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The Premature
Neonate
Claude Abdallah, MD, MSc
Preterm Neonates
• Morbidity and mortality in this population has
decreased over the past 25 years.
• In extremely low birth weight premature
neonate(<1000 g): mortality < 50% (80% in 1980).
• Contributing Factors:
- Use of surfactant shortly after birth,
- Specialization of neonatal care units, and
- Changes in mechanical ventilator therapy.
However, physiological challenges persist and affect
the anesthesia management.
Airway and Work of
Breathing
Spaeth JP, O'Hara IB, Kurth CD: Anesthesia for the micropremie.
Semin Perinatol 1998; 22:390-401.
Airway and Work of
Breathing
- Small airways : predispositon to obstruction and
difficulty with ventilation.
-
Insertion of an ETT increases resistance and work of
breathing far greater for the premie (2.5 or 3 mm
inside diameter [ID]): (Resistance to airflow is inversely
proportional to the fifth power for large airways and to the fourth
power of the radius for small airways. )
- Additional partial occlusion from loss of muscle tone
during anesthesia.
Pediatr Crit Care Med. 2009;10(1):1-11.
Effect of airway pathology
• Subglottic stenosis,
• Tracheal stenosis,
• and Tracheobronchomalacia
occur commonly in the micropremie increase
further resistance to airflow and work of
breathing.
• Also, may necessitate the placement of even a
smaller ETT>> airway resistance from the stenosis
distal to the endotracheal tube
POSTNATAL DEVELOPMENT OF
THE LUNGS AND THORAX
• The respiratory system is
not fully developed at
birth.
• The morphologic and
physiologic development
of the lungs continues
throughout the first years
of life.
• Alveolar formation begins
only about the 36th week
of gestation.
• Thick-walled saccular
spaces  decrease lung
compliance.
Production of Surfactant
-Begins between 23 to 24 weeks
of gestation,
-Remain inadequate until 36
weeks of gestation lung
volumes and compliance are
decreased increase
intrapulmonary shunt and
ventilation/perfusion mismatch
and increase the risk of hypoxia.
-Anesthesia further
decreases V/Q mismatch.
Ventilation with continuous PEEP
during anesthesia required but
limited:
Susceptibility to O2 toxicity,
barotrauma, and development
of bronchopulmonary dysplasia.
RAPID DESATURATION IN
PREMIES?WHY?
-
Lung volume disproportionately small
-Higher metabolic rates in infants: The neonatal oxygen consumption is
approximately 6 ml/kg/min versus 3 ml/kg/min in the adult
• Even under normal circumstances the immature cardiac and
respiratory systems must function near maximum to support this
metabolic demand.
-Elastic recoil pressure of the lung and thorax are low
• Poorly developed thoracic muscle mass
• Increasing respiratory rate rather than tidal volume
• The diaphragm is the primary respiratory muscle – has fewer highoxidative muscle fibers and is less resistant to fatigue than the adult
diaphragm.
• Mechanical challenge: Ribs “Raised” small increase in thoracic
cavity volume with contraction of the diaphragm.
,
Respiratory Control and Prematurity
Response to hypoxia:
Biphasic Ventilatory Response
- Initially, ventilation increases during hypoxia,
but after several minutes,
- Ventilation decreases and apnea may ensue.
Anesthetic drugs:
- depress the ventilatory responses to both
hypoxia and hypercapnia.
Anesthesiology
59:495-498, 1983
Editorial
Life-threatening Perioperative Apnea
in the Ex-”premie”
George A. Gregory and David Steward
Post anesthetic Care & Discharge of Neonates
• Full Term Infant (Born at PCA* ≥ 37 weeks) and otherwise
healthy:
• If ≤ 45 weeks PCA: Overnight stay in hospital in monitored bed.
• Must have at least 12 hours of apnea-free period prior to
discharge.
• Preterm Infant (Born at PCA <37 weeks) and otherwise healthy:
• If ≤ 55 weeks PCA: Overnight stay in hospital in monitored bed.
