Common Endocrine Issues in the Pediatric Intensive Care Unit
2013; Elsevier BV; Volume: 29; Issue: 2 Linguagem: Inglês
10.1016/j.ccc.2012.11.006
ISSN1557-8232
AutoresAmélie von Saint André-von Arnim, Reid Farris, Joan Roberts, Ofer Yanay, Thomas V. Brogan, Jerry J. Zimmerman,
Tópico(s)Cardiovascular Syncope and Autonomic Disorders
Resumo•Critical illness pathogen-associated molecular patterns (PAMPS) and damage-associated molecular patterns (DAMPS) activate the neurogenic-endocrine-inflammatory stress response.•Antidiuretic hormone (ADH), the renin-angiotensin-aldosterone axis, and natriuretic peptide signaling normally govern sodium and water homeostasis, all of which can be disrupted in critical illness.•Stress-mediated protein catabolism provides amino acid substrate for gluconeogenesis, the antecedent to hyperglycemia commonly associated with critical illness; however, it remains unclear if strict glycemic control is beneficial in improving outcomes among critically ill children.•Diabetic ketoacidosis (DKA) continues to represent a common admission diagnosis among pediatric intensive care patients, and cerebral edema (ischemia-reperfusion injury, impaired cerebral blood flow regulation, altered blood-brain barrier, effective osmolality imbalance) remains a potentially fatal complication encountered during DKA management.•Critical illness related corticosteroid insufficiency (CIRCI) is commonly encountered in pediatric intensive care, but practitioners prescribing replacement corticosteroid, should be aware of not only the anti-inflammatory and hemodynamic stabilizing properties of the class of agents, but also the potential for enhanced muscle catabolism, hyperglycemia, hypernatremia, and acquired immunodeficiency adverse drug effects.•Both insufficient and excess thyroid hormone can produce life-threatening illness. Critical non-thyroidal illness (also known as euthyroid sick syndrome) is common among critically ill patients, but it remains controversial if normalizing total and free tri-iodothyronine in this setting is beneficial. Multiple stimuli encountered in critical illness activate an acute stress response.1Molina P.E. Neurobiology of the stress response: contribution of the sympathetic nervous system to the neuroimmune axis in traumatic injury.Shock. 2005; 24: 3-10Crossref PubMed Scopus (54) Google Scholar, 2Baumann H. Gauldie J. The acute phase response.Immunol Today. 1994; 15: 74-80Abstract Full Text PDF PubMed Scopus (1733) Google Scholar Such afferent stimuli include pain, visual, auditory, and olfactory stimuli, baroreceptor, chemoreceptor and stretch receptor activation as well as inflammation. With regards to these stimuli, various surveillance aspects of innate immunity recognize pathogen-associated molecular patterns (PAMPS).3Abreu M.T. Arditi M. Innate immunity and toll-like receptors: clinical implications of basic science research.J Pediatr. 2004; 144: 421-429Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar Perhaps less well appreciated are recognition systems for damage-associated molecular patterns (DAMPS), which arise after critical illness tissue injury.4Zhang Q. Raoof M. Chen Y. et al.Circulating mitochondrial DAMPs cause inflammatory responses to injury.Nature. 2010; 464: 104-107Crossref PubMed Scopus (502) Google Scholar For example, mitochondrial damage may lead to release of N-formyl proteins as well as bacterial DNA, both perceived as foreign antigens. Accordingly, both infection and tissue injury can activate the stress response through inflammation signaling via recognition of PAMPS and DAMPS. Various mediators that provide afferent signaling for the stress response are transported to the brain and cross the blood-brain barrier via fenestrated capillaries and activated cytokine transport. In addition, afferent signaling is also provided by the vagus and other nerve input.1Molina P.E. Neurobiology of the stress response: contribution of the sympathetic nervous system to the neuroimmune axis in traumatic injury.Shock. 2005; 24: 3-10Crossref PubMed Scopus (54) Google Scholar Afferent stress signals are integrated at the level of the hypothalamus, where a neurogenic-endocrine-inflammation stress response ensues.1Molina P.E. Neurobiology of the stress response: contribution of the sympathetic nervous system to the neuroimmune axis in traumatic injury.Shock. 