

TNF release also causes the release of granulocyte–macrophage colony-stimulating factor (GM-CSF), interferon-α, and IL-1.

IL-1 is produced primarily by macrophages and monocytes. IL-1, previously known as the endogenous pyrogen, plays a central role in stimulating a variety of host responses, including fever production, lymphocyte activation, and endothelial cell stimulation, to produce procoagulant activity and to increase adhesiveness.

IL-1 also causes the induction of the inhibitor of tissue plasminogen activator and the production of GM-CSF. These effects are balanced by the release of platelet-activating factor and arachidonic metabolites.

IL-2, also known as T-cell growth factor, is produced by activated T-lymphocytes and strengthens the immune response by stimulating cell proliferation.

Its clinically apparent side effects include capillary leak syndrome, tachycardia, hypotension, increased cardiac index, decreased SVR, and decreased left ventricular ejection fraction.

Question 74

Why is there a high mortality rate with neonatal sepsis?

Answer 74

The neonate’s host defense can usually respond successfully to ordinary microbial challenge. However, defense against major challenges appears limited, which provides an explanation for the high mortality rate with major neonatal sepsis.

As in adults, the immune system consists of four major components:
cell-mediated immunity (T-cells),
complement system,
antibody-mediated immunity (B-cells), and
macrophage–neutrophil phagocytic system.

The two most important deficits in newborn host defenses that seem to increase the risk of bacterial sepsis are the quantitative and qualitative changes in the phagocytic system and the defects in antibody-mediated immunity.

The proliferative rate of the granulocyte–macrophage precursor has been reported to be at near-maximal capacity in the neonate.

However, the neutrophil storage pool is markedly reduced in the newborn compared with the adult.

After bacterial challenge, newborns fail to increase stem cell proliferation and deplete their already reduced neutrophil storage pool.

Numerous in vitro abnormalities have been demonstrated in neonatal polymorphonuclear neutrophils, especially in times of stress or infection. These abnormalities include decreased deformability, chemotaxis, phagocytosis, C3b receptor expression, adherence, bacterial killing, and depressed oxidative metabolism.

Chemotaxis is impaired in neonatal neutrophils in response to various bacterial organisms and antigen–antibody complexes.

Granulocytes are activated by their interaction with endothelial cells followed by entry into secondary lymphoid issues via the endothelial venules.

Initial adhesion of granulocytes is dependent on their expression of l-selectin, a cell adhesion molecule expressed on the granulocyte cell surface.

Evaluation of cord blood has demonstrated a significantly lower expression of l-selectin on granulocyte surfaces when compared with older newborn (5 days old) and adult samples, indicating a depressed level of interaction with vascular endothelial cells at the initial stage of adhesion.

Although phagocytosis has additionally been demonstrated to be abnormal in neonatal phagocytes, it appears that this phenomenon is most likely secondary to decreased opsonic activity rather than an intrinsic defect of the neonatal polymorphonuclear neutrophils.

Currently, there is inconclusive evidence to support or refute the routine use of granulocyte transfusions in the prevention or treatment of sepsis in the neonate.

Preterm and term newborns have poor responses to various antigenic stimuli, reduced gamma globulin levels at birth, and reduced maternal immunoglobulin supply from placental transport.

Almost 33% of infants with a birth weight less than 1500 g develop substantial hypogammaglobulinemia.

IgA and IgM levels are also low due to the inability of these two immunoglobulins to cross the placenta.

Thus, neonates are usually more susceptible to pyogenic bacterial infections because most of the antibodies that opsonize pyogenic bacterial capsular antigens are IgG and IgM.

In addition, neonates do not produce type-specific antibodies because of defects in the differentiation of B-lymphocytes into immunoglobulinsecreting plasma cells and in T-lymphocyte-mediated facilitation of antibody synthesis.

In the term infant, total hemolytic complement activity, which measures the classic complement pathway, constitutes approximately 50% of adult activity.

The activity of the alternative complement pathway, secondary to lowered levels of factor B, is also decreased in the neonate.

