PICU Endocrine Issues

Adrenal Insufficiency

Cortisol Physiology

• Stress--> Hypothalamus produces CRH--> Anterior Pituitary produces ACTH--> Adrenal gland (Zona fasiculata) produces Cortisol

Figure 1: The HPA Axis

• Cortisol secretion in the PICU often mediated by inflammation with elevated levels of IL-1, IL-2, and IL-6 stimulating increased cortisol production while TNF-a is thought to downregulate cortisol secretion

• Cortisol has approximately 1% of the mineralcorticoid activity of aldosterone

• Biologic duration of action ~8 hours

• Cortisol modulates the transcription of thousands of gene (estimated at up to 20% of the entire genome)

• Cortisol is antinflammatory, inhibiting NF-KB (central switch for inflammation) via increasing production of IKB (inhibits NF-KB). It also downregulates T and B cell proliferation and macrophage inhibitory factor

• Cortisol also affects hemodynamics by: enhancing cardiac contractility, upregulating vasoactive receptors, increasing production of catecholamines, and reducing vascular permeability

• Cortisol also promotes catabolism, augmenting the effects of glucagon and inhibiting the effects of insulin (serving as a counter-regulatory hormone). This is one of the key mechanisms of criticall illness induced hyperglycemia

• Patients with high baseline cortisol levels and failure to have a delta of 9 mcg/dl in cortisol in response to ACTH stimulation represent those at the highest risk of morbidity/mortality

Assessment of Adrenal Insufficiency

• Classically defined as a random level <10 µg/dl (normal healthy controls have cortisol levels of 5-10 µg/dl but in periods of stress, increase up to 20-25 µg/dl) or a delta <9 µg/dl in response to an ACTH stimulation test

• ACTH Stim test: Normal dose 250 mcg (can consider 125 mcg for <30 kg) with measurement of cortisol at baseline and 60 minutes later. Low dose stim uses 1 mcg but has not been as well studied and may not be as sensitive of a test (up to 50% of a healthy adult cohort failed to show a delta of 9 µg/dl with low dose stim test)

Causes of Adrenal Insufficiency

• Primary: This is due to damage to the adrenal glands (ie due to autoimmune disease such as with Addison's disease or hemorrhage as in Waterhouse-Friedrichsen Disease) or congential adrenal hyperplasia (21 hydroxylase or 11 hydroxylase deficiency). Symptoms include vomiting, abdominal pain, chronic hyperpigmentation, hyperkalemia, and shock

• Secondary: Most common form seen in the PICU. May be due to etomidate use (inhibits 11B hydroxylase in the synthesis pathway), chronic steroid use with subsequent suppression of ACTH, or due to critical illness which limits cortisol production as well as increases tissue resistance

Treatment

• CORTICUS, the largest trial (499 pts) of hydrocortisone therapy for septic shock (adult patients) demonstrated no difference in mortality with the use of hydrocortisone. This was in contrast to an initial study by Annane (JAMA 2002)

• Current practice is to utilize hydrocortisone (generally 2 mg/kg IV q6 up to 50 mg IV q6) in refractory septic shock (ie 2-3 vasoactives at high doses with persistent shock), recognizing the evidence for this practice is quite limited. The use of hydrocortisone may be otherwise justified if there is diagnosed adrenal insufficiency, recent etomidate exposure, or recent chronic steroid use

• Potential adverse effects of utilizing steroids include increased hospital acquired infections, increased incidence of septic shock, hyperglycemia, exacerbation of ICU related myopathy or weakness, and GI bleeding (in earlier trials utilizing higher doses of steroids)

Figure 2: Relative Steroid Potencies

Hyperglycemia

• Critical illness--> increased cortisol, epinephrine, glucagon (all counter-regulatory hormones) which counteract the effect of insulin, leading to relative insulin resistance, glycogenolysis, gluconeogenesis, catabolism, and thus hyperglycemia

• Hyperglycemia has been clearly linked to worse outcomes and increased rates of infection^5-9

Treatment

• van den Berghe et al published the first landmark trial of tight glycemic control (NEJM, 2001), demonstrating a nearly 50% reduction in mortality for mechanically ventilated adults in a critical care unit in Leuven, Belgium (~60% post-cardiac surgery) when targeting glucose levels of 80-110 vs. 180-200 mg/dl. n=1548

• However, Finfer et al found in the NICE-SUGAR study increased mortality (27.5 vs 24.9%, p=0.02) with tight glucose control (80-110 mg/dl) vs conventional therapy (<180 mg/dl) as well as increased rates of hypoglycemia (6.8 vs .5%, p <0.001). n=6104