2005; 24: 3-10Crossref PubMed Scopus (54) Google Scholar, 5Besedovsky H.O. del Rey A. Immune-neuro-endocrine interactions: facts and hypotheses.Endocr Rev. 1996; 17: 64-102Crossref PubMed Google Scholar, 6Turnbull A.V. Rivier C.L. Regulation of the hypothalamic-pituitary-adrenal axis by cytokines: actions and mechanisms of action.Physiol Rev. 1999; 79: 1-71Crossref PubMed Google Scholar Forward and reverse servo signaling occurs between each major biochemical element of the stress response. Four primary efferent events are activated and summarize the activity of the acute stress response: The former has evolved to contain and eliminate foreign antigens, particularly infectious.7Franchi L. Nunez G. Immunology. Orchestrating inflammasomes.Science. 2012; 337: 1299-1300Crossref PubMed Scopus (8) Google Scholar This system is mediated through toll-like receptor signaling and augmentation of proinflammatory nuclear transcription factor pathways. Complement, lectin-binding proteins, and activation of macrophages, endothelial cells, neutrophils, and natural killer cells represent additional elements of the innate immune system. Increased production of interleukin 6 (IL-6) stimulates synthesis of acute phase proteins, including C-reactive protein, fibrinogen, and α2-macroglobulin. Simultaneously, antiinflammatory mediator production is also upregulated in part via signaling via the vagus nerve, with nerve endings terminating on splenic and hepatic macrophages that activate the α-7 subunit of the acetylcholine receptor, resulting in decreased production of proinflammatory mediators with tumor necrosis factor α (TNF-α) being most extensively investigated to date.8Rosas-Ballina M. Olofsson P.S. Ochani M. et al.Acetylcholine-synthesizing T cells relay neural signals in a vagus nerve circuit.Science. 2011; 334: 98-101Crossref PubMed Scopus (143) Google Scholar, 9Tracey K.J. Cell biology. Ancient neurons regulate immunity.Science. 2011; 332: 673-674Crossref PubMed Scopus (12) Google Scholar Discussion of the feedback role of the parasympathetic nervous system has already been mentioned in regard to development of a compensatory antiinflammatory response.10Bone R.C. Sir Isaac Newton, sepsis, SIRS, and CARS.Crit Care Med. 1996; 24: 1125-1128Crossref PubMed Scopus (664) Google Scholar Increased sympathetic activity promotes catecholamine synthesis and release that serves several functions: cardiac output and blood pressure are sustained via increases in heart rate as well as systemic vascular resistance. Catecholamine release also inhibits insulin release and action, and stimulates both glucagon and adrenocorticotropic hormone (ACTH) production. Glucagon mediates acute glucose energy substrate availability and ACTH stimulates cortisol production, with effects on transcription and translation of hundreds of genes (discussed later under CIRCI).11Galon J. Franchimont D. Hiroi N. et al.Gene profiling reveals unknown enhancing and suppressive actions of glucocorticoids on immune cells.FASEB J. 2002; 16: 61-71Crossref PubMed Scopus (287) Google Scholar Glucocorticoids, glucagon, and growth hormone (GH) are upregulated with concurrent modulation of thyroid activity. Both cortisol and thyroid hormone contributions to the stress response are discussed in subsequent sections of this article. This cascade results in reclamation of water via upregulation of aquaporin channels and enhanced reabsorption of sodium via aldosterone signaling in the renal collecting tubules. Alterations in antidiuretic hormone (ADH) states in the pediatric intensive care unit (PICU) are also discussed in the next section of this article. Renal macula densa cells in concert with contractile mesangial cells of the glomerulus sense increased α-adrenergic activity, distal convoluted tubule chloride/sodium concentration changes, and decreased perfusion and subsequently signal modified fenestrated endothelial cells in the renal afferent arteriole to produce and release renin from the so-called juxtaglomerular apparatus. Brain-kidney nerve connections can also directly activate this cascade. Renin converts hepatic-synthesized angiotensinogen to angiotensin 1. Subsequently, angiotensin-converting enzyme located diffusely among endothelial cells, but particularly in the pulmonary endothelia, catalyzes the conversion on angiotensin 1 to angiotensin 2. Angiotensin 2 facilitates a variety of activities essential to the acute stress response, as summarized in Box 