Landmark Articles In Neonatology: Basis For Current Clinical - - PowerPoint PPT Presentation

Landmark Articles In Neonatology: Basis For Current Clinical Practice

Smeeta Sardesai, MD, Ms Ed, FAAP Associate Professor of Pediatrics Associate Professor of Pediatrics Associate Director Neonatal-Perinatal Medicine Fellowship Program Keck School of Medicine University of Southern California

Disclosure

Who’s hiding what? “ I have nothing to hide!”

• Thermoregulation
• Respiratory Support

Key Areas That Provide The Basis For The Care of All Neonates

• Nutrition

“If we can just maintain these weaklings warm from the time they are born we will be able to save a great majority

• f them, leaving the warmth of their mother’s womb is the

greatest challenge they face…..”

• Dr. Stephane Tarnier, 1880.
• Tarnier’s (1880) most important contribution was

introduction of incubators. introduction of incubators.

• He compared premature infant mortality before and after

the introduction of the device in a large case series (500 infants).

• Mortality of infants in the1200 to 2000gm range fell from

66% to 38%.

• Blackfan and Yaglou in 1933 made serial observations of

body temperature and outcomes of preterm infants.

• The authors concluded that subnormal temperature is

characteristic of prematurity which should be preserved.

Thermoregulation in Preterm Infants

• This paper led to preterm babies being nursed in

inappropriately low environmental temperatures.

• Blackfan KD, et al. The premature infant: a study of the effects of atmospheric

conditions on growth and development. Am J Dis Child 1933;46:1175–1236.

• In 1958, Silverman et al. in a randomized controlled trial
• bserved that prematurely born infants nursed in

incubators maintained at a temperature of 31.7°C during the first 5 days of life had a better survival rate than those nursed at 28.9°C (84% versus 68%).

Landmark Article on Thermoregulation in Neonates

• The beneficial effect was observed in all birthweight

categories.

Optimizing the thermal environment has proven significant for improving the chances of survival for small infants.

Silverman W.A., et al. Pediatrics 1958; 22: 876-886.

• Remarkable progress has been made in the production of

infant incubators, which are currently highly technological devices.

The most important thing: Infants should be nursed in the neutral thermal environment and have a core body temperature between 36.5 – 37.20 Celsius.

125 years Later…..

• Admission temperature (<35°C) was inversely related to

mortality, with a 28% increase in death and 11% increase in late

• nset sepsis for every 1°C decrease in temperature.
• Retrospective observational study, at 29 NICUs in the Canadian

Temperature in Preterm Infants in 21st Century

• Laptook AR, et al. Admission Temperature of Low Birth Weight Infants:

Predictors and Associated Morbidities. Pediatrics 2007:119;e643-e649.

Retrospective observational study, at 29 NICUs in the Canadian Neonatal Network of 9,833 inborn infants born at <33 weeks' gestation found that the relationship between admission temperature and adverse neonatal outcomes was U-shaped.

• The lowest rates of adverse outcomes were associated with

admission temperatures between 36.5°C and 37.2°C.

• Lyu Y, et al. JAMA Pediatr. 2015;169(4): e150277.

• Key interventions that reduce heat loss after birth:
• Increasing ambient temperature in the delivery room.
• Use of heated humidified gases.
• Use of exothermic or thermal mattresses.
• Use of heat loss barriers: head covers or plastic body covers.
• Skin-to-skin kangaroo mother care.

Implications for Practice

• Skin-to-skin kangaroo mother care.
• Implementation of a multidisciplinary guideline improves

preterm infant admission temperatures.

Knobel-Dail, RB. Role of effective thermoregulation in preterm neonates. Research and Reports in Neonatology 2014, 4:147-156. J Perinatol. (Virginia) 2017 Jul 20. doi:10.1038/jp.2017.112. J Pediatr (Rio J). 2017 Sep 6. pii: S0021-7557

• Thermoregulation
• Respiratory Support:
• Supplemental O2.
• Surfactant.

Key Areas That Provide The Basis For The Care of All Neonates

• Surfactant.
• Mechanical Ventilation.
• Non Invasive ventilation.
• Antenatal steroids.
• Nutrition

• 1902: Budin recommended O2 inhalation for cyanotic episodes

in premature infants.

• 1917: Ylppö advised that O2 be introduced into the stomach by

a tube as a means of resuscitating premature infants and to manage apnea.

• 1922: Hess recommended continuous or intermittent showers of

Supplemental Oxygen for Preterm Infants

O2 in the attempt to ward off cyanotic attacks.