Fibronectin, a plasma protein that promotes reticuloendothelial clearance of invading microorganisms, is deficient in neonatal cord plasma.

Question 75

What is the role of IVIG in neonatal sepsis?

Answer 75

The use of intravenous immunoglobulins (IVIGs) for the prophylaxis and treatment of sepsis in the newborn, especially the preterm, low birth weight infant, has been studied in numerous trials with varied outcomes.

In one study, a group of infants weighing 1500 g was treated with 500 mg/kg of IVIG each week for 4 weeks and compared with infants who were not treated with immunoglobulin.

The death rate was 16% in the IVIG-treated group compared with 32% in the untreated control group.

Another analysis examined the role of IVIG to prevent and treat neonatal sepsis. A significant (but only marginal) benefit was noted from prophylactic use of IVIG to prevent sepsis in low birth weight premature infants.

However, using IVIG to treat neonatal sepsis produced a greater than 6% decrease in the mortality rate.

A review of 19 randomized control trials found a 3% decrease in the incidence of neonatal sepsis in preterm infants without a significant difference in all-cause and infection-related mortality when prophylactic IVIG was administered.

Based on the marginal reduction of neonatal sepsis without a reduction in mortality, routine use of prophylactic IVIG cannot be recommended.

Question 76

What is the role of CSF in neonatal sepsis?

Answer 76

Colony-stimulating factors (CSFs) are a family of glycoproteins that stimulate proliferation and differentiation of hematopoietic cells of various lineages. GM-CSF and granulocyte CSF (G-CSF) have similar physiologic actions.

Both stimulate the proliferation of bone marrow myeloid progenitor cells, induce the release of bone marrow neutrophil storage pools, and enhance mature neutrophil effect or function.

Preliminary studies of GM-CSF in neonatal animals demonstrate enhancement of neutrophil oxidative metabolism as well as priming of neonatal neutrophils for enhanced chemotaxis and bacterial killing.

Both GMCSF and G-CSF induce peripheral neutrophilia within 2–6 hours of intraperitoneal administration. This enhanced affinity for neutrophils returns to normal baseline level by 24 hours.

Studies have confirmed the efficacy and safety of G-CSF therapy for neonatal sepsis and neutropenia.

Other investigations have demonstrated no longterm adverse hematologic, immunologic, or developmental effects from G-CSF therapy in the septic neonate.

Prolonged prophylactic treatment in the very low birth weight neonate with recombinant GM-CSF has been shown to be well tolerated and to result in a significant decrease in the rate of nosocomial infections.

Question 77

What is unique to the newborn in septic shock?

Answer 77

Unique to the newborn in septic shock is the persistence of fetal circulation and resultant pulmonary hypertension.

In fact, the rapid administration of fluid can further exacerbate this problem by causing left-to-right shunting through a patent ductus arteriosus (PDA) and subsequent congestive heart failure from ventricular overload.

Infants in septic shock with a new heart murmur should undergo a cardiac echocardiogram.

If present, a PDA may warrant treatment with indomethacin (prostaglandin inhibitor) or surgical ligation to achieve closure, depending on the clinical picture.

Question 78

What are some considerations in the care of the neonate in septic shock?

Answer 78

The critical care of a neonate/infant in septic shock can be extremely challenging.

Septic shock has a distinctive clinical presentation and is characterized by an early compensated stage where one can see a decreased SVR, an increase in cardiac output, tachycardia, warm extremities, and an adequate urine output.

Later in the clinical presentation, septic shock is characterized by an uncompensated phase in which one will see a decrease in intravascular volume, myocardial depression, high vascular resistance, and a decreasing cardiac output.

Management of these patients is based on the principles of source control, antibiotics (broad-spectrum, institutionally based when possible and including antifungal agents as warranted), and supportive care.

Patients with severe septic shock often do not respond to conventional forms of volume loading and cardiovascular supportive medications.

The administration of arginine vasopressin has been shown to decrease mortality in adult patients with recalcitrant septic shock.