1.Box 1Activities of angiotensin 2•Increases systemic vascular resistance and blood pressure•Mediates aldosterone production by adrenal cortex•Augments plasminogen activator inhibitor 1 release•Stimulates thirst and salt craving•Enhances release of vasopressin, ACTH, and norepinephrine•Increases sodium reabsorption directly•Promotes afferent and efferent renal vasoconstriction•Induces cardiomyocyte hypertrophy•Facilitates nuclear transcription factor NFkB activity •Increases systemic vascular resistance and blood pressure•Mediates aldosterone production by adrenal cortex•Augments plasminogen activator inhibitor 1 release•Stimulates thirst and salt craving•Enhances release of vasopressin, ACTH, and norepinephrine•Increases sodium reabsorption directly•Promotes afferent and efferent renal vasoconstriction•Induces cardiomyocyte hypertrophy•Facilitates nuclear transcription factor NFkB activity ADH and thirst maintain plasma osmolality in a narrow range, between 275 and 295 mOsm/L. ADH is produced in the supraoptic and paraventricular nuclei of the hypothalamus, and transported through axonal processes to the capillary plexi in the posterior pituitary. ADH binds to V2 receptors located on principal cells in the renal collecting ducts. This binding leads to a cyclic adenosine monophosphate–mediated increase in permeability of the luminal cell membrane, allowing back diffusion of water from the tubules to the plasma, and concentrating the urine via aquaporin-2 water channels. ADH is primarily regulated by osmoreceptors in the anterior hypothalamus. Nonosmotic regulatory factors include volume depletion and cardiac failure, as well as pain, nausea, and medications. Syndrome of inappropriate ADH (SIADH) is a common disorder in the intensive care unit (ICU) characterized by the inability to suppress the secretion of ADH, resulting in partially impaired water excretion and hyponatremia. Criteria for the diagnosis of SIADH include hyponatremia, plasma hypotonicity, inappropriate urine concentration for the degree of plasma hypotonicity, natriuresis despite hyponatremia, euvolemia, and exclusion of other causes of euvolemic hypo-osmolality (hepatic, renal, thyroid, and adrenal dysfunction).12Schrier R.W. Bansal S. Diagnosis and management of hyponatremia in acute illness.Curr Opin Crit Care. 2008; 14: 627-634Crossref PubMed Scopus (38) Google Scholar Hyponatremia is initially mediated by inappropriate ADH-induced water retention. The ensuing volume expansion activates secondary natriuretic mechanisms. Renin and aldosterone activities downregulate, resulting in sodium and water loss and restoration of near euvolemia. The net effect is that, with chronic SIADH, sodium loss is more prominent than water retention.13Adrogue H.J. Madias N.E. Hyponatremia.N Engl J Med. 2000; 342: 1581-1589Crossref PubMed Scopus (793) Google Scholar Hence, urine osmolality is inappropriately high compared with plasma osmolality, and urine sodium levels are generally greater than 20 mEq/L. Conditions associated with SIADH are multiple and are summarized in Box 2.Box 2Conditions associated with SIADH•Central nervous system (CNS) disease (infections, head trauma, brain tumors, cerebral thrombosis or hemorrhage, Guillain-Barré syndrome, postneurosurgical procedures)•Pulmonary conditions (pneumonia, asthma, pneumothorax, positive pressure ventilation)•Malignancies (lymphoma, Ewing sarcoma, mesothelioma, bronchogenic carcinomas)•Multiple drugs (eg, vincristine, cyclophosphamide, carbamazepine, barbiturates, opiates, tricyclic antidepressants, salicylates) •Central nervous system (CNS) disease (infections, head trauma, brain tumors, cerebral thrombosis or hemorrhage, Guillain-Barré syndrome, postneurosurgical procedures)•Pulmonary conditions (pneumonia, asthma, pneumothorax, positive pressure ventilation)•Malignancies (lymphoma, Ewing sarcoma, mesothelioma, bronchogenic carcinomas)•Multiple drugs (eg, vincristine, cyclophosphamide, carbamazepine, barbiturates, opiates, tricyclic antidepressants, salicylates) The severity of clinical manifestations depends on the rate of decrease in serum sodium, which determines the risk for cellular swelling, and cerebral edema. Hyponatremia developing over days to weeks may be symptom-free as a result of adaptation of brain cells. Rapid changes in serum sodium levels can result in nausea, vomiting, muscle cramps, decreased deep tendon reflexes, lethargy, coma, focal