Definition

Adrenal insufficiency in preterm newborns and to a lesser extent in late preterm and term newborns is due to a:

1. 
   

   Transient adrenocortical insufficiency of prematurity (TAP): an “immature” hypothalamic-pituitary-adrenal (HPA) axis with reduced capability of the adrenal glands to produce cortisol secondary to intermediate enzyme deficiency in the steroidogenesis pathway, but with rapid recovery of the hormonal axis in early (∼14 days) postnatal life

   
   
2. 
   

   Relative adrenal insufficiency: failure to produce adequate quantity of stress hormone resulting in inappropriately low-circulating cortisol concentration for the degree of stress or illness experienced (a condition similar to that observed in critically ill adults with seemingly normal adrenal function)

Adrenal insufficiency due to congenital adrenal hyperplasia (CAH) is a different condition and not covered in this chapter.

Incidence

1. 
   

   The exact incidence of TAP and adrenocortical insufficiency in late preterm or term newborns is not known. This is because the normal range of serum cortisol concentration in this age group is difficult to define, and the level that constitutes clinical adrenal impairment has not been ascertained (see Diagnosis).

   
   
2. 
   

   The earlier the gestation (primarily in those born <30 weeks), the higher is the chance of developing this condition.

   
   
   
   
   1. 
      

      It is fallacious to assume that all preterm infants with improvement of blood pressure after receiving systemic corticosteroids are due to TAP, because corticosteroids per se can also elevate the blood pressure in adrenal competent subjects.

      
      
   2. 
      

      Those infants with genuine cortisol deficiency will respond promptly and dramatically to a “replacement” or “stress” dose of corticosteroids.

Pathophysiology

1. 
   

   TAP is most likely due to delay in maturation of the HPA axis, resulting in decreased ability of the adrenal glands to produce adequate amount of cortisol.

   
   
2. 
   

   Adrenocortical insufficiency is likely related to ineffective adrenal steroidogenesis secondary to immature intermediate enzymes, eg, 11β-hydroxylase and 3β-hydroxysteroid dehydrogenase activity of the glucocorticoid pathway and manifests as increased cortisol precursors/cortisol ratios.

   
   
3. 
   

   This may be associated with normal fetal development of the adrenal glands that generally do not synthesize cortisol de novo until 30 weeks’ gestation, and utilize placental progesterone for production of cortisol, thereby bypassing the intermediate enzymes during the process.

   
   
4. 
   

   Although the use of antenatal corticosteroids has been shown to suppress the adrenal glands in preterm infants, no significant association has been reported between antenatal corticosteroids usage and TAP. However, prolonged use of steroids during the neonatal period may contribute to the relative adrenal insufficiency seen in infants following their NICU course.

   
   
5. 
   

   Inadequate circulating cortisol can have two major clinical consequences in preterm infants.

   
   
   
   
   1. 
      

      Chronic lung disease: Reduced ability to suppress inflammation can lead to exaggeration of inflammatory responses in the lungs, giving rise to increased risks of developing chronic lung disease.

      
      
   2. 
      

      Cardiovascular instability: Decreased ability to maintain hemodynamic stability resulting in refractory hypotension and cardiovascular collapse.

   
   
6. 
   

   Transient adrenocortical insufficiency in late preterm or term infants may be related to the above described mechanism, and in addition, transitional changes of hormone production from intrauterine to extrauterine life in the HPA axis.

   
   
   
   
   1. 
      

      During intrauterine life, CRH produced by the placenta plays a key role in determining the timing of parturition and maintaining homeostasis of the fetus. The sequence of events is as follows:

      
      

      ↑ CRH production by the placenta in late gestations →↑ placental-CRH in fetus → stimulate fetal cortisol production →↓ fetal hypothalamic-CRH production (negative-feedback mechanism), but paradoxically further ↑ placental-CRH production (positive-feedback mechanism) → sudden ↓ of circulating placental-CRH after birth → hypothalamus of the newborn remains transiently suppressed + pituitary gland remains transiently blunted after prolonged exposure to high-circulating CRH level in intrauterine life → transient adrenal insufficiency in sick late preterm or term newborns is due to maladaptation of the HPA axis in the immediate extrauterine life.

Risk factors

1. 
   

   Prematurity: Gestational age 30 weeks is probably the most important factor associated with the development of TAP.

   
   
2. 
   

   Early postnatal age: Most TAP occurs within the first 14 days of life, and the majority of cases presents within the first few days of life.

   
   
3. 
   

   Perinatal stress: Stressful situations and critical illnesses, eg, respiratory distress syndrome requiring mechanical ventilation, neonatal sepsis, congenital diaphragmatic hernia, surgery, etc, will render the infant vulnerable to the development of TAP.

   
   
4. 
   

   Duration of corticosteroid use: Contributes to the degree of suppression of the adrenal glands.

Clinical presentation

1. 
   

   Signs and symptoms

   
   
   
   
   1. 
      