Vasopressin (see Table 1.6), also known as antidiuretic hormone (ADH), is made in the posterior pituitary and plays a primary role in water regulation by the kidneys.

In septic shock, vasopressin has profound effects on increasing blood pressure in intravascular depleted states.

Sparked initially by a randomized, double-blinded, placebo-controlled study in adults that demonstrated a beneficial effect of vasopressin in recalcitrant septic shock, its utilization in the pediatric population has become common.

Question 79

Which of the following is true in relation to a newborn?

A Premature infants are those whose weight is below the 10th percentile for age.

B Premature infants are those whose height is below the 10th percentile for age.

C Large for gestational age (LGA) are those whose weight is above the 98th percentile.

D LGA are those whose weight is above the 95th percentile.

E Small for gestational age (SGA) are those whose birthweight is <2500 g.

Answer 79

C Large for gestational age (LGA) are those whose weight is above the 98th percentile.

Newborns are classified based on gestational age and weight.

Pre- term infants are those born before 37 weeks of gestation.

Term infants are those born between 37 and 42 weeks of gestation, whereas post-term infants have a gestation that exceeds 42 weeks.

Newborns with weight at or above the 90th percentile are LGA and those below the 10th percentile are SGA.

Newborns whose weight falls between these extremes are appropriate for gestational age.

Infants born before 37 weeks of gestation, regardless of birthweight, are considered premature. A premature infant has thin and transparent skin with an absence of plantar creases, soft malleable fingers, and ears with poorly developed cartilage. In females, the labia minora appear enlarged and the labia majora appear small. In males, the testes are usually undescended and the scrotum is underdeveloped.

SPSE 1

Question 80

Which of the following is true for SGA?

A Symmetrical SGA suggests insults late in pregnancy.

B Asymmetrical SGA suggests fetus affected from early pregnancy.

C Asymmetrical SGA is at a higher risk of complications.

D Severe malnutrition is a cause of symmetrical SGA.

E Maternal substance abuse leads to asymmetrical SGA.

Answer 80

C Asymmetrical SGA is at a higher risk of complications.

SGA is defined as birthweight below the 10th percentile for gestational age. Symmetrical (proportional) SGA infants have all growth parameters symmetrically small. They usually suggest fetus affected from early pregnancy (e.g. constitutional or chromosomal disorder, intrauterine infections such as cytomegalovirus, rubella or toxoplasmosis, anaemia, maternal substance abuse).

On the other hand, asymmetrical (disproportional) SGA infants have their weight centile < length and head circumference because of intrauterine growth retardation due to insult late in pregnancy (e.g. pre-eclampsia, severe malnutrition). Asymmetrical SGA infants are particularly at risk of complications.

Symmetrical SGA infants often stay small, and later average intellectual ability is slightly reduced compared with appropriately grown infants. It has been suggested that these infants are at an increased risk of developing coronary vascular disease, stroke, obesity and hypertension in later life.

SPSE 1

Question 81

Which of the following indicates normal growth for a term neonate?

A Birthweight doubles by 5 months.

B Birthweight doubles by 6 months.

C Weight is four times birthweight by 12 months.

D Body length doubles by 12 months.

E Body length triples by 12 months.

Answer 81

A term newborn grows at a rate of 25–30 g/day over the first 6 months of life, doubling its birthweight by 5 months of age.

An average infant triples his or her birthweight by 12 months, and by 3 years the weight is four times the birthweight.

By the end of the first decade, the weight increases 20-fold.

Body length increases 50% by the end of the first year of life and increases threefold by the end of the first decade.

The pre-term infant’s growth pattern is quite distinct from that of a term infant.

Loss of 15% of a pre-term infant’s birthweight is usual in the first 7–10 days of life, compared with a 7%–10% weight loss for a term infant.

After the initial period of weight loss, a pre-term infant gains weight at a much slower rate of 10–20 g/day.

SPSE 1

Question 82

Anaesthetists need to be concerned about the possibility of loose teeth in children until what age?