• Must have at least 12 hours of apnea-free period prior to
discharge.
Ex-premature infants should not undergo anesthesia for elective
surgery until they are at least 56 weeks of PCA and Hct > 30%.
A minimal stay of 2 hours of apnea free period in PACU is
required for all these patients. If needed, they should be
transported with monitoring and accompanied by a registered
nurse.
Kurth et al, 1987
Prospective study using
pneumography
47 premature infants
37% incidence of postop. prolonged
apnea in infants 32 - 55 wks. PCA
Initial episode may occur as late as
12 hrs. postop.
All types of surgical procedures,
including NEC and VP shunts
How about caffeine?
Incidence of Perioperative Apnea and PB:
Caffeine 5mg/kg
Caffeine
Postop. prolonged apnea none
with bradycardia
Postop. PB
none
Controls
8(73%)*
2(18%)
Postop. apnea < 15 sec
8(89%)
1(9%)
Postop. caffeine level
mg/L (range)
5-8.6
zero
Periodic Breathing
•Three or more periods of apnea 3-15 secs. separated by < 20 secs. of normal
respiration
Incidence of Postoperative Apnea, PB and
Desaturation: Caffeine 10mg/kg
Caffeine
Postop. prolonged apnea none
Postop. PB >1%
none
Postop. desat.< 90%
none
Postop. caffeine level
mg/L (range)
15-19
Controls
13(8%)*
4(25%)
8(50%)
zero
• Caffeine concentrations as low as 3-5
mg/L can decrease apneic spells in
neonates, Brief apnea persisted
• Plasma concentrations of 8-20 mg/L
are required for optimal response
• No toxicity(????) with concentrations
as high as 50 mg/L
Survival without disability to age 5 years after neonatal caffeine therapy
for apnea of prematurity. JAMA. 2012 Jan 18;307(3):275-82.
• Five-year follow-up in academic hospitals.
Randomized, placebo-controlled. Caffeine for
Apnea of Prematurity Study. A total of 1640 children
with birth weights of 500 to 1250 g.
• The combined outcome of death or disability was
not significantly different for the 833 children
assigned to caffeine from that for the 807 children
assigned to placebo.
Postoperative Apnea in Former
Preterm Infants
Spinal vs General Anesthesia
Incidence of Postoperative Apnea and PB
General
Anesthesia
Prolonged Apnea
with bradycardia
5(31%)
PB > 1%
1
Intubation or
ventilation
0
Spinal
Spinal +
Anesthesia Ketamine
0
8(89%)*
0
2
0
0
Is Preoperative Transfusion
Necessary?
Postoperative Complications
Hct > 30%
Brief Apnea
0
Hct < 30%
0
PB > 1%
0
20%
Prolonged Apnea
21%
80%*
Bradycardia
0
20%
Summary
• Anemia in preterm infants
increased incidence of postop.
apnea
• Anemic infants had high HbF and low
2,3 DPG
• Defer elective surgery
• Close postoperative monitoring
Anesthesiology
82:809-822, 1995
Postoperative Apnea in Former Preterm Infants after Inguinal
Herniorrhaphy
Metanalysis of previous studies
Limitations:
Small number of patients
Significant variation of incidence of apnea between different
institutions
Considerable variation in the duration and type of monitoring
and definitions of apnea
Predicted probability of apnea
after leaving recovery room by
weeks postconceptual age
(weeks) for infants who did not
have apnea in recovery room or
anemia . Bottom marks indicate
the number of data points by
postconceptual age. The risk
does not fall below 1% with 95%
statistical confidence until 56
weeks postconceptual age.
Anesthesiology. 82(4):809-822, April 1995.
Fisher D
Anesthesiology
82:807-808,1995
“.....Establishing policy regarding
the postop. management of expremature infants undergoing
inguinal hernia repair requires a
decision regarding acceptable
risk”
Pediatric Anesthesia 22 (2012) 1139-1141
Thermoregulation &
Premature Neonate
Small size and
Increased surface-area-to-volume ratio.