• 1923: Bakwin noted that when O2 was administered early,

subsequent cyanotic attacks were fewer in number and more readily amenable to treatment.

• To reap full benefit from treatment, Bakwin recommended that O2 be

given over a long period of time, preferably in a closed chamber.

• By the 1930’s, the notion of “if a little is good, a lot should

be better” was espoused and liberal use of O2 was the standard of treatment for cyanotic infants.

Supplemental Oxygen for Preterm Infants

That was the beginning of “ROUTINE” use of supplemental O2 in the care of small or preterm infants.

• 1940s: Liberal use of O2, and inability to measure arterial

O2 tension, many preterm infants developed childhood blindness.

• 1951: Kate Campbell described that the liberal use of O2

was directly linked to ROP and blindness.

Supplemental Oxygen for Preterm Infants

• Campbell K: Intensive oxygen therapy as a possible cause of retrolental

fibroplasia: a clinical approach. Med J Aust 1951;2:48–50.

• First RCT of comparing routine O2 (>50% for 28 days)

with curtailed O2 (<50% only for cyanosis or respiratory difficulty) showed:

• No appreciable increase in mortality with curtailed oxygen
• Two thirds reduction in the rate of cicatricial ROP.
• fibroplasia: a clinical approach. Med J Aust 1951;2:48–50.
• Bolton DP, Cross KW. Further observations on cost of preventing

retrolental fibroplasia. Lancet. 1974;1(7855):445–448.

• O2 concentrations > 40% were considered dangerous and

incubators were designed so that no more than 40% O2 could be delivered.

• Increased mortality of infants with respiratory distress

syndrome (RDS).

Effect of Restrictive Use of Oxygen

syndrome (RDS).

• Increase in cerebral palsy in surviving preterm infants.

Avery ME.: J Pediatr 1960;57:553–559. McDonald AD: Arch Dis Child 1963; 38:579–588.

It has been estimated that EACH SIGHTED INFANT GAINED, MAY HAVE COST SOME 16 DEATHS

• There are two opposing concerns.
• Lower O2 levels (targeting SpO₂ at < 90%) may impair

neurodevelopment or result in death. Higher O levels (targeting SpO₂ > 90%) may increase

Use of Oxygen in Current Practice

• Higher O2 levels (targeting SpO₂ > 90%) may increase

severe ROP or chronic lung disease. Oxygen Use in Neonatal Care: A TWO-EDGED SWORD

• Systematic reviews and metanalysis of 5 trials.

1.

Canadian Oxygen Trial [COT]

2.

Surfactant, Positive Pressure, and Oxygenation Randomized Trial [SUPPORT]

3.

Benefits of Oxygen Saturation Targeting trial

In Search of Optimal Oxygen Saturations

[BOOST-II] (Australia, New Zealand and UK)

• Askie LM, et al. Cochrane Database Syst Rev. 2017;4:
• CD011190. Epub 2017 Apr 11.
• Manja V, et al. Pediatrics. 2017;139(1).
• Stenson BJ. Neonatology. 2016;109(4):352-8.

• Low SpO₂ at < 90% target range:
• Higher rate of mortality at 18 to 24 months corrected age.
• Higher incidence of NEC.
• Lower incidence of ROP requiring treatment.

No difference in the:

Effects of Targeting Lower Versus Higher Arterial Oxygen Saturations

• No difference in the:
• Combined outcome of death and major disability at 24 months

corrected age.

• Neurodevelopmental outcome, blindness, severe hearing loss, or

cerebral palsy.

• Askie LM, et al. Cochrane Database Syst Rev. 2017;4: CD011190. Epub 2017 Apr 11.
• Manja V, et al. Pediatrics. 2017;139(1).
• Stenson BJ. Neonatology. 2016;109(4):352-8.

• We still don’t know the target range of oxygen saturations

in very preterm infants to ensure optimal survival without disability and the lowest possible rate of ROP.

• AAP Clinical Report states that targeted SpO2 range of

90% to 95% may be safer than 85% to 89% at least for

Supplemental Oxygen for Preterm Infants 115 Years Later…

90% to 95% may be safer than 85% to 89% at least for some infants. Avoid Hyperoxia Without Permitting Hypoxemia

Committee on Fetus and Newborn. Pediatrics 2016;138(2):e20161576.

Artificial Surfactant Therapy

• The clinical era of surfactant replacement opened with the

seminal article by Fujiwara.

– Demonstrated the acute beneficial effects of natural surfactant in 10 preterm infants with RDS to a bolus of modified bovine surfactant given endo-tracheally.

Fujiwara T, et al. Lancet 1980, 315:55–59.