• Agus et al found in the SPECS trial no difference in infection rates, mortality, length of stay with tight glycemic control in postoperative pediatric cardiac surgery patients when compared to standard therapy. The incidence of severe hypoglycemia <40 mg/dl was only 3% in the intensive insulin group utilizing a continuous glucose monitor. n=980

• The CHiP study of 1369 PICU patients (60% had undergone cardiac surgery) in England also found no differences in major clinical outcomes such as mortality or ventilator free days, although the incidence of hypoglycemia was higher in the tight glycemic control group (7.3 vs 1.5% p<0.001)

• HALF-PINT (Heart and Lung Failure-Pediatric Insulin Titration Trial) is a multi-institutional NIH-funded study investigating tight glyemic control in the PICU population. The trial was stopped by the DSMB at the first interim analysis and did not show benefit to tight glucose control with some concern for hypoglycemia in the intervention arm.

• Current practice, given the available evidence, is to avoid hyperglycemia, particularly when it is above the renal threshold for reabsorption (180-200 mg/dl) but given the risk of hypoglycemia and questionable benefit of tight glycemic control, to generally target blood glucose levels of 110-180 mg/dl as opposed to 80-110 mg/dl.

Thyroid Dysfunction

Sick Euthyroid Syndrome

• Occurs with critical illness, surgery, or malnutrition

• Labs: Marked decrease in T3, generally normal free T4 and TSH (can be somewhat low or even somewhat elevated), and generally increased rT3

• Generally not treated in the PICU as studies have revealed no benefit

• Some evidence for supplementation of T3 in post-cardiac surgery patients with subsequent improvement in myocardial contractility

References

1) D. Annane, V. Maxime, F. Ibrahim, et al.: Diagnosis of adrenal insufficiency in severe sepsis and septic shock. Am J Respir Crit Care Med. 174 (12):1319-1326 2006 16973979

2) D. Annane, V. Sebille, C. Charpentier, et al.: Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA.288 (7):862-871 2002 12186604

3) C.L. Sprung, D. Annane, D. Keh, et al.: Hydrocortisone therapy for patients with septic shock. N Engl J Med. 358 (2):111-124 2008 18184957

4) P.E. Marik, S.M. Pastores, D. Annane, et al.: Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: consensus statements from an international task force by the American College of Critical Care Medicine. Crit Care Med. 36 (6):1937-1949 2008 18496365

5) A.R. Yates, P.C.I.I. Dyke, R. Taeed, et al.: Hyperglycemia is a marker for poor outcome in the postoperative pediatric cardiac patient. Pediatr Crit Care Med. 7(4):351-355 2006 16738506

6).R.G. Branco, P.C. Garcia, J.P. Piva, et al.: Glucose level and risk of mortality in pediatric septic shock. Pediatr Crit Care Med. 6 (4):470-472 2005 15982437

7) A. Cochran, E.R. Scaife, K.W. Hansen, et al.: Hyperglycemia and outcomes from pediatric traumatic brain injury. J Trauma. 55 (6):1035-1038 2003 14676647

8)D.C. Gore, D. Chinkes, J. Heggers, et al.: Association of hyperglycemia with increased mortality after severe burn injury. J Trauma. 51 (3):540-544 2001 11535907

9) N.J. Hall, M. Peters, S. Eaton, et al.: Hyperglycemia is associated with increased morbidity and mortality rates in neonates with necrotizing enterocolitis. J Pediatr Surg. 39 (6):898-901 2004 15185221

10) G. van den Berghe, P. Wouters, F. Weekers, et al.: Intensive insulin therapy in the critically ill patients. N Engl J Med. 345 (19):1359-1367 2001 11794168

11) S. Finfer, et al.: for the NICE-SUGAR Study Investigators: Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 360 (13):1283-12972009 19318384

12) Agus MS, Steil GM, Wypij D, Costello JM, Laussen PC, Langer M, Alexander JL,Scoppettuolo LA, Pigula FA, Charpie JR, Ohye RG, Gaies MG; SPECS Study Investigators. Tight glycemic control versus standard care after pediatric cardiac surgery. N Engl J Med. 2012 Sep 27;367(13):1208-19. Epub 2012 Sep 7. PubMed PMID: 22957521; PubMed Central PMCID: PMC3501680.

13) Macrae D, Grieve R, Allen E, Sadique Z, Morris K, Pappachan J, Parslow R,Tasker RC, Elbourne D; CHiP Investigators. A randomized trial of hyperglycemic control in pediatric intensive care. N Engl J Med. 2014 Jan 9;370(2):107-18.