Increased thermal conductance .
Limited range of the neutral thermal environment= Range of ambient temp.
at which metabolic rate is minimal.
Normal body temp. range for a neonate is 36.5 to 37.7 °C.
Temp. below 36 °C are considered hypothermic.
Predisposition to APNEA, BRADYCARDIA, and/or METABOLIC
ACIDOSIS.
Maximum ventilatory response to PCO2 decreases.
Extubation and Transfer Criteria
Non Shivering
Thermogenesis
-Principally metabolism of brown fat (2-6% of TBW).
-Brown fat differentiates at the 26 to 30 weeks gestational
period.
-Multinucleated cells, numerous mitochondria.
-Abundant vascular supply and innervation.
-COST: increases in norepinephrine (3X), glucocorticoids and
thyroxine production.
Prevention of hypothermia is extremely important
Thermoregulatory Thresholds
The intersection of line with the temp scale: threshold.
Interthreshold range: Core temperatures not triggering autonomic thermoregulatory responses: 0.2-0.4 deg. C
ASessler DI: Temperature monitoring. In Miller RD (ed): Anesthesia, 4th ed. New York, Churchill Livingstone, 1994, p 1363.
Effects of Mild Hypothermia
-
Stress response: V-C (incr. SVR, CVP).
-
Decreased RBF and GF. Cold diuresis, impaired sodium
reabsorption = hypovolemia.
-
Impaired coagulation: Defect in platelet fction & clotting
factors.
-
Leftward shift of oxy-Hb dissociation curve + BMR=
deleterious effect.
-
Increased wound infections (immune function & v-c).
Duration of hosp. by 20%.
-
Shivering: Increase in wound pain and in intraocular and
intracranial pressures.
Effects of Anesthesia Medications
on Thermoregulation
• Volatile anesthetics: Hypothalamus + direct
vasodilatory effect. Inhibit brown fat
thermogenesis. Dose-dependent.
• Opioids: reduce vasoconstriction.
• Barbiturates: peripheral vasodilation.
• Ketamine : less thermoregulatory effect.
• Muscle relaxants: prevent shivering
thermogenesis by effect on muscle tone.
Pharmacological Effects of
Hypothermia
• Decreased hepatic & renal blood flow & metabolism
=Prolongation of drug effects.
• Protein binding increases as body temperature decreases.
• The MAC of inhalational agents is 5-7% per 1C in core
temp, but no change in speed of inhalational induction.
• Prolong the duration of neuromuscular blocking agents.
• Delays discharge from PACU and may prolong the need for
mechanical ventilation.
Cycle resulting from cooling in the neonate.
(From Klaus M and Fanaroff A: Care of the high-risk neonate, ed. 3, Philadelphia, WB Saunders Co.)
Covering the infant’s head with plastic wrap can greatly reduce the evaporative heat loss.
During maxillofacial surgery, rectal temp. increased in infants given forced-air but remained nearly
constant in patients warmed with circulating-water. (From Kurz et al. Anesth Analg 77:89, 93).
Anesthetics and the
Immature Brain
•
•
Of particular concern are the reports in immature rats showing that prolonged exposure
to isoflurane, ketamine, or midazolam …precipitates apoptosis in many regions of the
brain.
Attributed to the neurotransmitters glutamate and γ-aminobutyric acid, which act as
trophic factors in the developing brain
•
Based on the life cycle of the rat compared with the human, the 4-day, 7-day, 10-day,
and 14-day postnatal age rat corresponds to 28-week gestation, 32-week gestation, 40week gestation, and 55-week postconceptual age human.
•
Prolonged exposure at very high concentrations.
•
Potential for neurotoxicity from inhaled anesthetics, midazolam, and ketamine.. may be
greater in preterm infants than full-term infants, although there is no evidence that similar
neurotoxicity occurs in humans at any age exposed to any anesthetics.