A 1 year
B 3 years
C 6 years
D 9 years
E 12 years

Answer 82

E 12 years

Humans have two sets of teeth. The teeth that appear first are called milk teeth. These teeth are later shed and are replaced by a set of permanent teeth.

Milk teeth start appearing at 6 months of age. The first milk teeth to appear are the lower central incisors.

All milk teeth erupt by 3 years of age. The milk teeth are shed from 6 years onwards until about 10 years of age.

The permanent teeth appear by 6 years of age.

Between 6 and 9 years the child has some milk teeth as well as some permanent teeth and this period is called the mixed dentition period.

By 12 years of age, all the milk teeth should be shed and be replaced by the permanent teeth.

SPSE 1

Question 83

Which of the following is not a primitive reflex?

A Moro reflex
B grasp reflex
C rooting reflex
D stepping reflex
E parachute reflex

Answer 83

E

Normally developing infants demonstrate a number of early or primitive reflexes that disappear by 4–6 months.

1 moro reflex: sudden head extension causes symmetrical extension of limbs followed by flexion.

2 Grasp reflex: fingers or toes grasp an object placed on the palm or sole.

3 Rooting reflex: head turns towards a tactile stimulus placed near the mouth.

4 Stepping reflex: an infant held vertically will develop stepping motions when the sole of a foot touches a hard surface.

5 Asymmetrical neck reflex: when lying supine, if the head is turned, a ‘fencing posture’ is adopted with the outstretched arm on the side to which the head is turned.

The parachute reflex is a postural reflex, rather than a primitive reflex.

Postural reflexes emerge later to provide the basis for the control of automatic balance, posture and voluntary movement.

SPSE 1

Question 84

Which of the following is true regarding gross motor development?

A At 6 weeks infants should hold head upright when held sitting.

B Infant should sit without support by 6 months.

C Infants should be cruising round edge of furniture by 6 months.

D By 2 months all children should be walking independently.

E By 2 years a child can skip on both feet.

Answer 84

B Infant should sit without support by 6 months.

Gross motor development shows rapid progression in the first 18 months.

A newborn’s head lags on pulling to a sitting position but is held in extension in ventral suspension.

At 6 weeks an infant lifts its head on lying prone and moves it from side to side, and at 3 months holds head upright when held sitting.

By 6 months an infant should sit without support.

This relies on two reflexes, which the baby must have developed, including the parachute reflex in response to falling and the righting reflex to position head and body back to vertical on tilting.

An infant becomes mobile by crawling or bottom shuffling or commando crawling.

By 10 months infants tend to cruise round the edge of furniture.

By 12 months, only 50% of infants are walking independently.

Children tend to learn advanced motor skills after 1 year and learn to run and jump and kick a ball by 20 months.

At 4 years of age, they can hop on one leg, go up and down stairs one leg at a time, and ride a bike.

By 5 years of age they can skip on both feet.

SPSE 1

Question 85

Which of the following is true regarding fine motor development?

A Infants’ pincer grip develops by 6 months.

B Infants’ palmar grip develops by 6 weeks.

C An infant at 6 weeks turns head from side to side to follow an object.

D By 6 months an infant uses index finger to point to objects.

E By 3 years a child can draw a triangle.

Answer 85

C An infant at 6 weeks turns head from side to side to follow an object.

Fine motor skills are dependent on good vision. Hence these skills should be assessed alongside visual development.

A newborn can fix and follow a near face moving across the field of vision.

By 6 weeks, the infant is more alert and can turn the head side to side.

As the primitive grasp reflex starts to decrease, infants will start to reach for objects. At 6 months, grip is with the whole palm (palmar grasp); the infant holds objects with both hands and will bang them together and transfers objects between hands.

By 10 months infants demonstrate pincer grip using thumb and first finger and by 12 months infants use index finger to point to objects.

Fine motor skills can be assessed with pencil control and building bricks.

At 14 months infants begin to scribble and at 3 years they can draw a circle and copy or make a bridge with building bricks.

At 4 years they can draw and copy a cross.