deficits, and seizures. There is marked individual variability regarding the degree of hyponatremia at which symptoms become apparent. Most patients develop seizures and coma with acute hyponatremia of less than 120 mEq/L.14Lynch R.E. Wood E.G. Fluid and electrolyte issues in pediatric critical illness.in: Fuhrman B. Zimmerman J.J. Pediatric critical care. Elsevier, Philadelphia2011: 944-962Crossref Scopus (2) Google Scholar Fluid restriction is the mainstay of therapy for SIADH. The total intake must be less than insensible losses and urinary output combined, which is generally around 0.75 L/m2 body surface area or less. Further therapies depend on the presence or absence of CNS symptoms or imaging suggestive of cerebral edema, and the rate of hyponatremia development. For hyponatremia that has been present for less than 4 hours and is not associated with CNS symptoms, serum sodium correction can be safely corrected at rates of 0.7 to 1.0 mEq/L/h.14Lynch R.E. Wood E.G. Fluid and electrolyte issues in pediatric critical illness.in: Fuhrman B. Zimmerman J.J. Pediatric critical care. Elsevier, Philadelphia2011: 944-962Crossref Scopus (2) Google Scholar If hyponatremia has developed over a longer time interval or if CNS symptoms are present, the goal is to increase serum sodium levels slowly at a rate of 0.5 mEq/L/h to avoid osmotic demyelination syndrome.14Lynch R.E. Wood E.G. Fluid and electrolyte issues in pediatric critical illness.in: Fuhrman B. Zimmerman J.J. Pediatric critical care. Elsevier, Philadelphia2011: 944-962Crossref Scopus (2) Google Scholar Symptoms of osmotic demyelination may include obtundation, tremor, amnesia, quadriplegia, coma, and seizures.15Kumar S. Fowler M. Gonzalez-Toledo E. et al.Central pontine myelinolysis, an update.Neurol Res. 2006; 28: 360-366Crossref PubMed Scopus (48) Google Scholar In hyponatremic patients with signs of acute CNS cellular swelling, an initial rapid bolus of 5 to 6 mL/kg of 3% saline increases the serum sodium by approximately 5 mEq/L and can help stabilize cerebral swelling and avoid impending herniation. Further sodium needs in symptomatic patients can be replaced using 3% saline infusion according to the calculated sodium deficit: sodium deficit [mEq] = 0.6 × body weight [kg] × (125-measured [Na]). Frequently, a regimen of 3% saline at 1 to 2 mL/kg/h with periodic administration of loop diuretic to promote water excretion is an effective and safe regimen for patients with acute hyponatremia. Sodium levels should be monitored every 2 hours, initially. Further fluid restriction may be necessary if sodium levels do not normalize. In adults, use of the ADH V1 and V2 receptor antagonist conivaptan has been reported to increase urine volume and reduce urine osmolality in hyponatremia and fluid-retaining states.16Kumar S. Berl T. Vasopressin antagonists in the treatment of water-retaining disorders.Semin Nephrol. 2008; 28: 279-288Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar, 17Wright W.L. Asbury W.H. Gilmore J.L. et al.Conivaptan for hyponatremia in the neurocritical care unit.Neurocrit Care. 2009; 11: 6-13Crossref PubMed Scopus (31) Google Scholar, 18Murphy T. Dhar R. Diringer M. Conivaptan bolus dosing for the correction of hyponatremia in the neurointensive care unit.Neurocrit Care. 2009; 11: 14-19Crossref PubMed Scopus (43) Google Scholar Although pediatric usage has been reported, further data are necessary to evaluate its role in children.19Rianthavorn P. Cain J.P. Turman M.A. Use of conivaptan to allow aggressive hydration to prevent tumor lysis syndrome in a pediatric patient with large-cell lymphoma and SIADH.Pediatr Nephrol. 2008; 23: 1367-1370Crossref PubMed Scopus (9) Google Scholar Cerebral salt wasting (CSW) is characterized by hyponatremia and extracellular volume depletion caused by inappropriate sodium wasting in the urine in the setting of CNS disease.20Gutierrez O.M. Lin H.Y. Refractory hyponatremia.Kidney Int. 2007; 71: 79-82Crossref PubMed Scopus (11) Google Scholar The mechanism by which cerebral disease leads to renal salt wasting is poorly understood, and some believe that CSW does not really exist.21Singh S. Bohn D. Carlotti A.P. et al.Cerebral salt wasting: truths, fallacies, theories, and challenges.Crit Care Med. 2002; 30: 2575-2579Crossref PubMed Google Scholar, 22Carlotti A.P. Bohn D. Rutka J.T. et al.A method to estimate urinary electrolyte excretion in patients at risk for developing cerebral salt wasting.J Neurosurg. 