Arguments- Drug Dose
•
Anesthetic requirements for injectable agents
much higher in small animals
•
•
•
Propofol 100x
Ketamine 10x
Higher doses led to much higher blood levels
Prematurity &
Cardiovascular System
Greater risk of cardiovascular collapse during anesthesia:
Structural: More connective tissue, less organized contractile elements
Increased dependence on extracellular calcium concentration.
Less compliant fetal heart has a flatter Frank-Starling curve
Less sensitive to catecholamines because of near-maximal baseline βadrenergic stimulation.
• Cardiac output depends more on heart rate in the premature than the full
term neonate.
The high resting heart rate in the premature does not permit cardiac output to
increase to the same extent as full term.
•
•
•
•
•
Prematurity and
Circulation
• Small absolute blood volumelittle blood loss
during surgery can cause hypovolemia, and shock.
• Autoregulation is not well developed in the premie,
heart rate may not increase with hypovolemia 
blood flow and oxygen delivery to the brain and
heart may decrease with little blood loss.[
• Anesthesia blunts baroreflexes in the micropremie,
further limiting the ability to compensate for
hypovolemiapredispose the micropremie to
cardiovascular collapse during major surgery.
Circulating Blood Volume in Micropremature Infants, Premature
Infants, Full-Term Neonates, Infants, and Children
Micropremie
Premie
Full-term
neonate
Infant
Child
Blood Volume
(mL/kg)
110
100
90
80
70
Weight (kg)
1
1.75
3
Total Blood
Volume (mL)
110
175
270
25 mL Blood
Loss
Percentage
Total Blood
Volume (%)
23
14
9
10
20
800
1400
3
2
Neurologic Development
•
•
•
•
•
The impact of premature birth on the central nervous system (CNS) depends
on gestational age at birth and the severity of cardiovascular, respiratory, and
other postnatal stressors.
The area of the brain most susceptible to injury in the micropremie is the
periventricular white matter.
The white matter consists of preoligodendrocytes, astrocytes, and neuronal
axons.
Late in the second trimester (24–27 weeks' gestation), preoligodendrocytes
and astrocytes multiply tremendously and most cortical and subcortical
structures begin to develop.
The periventricular white matter is a “watershed region” and sus-ceptible to
poor perfusion and hypoxic-ischemic injury during conditions of hypotension,
low cardiac output, hypoxemia, and hypocarbia.
Intraventricular
Hemorrhage
Premature neonates are more likely to exhibit severe
long-term neurocognitive sequelae,
Risk factors include fetal distress, vaginal delivery, low
APGAR scores, metabolic acidosis, hypercapnia, and
the need for mechanical ventilation. Respiratory distress
syndrome, seizures, pneumothoraces, hypoxemia,
acidosis, severe hypocarbia, and the use of vasopressor
infusions.
Rapid fluctuations in cerebral blood flow, cerebral
blood volume, and cerebral venous pressure appear to
play a role in the development of IVH
.Factors that may decrease the incidence and severity of
IVH include administration of sedation with opioids,
antenatal glucocorticoids, or indomethacin
Grade 1: hemorrhage
limited to the germinal
matrix
Grade 2: hemorrhage
extending into the
ventricular system
Grade 3: hemorrhage
into the ventricular
system and with
ventricular dilatation
Grade 4: hemorrhage
extending into brain
parenchyma.
Retinopathy of
Prematurity
• Occurs in approximately 50% of extremely low birth
weight infants, with the incidence being inversely
proportional to birth weight and gestational age.
• Variations in arterial oxygenation (hypoxia or
hyperoxia) and exposure to bright light appear to
play a role.
• During anesthesia, we use the lowest inspired
oxygen concentration that provides oxygen
saturations between 92% and 96% and strive to
avoid significant fluctuations in oxygen saturations.