• The introduction of surfactant treatment was associated

with overall decrease in neonatal mortality in the USA.

• Considered a cost-effective therapy for RDS compared

with other therapeutic interventions in premature infants.

Fujiwara T, et al. Lancet 1980, 315:55–59.

Surfactant therapy has been a major contribution to care

• f the preterm newborn during the past 35 years

Mechanical Ventilation

Bloxsom Air Lock, 1952

• The first infant positive pressure ventilator:
• Dr. Maria Delivoria-Papadopulus, 1961
• The first negative pressure ventilator: Dr.

Mildred Stahlman, 1961

Arch Dis Child. 1964;39:481–484

Introduction of widespread mechanical ventilation in the NICU during 1960s and 1970s

Syndrome of Bronchopulmonary Dysplasia

• In 1967, Northway et al. first described

bronchopulmonary dysplasia (BPD), that developed in premature infants exposed to mechanical ventilation and

• xygen supplementation.
• Northway, et al. NEJM, February 1967;276:357–374.
• Northway's original definition has been extensively

modified over the last 4 decades.

Effect of Endotracheal Mechanical Ventilation on BPD

• Fischer HS, Bührer C. Pediatrics. 2013 Nov;132(5):e1351-60.

Avoiding eMV in infants <30 weeks' GA have beneficial impact on preventing BPD.

N =3289

• Shift towards gentler and less invasive forms of

respiratory support in an effort to avert adverse pulmonary outcome.

Noninvasive Ventilation (NIV)

• Recognition of newborn’s glottis maneuvers as a means to retain

lung volume.

• This observation led to the use of CPAP:
• Gregory box: Gregory GA, et al. N Engl J Med. 1971; 284(24):1333-40.
• CPAP by face mask: Rhodes P, Hall R. Pediatrics. 1973;52:1–5.

Introduction of CPAP

Harrison VC, et al. Pediatrics 1968; 41(3):549.

• Significant decrease in mortality in infants > 1,500 g with RDS.
• End-distending pressure using nasal catheters positioned in the midnares.

Kattwinkel J, et al. Pediatrics. 1973;52:131–134.

Head Box for CPAP Face Mask Nasal Prongs for CPAP

• 37 years after Gregory’s initial signpost, first RCT of

Nasal CPAP or intubation at birth (COIN trial) for very preterm infants reported.

• Lower rate of death or BPD in CPAP group.
• Shorter duration of ventilation in the CPAP group.

Nasal CPAP or Intubation At Birth

• Recent data shows that routine use of CPAP significantly

reduces the combined outcome of BPD (assessed at 36 weeks’ PMA) or death in at-risk preterm infants, with a number needed to treat of 17.7.

Morley C.J. et al., COIN Trial. N Engl J Med 2008; 358:700-708.

Caffeine for Apnea of Prematurity (CAP Trial)

• Barbara Schmidt, et al. Caffeine Therapy for Apnea of
• Prematurity. N Engl J Med 2006; 354:2112-2121.
• Multicenter (Canada, USA, Australia, Europe and

Israel) randomized, placebo-controlled trial. N = 2,006.

• CAP trial showed reduction in BPD rates in infants

who received caffeine (36%) vs placebo group (47%) (OR: 0.63, 95%CI: 0.52-0.76; P < 0.001).

• Decrement of BPD rates was attributed to a shorter

duration (about 1 wk) of endotracheal intubation and positive pressure ventilation in the caffeine-treated patients compared with the controls.

• Liggins GC, Howie RN. A controlled trial of antepartum

glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants. Pediatrics. 1972;50(4):515.

• This paper showed that a single course of antenatal

corticosteroid therapy administered to women at risk for

Antenatal Corticosteroids in the Management of Preterm Birth

corticosteroid therapy administered to women at risk for preterm delivery reduced the incidence and severity of respiratory distress syndrome and mortality in offspring.

• In 1990, Crowley published a meta-analysis of 12

randomized controlled trials of antenatal corticosteroids, demonstrating that this therapy significantly reduced RDS and other neonatal morbidities such as intraventricular hemorrhage and necrotizing enterocolitis as well as

• verall neonatal mortality.

Landmark Trial for the Use of Antenatal Steroids

• verall neonatal mortality.
• It took 20 years for ACOG committee to approve

Antenatal corticosteroid therapy for fetal maturation.

Crowley P, et al. Br J Obstet Gynaecol. 1990; 97(1):11-25. Int J Gynaecol Obstet. 1995 Mar; 48(3):340-2.

• Using CPAP immediately after birth with subsequent selective

surfactant administration may be considered as an alternative to routine intubation with prophylactic or early surfactant therapy.