      Refractory hypotension: The most serious and frequent presentation is systemic hypotension. Typically, severe hypotension occurs in very immature and sick infants within the first few days of life. Systemic blood pressure is refractory to volume expanders (eg, normal saline) and vasopressors (eg, dopamine, dobutamine, and epinephrine), but responds readily to a replacement or stress dose of corticosteroids. It is also commonly observed that the improvement in blood pressure occurs promptly within 6 hours of corticosteroids treatment, resulting in rapid weaning and termination of vasopressor support within 72 hours.

      
      
   2. 
      

      Oliguria: Oliguria is commonly encountered during the refractory hypotensive phase. Anuria is rare.

      
      
   3. 
      

      Electrolyte disturbances: The manifestations of classical adrenal failure with hyponatremia and hyperkalemia are rarely observed. This may be related to the use of intravenous fluid supplemented with the deficient electrolytes in critically ill infants. Hyperkalemia requiring therapeutic treatment is unusual.

      
      
   4. 
      

      Absence of signs and symptoms of CAH: Clinical features of CAH, eg, ambiguous genitalia, pigmented skin lesions, etc, are conspicuously absent.

      
      
   5. 
      

      Impaired cardiac contractility: Echocardiography may reveal impaired cardiac contractility and decreased ejection fraction.

   
   
2. 
   

   Condition variability

   
   
   
   
   1. 
      

      Late-onset TAP (>14 days of life) or late-onset glucocorticoid-responsive circulatory collapse (>7 days of life) is probably the same disease entity as TAP, but presents later in life. The etiology is the same as TAP with adrenal insufficiency secondary to delayed maturation of adrenal glands after birth and associates with increased cortisol precursors/cortisol ratios. Clinical manifestations are also similar and affected preterm infants usually present with hypotension, oliguria, hyponatremia, and worsening of respiratory condition.

      
      
   2. 
      

      Transient adrenal insufficiency is much less common in late preterm or term infants. The majority of cases are critically ill infants, eg, neonatal sepsis or those who have undergone surgery for conditions such as congenital heart diseases and gastrointestinal anomalies. The clinical features are similar to TAP.

Diagnosis

As preterm, very low birthweight (VLBW) infants can have very low serum cortisol concentration <3.62 µg/dL (<100 nmol/L) and be completely asymptomatic, it is important to interpret the laboratory cortisol result in conjunction with clinical signs. The diagnosis of TAP should include

1. 
   

   Refractory hypotension and

   
   
2. 
   

   Inappropriately low serum cortisol concentration: The basal serum cortisol concentration is probably the most practical laboratory test to be performed during an emergency situation of life-threatening hypotension in sick VLBW infants.

   
   
   
   
   1. 
      

      Basal serum cortisol concentration <7.2 µg/dL (<200 nmol/L) has been proposed as a cutoff level for starting hydrocortisone treatment. This cutoff level corresponds to the 50th percentile of basal serum cortisol concentration in VLBW infants requiring vasopressor support, and 25th percentile in those not requiring vasopressors (data from 137 VLBW infants who underwent the hCRH test).

      
      

      or

      
      
   2. 
      

      More scientifically, basal serum cortisol concentration <25th “adjusted cortisol percentile” after taking into account the perinatal stress factors calculated from a mathematical model (http://www.sta.cuhk.edu.hk/pswong/ACortP.html) can be considered low in symptomatic hypotensive VLBW infants, while a level between 25th and 50th adjusted cortisol percentile is intermediate. The 50th percentile of the nonadjusted serum cortisol value also corresponds to ∼7.2 µg/dL (200 nmol/L) on day 1 in this population (data from 209 VLBW infants with serum cortisol measured serially on day 1, 4, 7, 14, and 21).

      
      

      or

      
      
   3. 
      

      Basal serum cortisol concentration <15 µg/dL (414 nmol/L) as extrapolated from critically ill adults has also been proposed to be a cutoff for diagnosing adrenal insufficiency in term newborns or older infants. In practice, VLBW infants with refractory hypotension secondary to TAP seldom have such a high level.

   
   
3. 
   

   Stimulation tests

   
   
   
   
   1. 
      

      hCRH stimulation test: hCRH (1 µg/kg) can be administered intravenously with plasma corticotropin (ACTH) concentrations measured at 0 (basal) and 15 minute (peak level), plus serum cortisol concentrations measured at 0 (basal) and 30 minute (peak level). For reference, the 25th, 50th, and 75th percentiles of basal (peak level) ACTH are 18.5 (33.3), 24.8 (46.8), and 33.8 (66.2) pg/mL [ie, 4.1 (7.4), 5.5 (10.4), and 7.5 (14.7) pmol/L], respectively, and those for basal (peak level) cortisol are 5.8 (12.9), 10.4 (18.6), and 18.3 (26.7) µg/dL [ie, 161 (357), 286 (513), and 506 (737) nmol/L], respectively at day 7.

      
      
   2. 
      