Renal and Metabolic
Function
•
•
•
•
•
Glomeruli continue to form postnatally until approximately 40 days
Fewer nephrons and smaller glomerular size, low cardiac output,
hypotension, and nephrotoxic drugs may inhibit glomerular growth
and development. Baseline plasma creatinine levels are higher with
increasing prematurity and remain elevated until 3 weeks of age.[
Susceptibility to hyponatremia because of reduced proximal tubular
reabsorption of sodium and water and reduced receptors for
hormones that influence tubular sodium transport.
Plasma potassium concentration occurs in preterm infants and results
from a shift in potassium from the intracellular to extracellular space.
Greater with decreasing gestational age and birth weight.
Low cardiac output and urine output may further increase serum
potassium concentrations and predispose to cardiac arrhythmias.
Glucose Regulation
• The micropremie is at risk for hypoglycemia as well
as hyperglycemia. Decreased glycogen and body
fat predispose to fasting hypoglycemia, whereas
decreased insulin production with infusion of
dextrose predisposes to hyperglycemia.[42,][43]
Glucose production is poorly regulated within a
large range of glucose and insulin concentrations.
The micropremie is also relatively insulin resistant
and requires a higher insulin infusion rate to reach
normoglycemia.[44] The use of total parenteral
nutrition and glucocorticoids places them at high
risk for hyperglycemia.
Glucose and the Brain
• Hyperglycemia in neonates appears to protect the brain from
ischemic damage. Strikingly different outcome between
neonates and adults.
• Relatively mild hypoglycemia is known to cause brain
damage in preterm infants: Limited stores of glucose and
consume glucose anaerobically.
• Administration of dextrose-containing fluids and close
monitoring of blood glucose levels is vital during anesthesia.
• Mild or moderate hyperglycemia during surgery is best
managed by reducing the rate of infusion of dextrosecontaining solutions and not administering insulin.
Hepatic and Hematologic
Function
•
Immature hepatic function
•
•
Reduced albumin synthesis enhancing the “free” concentration of anesthetic drugs .
Particular risk for spontaneous liver hemorrhage: during laparotomy for necrotizing
enterocolitis (NEC), is associated with large intravenous fluid resuscitation, and is difficult
to control surgically.
•
The ideal hematocrit level : controversial. Ht : 44% to 48%.
•
Liberal vs restrictive transfusion group: Restrictive transfusion group had a higher
incidence of intraparenchymal brain hemorrhage, periventricular leukomalacia, and
episodes of apnea.
•
The risks of blood transfusion should be weighed against the benefits of improved oxygen
delivery and fewer medical complications.
•
Thrombocytopenia (<150,000/mm3) occurs frequently (70% of micropremature infants.)
(sepsis, disseminated intravascular coagulation, and NEC are common causes.)
Preoperative evaluation : include a recent platelet count for major procedures.
Inhaled Agents
MAC in the micropremie is considerably less
than in full-term infants
LeDez KM, Lerman J: The minimum alveolar concentration
[MAC] of isoflurane in preterm neonates. Anesthesiology
1987; 67:301-307.
Intravenous Agents
• Half-life and clearance of fentanyl and morphine are
increased. Thus, for a given dose of fentanyl, higher plasma
fentanyl concentrations and a slower clearance of the drug
will occur in the micropremie, which serves to prolong
analgesia as well as prolong respiratory depression.
• Thiopental is that it depresses cardiac output and causes
venodilation and may precipitate cardiovascular collapse in
the setting of hypovolemia; it also has a very long half-life in
preterm and term infants.
• Recovery from propofol anesthesia is slower in micropremies
compared with term infants because they have less fat and
muscle tissue to redistribute the drug.
• Benzodiazepines are eliminated by the liver and thus can last
several hours in the micropremie with decreased liver function.
Arguments- Drug Dose
• MAC of isoflurane in infant mice is 2.26%
• Jevtovic-Todorovic et al showed significant
neurodegeneration with 0.75%(0.33 MAC)
Arguments - Lifespan
• Humans have a more prolonged synaptogenesis
period
• May require much longer exposure for significant
apoptosis