• If respiratory support with a ventilator is needed, then early

administration of surfactant followed by rapid extubation is

What Is Recommended For Practice?

administration of surfactant followed by rapid extubation is preferred to prolonged ventilation.

• We administer prophylactic caffeine therapy in extremely low

birth weight infants (BW <1000 g) to avoid intubation and mechanical ventilation, or to enhance extubation.

• AAP. Policy Statement: Pediatrics, January 2014, 133 (1):171.

• Thermoregulation
• Respiratory Support:
• Supplemental O2.
• Surfactant.

Key Areas That Provide The Basis For The Care of All Neonates

• Surfactant.
• Antenatal steroids.
• Mechanical Ventilation.
• Non Invasive ventilation.
• Nutrition

Feeding Practices

• Initial thirsting/starving:

– Norm in the US and UK in the 1940s.

• The infants were starved from 12 hours to 4 days after

birth.

• In the early 1960s serious doubts began to be expressed
• In the early 1960s serious doubts began to be expressed
• ver the wisdom of delaying the feeding of premature

infants.

• Neurological and intellectual impairment in infants of low

birthweight is related to the amount of weight loss after birth.

Freedman, A. M. (1961). The effect of hyperbilirubinemia on premature

• infants. Progress report. New York Medical College Department of

Psychiatry.

• The first detailed clinical study of early milk feeding to

premature infants was reported by Smallpeice and Davies.

• Compared “early fed group” (B. Wt between 1000 and 2000 g),

fed human breast milk within 2 hours of birth in volumes of 60 ml/kg/day, increasing to 160 ml by the fourth day to “late fed

Immediate Feeding of Premature Infants

group” (infants of comparable B. Wt), starved for at least 24 hours.

• The early fed infants regained B. Wt sooner and lost less Wt

than the late fed group. Bilirubin levels and symptomatic hypoglycemia was less in the early fed infants.

Smallpiece V., and Davies P.A.: Immediate feeding of premature infants with undiluted breast-milk. Lancet 1964; 2: pp. 1349-135.

• 1890: the discovery of the chemical composition of milk.
• 1920s: Introduction of formula that approximated human

milk.

• 1940s: Rapid growth of preterm infants who were fed

formulas with increased protein, Ca, P, Na and decreased

Formula Versus Human Milk

formulas with increased protein, Ca, P, Na and decreased saturated fats.

• 1950s: Introduction of polyethylene tubes for feeding.
• Gordon, H. H. Feeding of premature infants: A comparison of human and cow's milk.
• Am. J. Dis. Child.1947, 73:442-452.
• Royce S, et al. Indwelling polyethylene nasogastric tube for feeding premature infants.

Pediatrics 1951,8:79–81.

• In the 1960s and 70s, the use of tube feeding allowed full

enteral nutrition in preterm infants.

• Rapid advancement of tube feeding, led to development
• f NEC with increased enteral feedings.
• Feedings were routinely withheld for long periods (weeks) in
• rder to prevent NEC.

Feeding Practices

• rder to prevent NEC.
• In a systematic review (7 trials, 964 VLBWI) on timing of

introduction of nutritional enteral feeding to prevent NEC, early introduction of progressive enteral feeding (1 to 2 days of age) did not increase the risk of NEC, mortality,

• r feed intolerance.

Morgan J, et al. Cochrane Database Syst Rev. 2014, (12):CD001970.

• Observational studies, and meta-analyses comparing feeding with

formula milk versus donor breast milk, suggest that feeding with breast milk has major non-nutrient advantages for preterm or low birth weight infants.

• In a retrospective study of 550 VLBW neonates who received

Human Milk Feeding

• Henderson G, et al. Cochrane Database of Systematic Reviews 2007, Issue 4. Art.

No.: CD002972.

• In a retrospective study of 550 VLBW neonates who received

donor human milk and those who received mothers’ own milk (MOM) of 50% or more of hospital days, had significantly lower rates of NEC (3.4%) compared to infants who received MOM on fewer than 50% of hospital days (13.5% NEC).

• Chowning R, et al. Journal of Perinatology 2016, 36: 221-224.

“Mother's milk is the ideal food, and every premature infant should have it, if its variations and management are properly understood”... “The first milk after a premature labor is colostrum milk and has characteristics important for the child’s survival”.

Vanderpoel A. American Journal of the Medical Sciences 1901, 121:410-421. 121:410-421.

“Mother’s Milk is the Best” is still the motto today

“Study The Past If You Would Define The Future”

• Confucius
• Confucius