      ACTH stimulation test: Synthetic ACTH analog (1 µg/kg) can be administered intravenously with serum cortisol concentrations measured at 0 (basal) and 40 minute (peak level). A response <12% from the basal level may be considered abnormally low. For reference, mean (± standard deviations) cortisol levels at 0, 30, and 60 minute are 10 (± 5.1) µg/dL [277 (± 144) nmol/L], 20.1 (± 6.5) µg/dL [558 (± 180) nmol/L], and 27.2 (± 9.0) µg/dL [753 (± 250) nmol/L], respectively.

      
      
   3. 
      

      Currently, no consensus exists on the diagnosis of TAP using stimulation tests during the intensive care setting; however, these tests may be useful in determining adrenal function later on.

Management

1. 
   

   Approach to refractory hypotension: As the etiologies of hypotension in preterm infants can be due to nonendocrinologic causes, eg, high positive pressure ventilation, decrease vascular tone, poor cardiac contractility, hypovolemia, etc, neonatologists should first identify these treatable factors. Hypotensive patients may be first treated with volume expanders (eg, normal saline) and vasopressors (eg, dopamine, dobutamine, and epinephrine). The management plan for refractory hypotension secondary to suspected TAP is as follows:

   
   
   
   
   1. 
      

      Once maximum doses of dopamine and dobutamine (20 µg/kg/min for both vasopressors) are administered and epinephrine is being considered at this critical stage, serum cortisol concentration should be measured.

      
      
   2. 
      

      Awaiting the result, hydrocortisone (1 mg/kg/dose) can be administered as a “trial” dose. The cardiovascular response should be prompt (<6 hours of treatment) and dramatic if the underlying etiology is TAP, plus if the basal serum cortisol calculated from the adjusted cortisol percentile (http://www.sta.cuhk.edu.hk/pswong/ACortP.html) is <25th percentile or an absolute serum cortisol concentration <7.2 µg/dL (<200 nmol/L) in a sick infant, a “stress dose” hydrocortisone regime (1 mg/kg every 8 hours for 5 days) should be initiated. Serum cortisol concentration between 25th and 50th adjusted cortisol percentile or absolute levels between 7.2 µg/dL (200 nmol/L) and 15 µg/dL (414 nmol/L) may be considered intermediately low.

      
      
   3. 
      

      A thorough search for the underlying cause is essential and hydrocortisone can be continued if the initial response to systemic corticosteroids is promising.

      
      
   4. 
      

      A lower dose regime of hydrocortisone 0.5 mg/kg every 12 hours has also been suggested, but this dosage may not be sufficient for maintaining a stable blood pressure, especially in the first 24 hours of treatment.

      
      
   5. 
      

      A replacement or stress dose of hydrocortisone is preferable to high-dose dexamethasone for treatment of TAP.

   
   
2. 
   

   When to avoid hydrocortisone

   
   
   
   
   1. 
      

      During hydrocortisone treatment, neonatologists should be vigilant in detecting complications of steroid use, including spontaneous intestinal perforation (SIP), hyperglycemia, electrolyte disturbances, and sepsis. Urine output should be monitored.

      
      
   2. 
      

      Nonsteroidal inflammatory drugs, eg, indomethacin and ibuprofen, must not be given concomitantly with systemic corticosteroids in view of markedly increased risks of SIP.

      
      
   3. 
      

      Hydrocortisone should be avoided or discontinued if the adjusted cortisol percentile is >75th percentile or an absolute serum cortisol concentration >15 µg/dL (>414 nmol/L), and more importantly, if there has not been any initial response to the drug, since high-circulating cortisol levels may also predispose to SIP, intraventricular hemorrhage, and other adverse outcomes.

      
      
   4. 
      

      There is not sufficient evidence to support the routine or prophylactic use of systemic corticosteroids for treatment of all early hypotension in preterm infants because of potential serious adverse effects, and only a relatively small proportion of VLBW infants with TAP will genuinely benefit from the treatment.

   
   
3. 
   

   Approach to chronic lung disease

   
   

   Early hydrocortisone is not a standard treatment for prophylaxis of chronic lung disease. However, prophylactic hydrocortisone (1 mg/kg/d for 12 days, follows by 0.5 mL/kg/d for 3 days) can benefit amnionitis-exposed extremely low birthweight infants by decreasing mortality and improving survival without chronic lung disease.

Prognosis

1. 
   

   Short-term outcomes: Infants with refractory hypotension secondary to TAP usually respond promptly within hours to hydrocortisone treatment. Treated infants require significantly less volume expanders and vasopressors. The duration of vasopressor treatment is also significantly shortened and most cases can wean off all vasopressors within 72 hours. Recurrence of TAP after the initial successful treatment is rare. Unlike high-dose dexamethasone, short-term somatic or brain growth does not appear to be affected.

   
   
2. 
   

   Medium-term outcomes: Early hydrocortisone treatment for chronic lung disease has not been associated with neurodevelopmental impairment or increase in incidence of cerebral palsy in extreme low birthweight infants assessed at 18 to 22 months corrected age. Hydrocortisone treatment may even be beneficial to future neurodevelopment. Somatic growth is not affected.

   
   
3. 
   

   Long-term outcomes: To be confirmed by future studies.