By 5 years they can draw a triangle.

SPSE 1

Question 86

Which of the following is true regarding speech and language development?

A By 12 weeks an infant will begin to coo and laugh.

B By 6 months an infant will say ‘mama’ or ‘dada’.

C By 13 months an infant has a vocabulary of 10 words.

D By 18 months an infant progresses to three-word phrases e By 2 years an infant knows its age and several colours.

Answer 86

A By 12 weeks an infant will begin to coo and laugh.

Speech should be assessed along with hearing. Impaired hearing will affect language development.

Newborns will quieten to voices and startle to loud noises.

By 6 weeks they respond to mother’s voice and by 12 weeks will vocalise alone or when spoken to and begin to coo and laugh.

At 6 months, infants will use consonant monosyllables and by 8 months will use non-specific two-syllable babble (e.g. ‘mama’ or ‘dada’).

By 13 months their words become more appropriate.

By 18 months they have a vocabulary of 10 words and are able to demonstrate six parts of the body.

Their conversation becomes increasingly complex with sentence development in the second year.

At 20 months, they begin to combine two words together, progressing to three-word phrases by the age of 2 years.

By 3 years they know age and several colours.

SPSE 1

Question 87

Which of the following is true regarding social and behavioural development?

A An infant starts smiling by 6 weeks.

B An infant drinks from a cup by 8 months.

C By 12 months an infant uses a spoon to self-feed. D An infant can dress themselves by 18 months.

E All of the above.

Answer 87

A An infant starts smiling by 6 weeks.

At 6 weeks, the infant starts to smile and becomes socially responsive.

At 8 months, they demonstrate separation anxiety when separated from parents, and begin to start to feed self using fingers.

By 10 months they begin to wave ‘goodbye’.

At 12 months they will drink from a cup, and at 18 months use a spoon to feed self.

At 2 years they can remove some clothes and will try to dress self.

Some children will get potty-trained by 2 years, but others may take longer.

By 24 months children start to copy actions and activities that they see around them, and progress in the second year to play on their own or alongside peers in parallel play.

From 3 years they start to have interactive play, taking turns and following simple rules.

SPSE 1

Question 88

Which of the following is true regarding developmental assessment?

A Constant squints persistent beyond 8 weeks need to be referred to ophthalmologists.

B A child not sitting by 9 months needs to be referred for evaluation.

C A child not walking by 18 months needs to be referred for evaluation.

D A cognitive function IQ test score of >70 is normal.

E All of the above.

Answer 88

E All of the above.

Fine motor skills are dependent on good vision. Therefore fine motor skills are usually assessed alongside visual development.

Some infants may demonstrate an intermittent squint. Constant squints and all those persisting beyond the 8-week check must be referred to an ophthalmologist.

By 6 months an infant should sit without support. Children not sitting by 9 months should be referred for evaluation.

Likewise, by 12 months 50% of infants are walking independently and children not walking by 18 months must be referred for evaluation.

The Denver Developmental Screening Test is a relatively quick test of children’s abilities and an assessment of whether they have achieved their age-appropriate developmental milestones.

Cognitive function can be assessed by an IQ test, but this does not assess all skill areas and may be significantly affected by language problems.

An IQ >70 is considered normal,
50–69 as mild learning difficulty,
35–49 as moderate learning difficulty,
20–34 as severe learning difficulty and
<20 as profound learning difficulty.

SPSE 1

Question 89

Perinatal definitions

A Low birthweight
B Very low birthweight
C Extremely low birthweight
D Small for gestational age (SGA)
E Large for gestational age
F Pre-term
G Term birth
H Post-term
I Symmetrical SGA
J Asymmetrical SGA
K Clifford’s syndrome

From the list of options above, choose which one is the most likely definition for the presentation in each of the clinical scenarios. Each option may be used once, more than once, or not at all.

1 A 37-weeks neonate with a birthweight of 2000 g.

2 A 37-weeks neonate with a birthweight of 3000 g.

3 A 37-weeks neonate whose birthweight is under the 10th centile for gestational age.

4 A 37-weeks neonate whose birthweight is over the 90th centile for gestational age.

5 A 37-weeks neonate whose weight centile is less than length and head circumference.

Answer 89

1A, 2G, 3D, 4E, 5I

Newborns are classified based on gestational age and weight.

Pre-term infants are those born before 37 weeks of gestation.

Term infants are those born between 37 and 42 weeks of gestation, whereas post-term infants have a gestation that exceeds 42 weeks.

Newborns whose weight is at or above the 90th percentile are large for gestational age and those below the 10th percentile are SGA.

Newborns whose weight falls between these extremes are appropriate for gestational age.

Infants born before 37 weeks of gestation, regardless of birthweight, are considered premature.

A premature infant has thin and transparent skin with an absence of plantar creases, soft malleable fingers, and ears with poorly developed cartilage. In females, the labia minora appear enlarged and the labia majora appear small. In males, the testes are usually undescended and the scrotum is underdeveloped.

SGA is defined as birthweight <10th percentile for gestational age.

Symmetrical (proportional) SGA have all growth parameters symmetrically small. They usually suggest fetus affected from early pregnancy (e.g. constitutional or chromosomal disorder).

On the other hand, with asymmetrical (disproportional) SGA, the weight centile is < length and head circumference because of intrauterine growth retardation due to insult late in pregnancy (e.g. pre-eclampsia).

Asymmetrical SGA infants are particularly at risk of complications.

Symmetrical SGA infants often stay small and later average intellectual ability is slightly reduced compared with appropriately grown infants. It has also been suggested that these infants are at an increased risk of developing coronary vascular disease, stroke, obesity and hypertension in later life.

Low birthweight is birthweight <2500 g, very low birthweight is birthweight <1500 g and
extremely low birthweight is birthweight <1000 g.

SPSE 2

Question 90

Normal growth and dentition

A 2 months
B 6 months
C 10 years
D 12 years
E 6000 g
F 9000 g
G 7500 g
H 10–20 g/day
I 25–30 g/day
J 30–40 g/day

From the list above, choose which one most commonly represents the following scenarios. Each option may be used once, more than once, or not at all.

1 A term neonate has a birthweight of 3000 g. What would be the expected weight at 5 months?

2 A neonate born at 34 weeks’ gestation has a birthweight of 1900 g. What would be his expected weight gain?

3 A term neonate has a birthweight of 3000 g. He is seen at 12 months with a reducible inguinal hernia. What is his expected weight at 12 months of age?

4 Anaesthetist at surgery notices a very loose lower central milk tooth. What is the patient’s age likely to be?

Answer 90

1E, 2H, 3F, 4B

A term newborn grows at a rate of 25–30 g/day over the first 6 months of life, doubling its birthweight by 5 months of age.

An average infant triples his or her birthweight by 12 months, and by 3 years the weight is four times the birthweight.

By the end of first decade, the weight increases 20-fold.

Body length increases 50% by the end of the first year of life and increases threefold by the end of the first decade.

The pre-term infant’s growth pattern is quite distinct from that of a term infant.

An anticipated loss of 15% of a pre-term infant’s birthweight is usual in the first 7–10 days of life, compared with a 7%–10% weight loss for a term infant.

After the initial period of weight loss, a pre-term infant gains weight at a much slower rate of 10–20 g/day.

Humans have two sets of teeth. The teeth that appear first are called milk teeth. These teeth are later shed and are replaced by a permanent set of teeth called permanent teeth.

Milk teeth start appearing at 6 months of age. The first milk teeth to appear are the lower central incisors.

All milk teeth erupt by 3 years of age.

The milk teeth are shed from 6 years onwards until about 10 years of age.

The permanent teeth appear by 6 years of age.

Between 6 and 9 years of age the child has some milk teeth as well as some permanent teeth and this period is called the mixed dentition period.

By 12 years of age, all the milk teeth should be shed and they should be replaced by the permanent teeth.

SPSE 2