2001; 95: 420-424Crossref PubMed Google Scholar There are 2 theories for the pathophysiologic mechanisms for CSW: (1) central function of a circulating natriuretic factor and (2) disruption of neural input to the kidney.23Palmer B.F. Hyponatremia in patients with central nervous system disease: SIADH versus CSW.Trends Endocrinol Metab. 2003; 14: 182-187Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar, 24Palmer B.F. Hyponatraemia in a neurosurgical patient: syndrome of inappropriate antidiuretic hormone secretion versus cerebral salt wasting.Nephrol Dial Transplant. 2000; 15: 262-268Crossref PubMed Google Scholar The first theory is that a circulating factor impairs renal tubular sodium reabsorption.21Singh S. Bohn D. Carlotti A.P. et al.Cerebral salt wasting: truths, fallacies, theories, and challenges.Crit Care Med. 2002; 30: 2575-2579Crossref PubMed Google Scholar, 25Berger T.M. Kistler W. Berendes E. et al.Hyponatremia in a pediatric stroke patient: syndrome of inappropriate antidiuretic hormone secretion or cerebral salt wasting?.Crit Care Med. 2002; 30: 792-795Crossref PubMed Google Scholar, 26Harrigan M.R. Cerebral salt wasting syndrome: a review.Neurosurgery. 1996; 38: 152-160Crossref PubMed Scopus (162) Google Scholar The primary candidate is brain natriuretic peptide (BNP), which decreases sodium reabsorption and inhibits renin release.25Berger T.M. Kistler W. Berendes E. et al.Hyponatremia in a pediatric stroke patient: syndrome of inappropriate antidiuretic hormone secretion or cerebral salt wasting?.Crit Care Med. 2002; 30: 792-795Crossref PubMed Google Scholar, 27Berendes E. Walter M. Cullen P. et al.Secretion of brain natriuretic peptide in patients with aneurysmal subarachnoid haemorrhage.Lancet. 1997; 349: 245-249Abstract Full Text Full Text PDF PubMed Scopus (221) Google Scholar BNP may also decrease autonomic outflow at the level of the brainstem.28Levin E.R. Gardner D.G. Samson W.K. Natriuretic peptides.N Engl J Med. 1998; 339: 321-328Crossref PubMed Scopus (1430) Google Scholar The second theory is that the sympathetic nervous system facilitates sodium, uric acid, and water reabsorption in the proximal tubule, as well as renin release. Impaired sympathetic output could therefore explain the decreased proximal sodium and uric acid reabsorption, and the impaired release of renin and aldosterone. Renal salt wasting leads to volume depletion, which provides a baroreceptor stimulus for the release of ADH with water retention, which further exacerbates hyponatremia. Among patients with CNS disease and hyponatremia, CSW is less common than SIADH.29Ganong C.A. Kappy M.S. Cerebral salt wasting in children. The need for recognition and treatment.Am J Dis Child. 1993; 147: 167-169Crossref PubMed Google Scholar, 30Jimenez R. Casado-Flores J. Nieto M. et al.Cerebral salt wasting syndrome in children with acute central nervous system injury.Pediatr Neurol. 2006; 35: 261-263Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar, 31Taplin C.E. Cowell C.T. Silink M. et al.Fludrocortisone therapy in cerebral salt wasting.Pediatrics. 2006; 118: e1904-e1908Crossref PubMed Scopus (24) Google Scholar CSW has frequently been described in adults with subarachnoid hemorrhage, but can be associated with meningitis, encephalitis, poliomyelitis, CNS tumors, and after CNS surgery (and after trauma).20Gutierrez O.M. Lin H.Y. Refractory hyponatremia.Kidney Int. 2007; 71: 79-82Crossref PubMed Scopus (11) Google Scholar, 32Hannon M.J. Finucane F.M. Sherlock M. et al.Disorders of water homeostasis in neurosurgical patients.J Clin Endocrinol Metab. 2012; 97: 1423-1433Crossref PubMed Scopus (9) Google Scholar The typical onset of CSW is within the first 10 days after a neurosurgical procedure or event. Without volume replacement, it is associated with extracellular fluid depletion and signs of dehydration, such as orthostatic hypotension, dry mucous membranes, decreased skin turgor, and tachycardia. SIADH, on the other hand, is associated with a slightly increased or normal extracellular volume status. CSW should be considered in patients with CNS disease and hyponatremia (<135 mEq/L) with a low plasma osmolality; an increased urine osmolality caused by renal sodium wasting and ADH secretion in response to volume depletion; an increased urine sodium concentration caused by salt wasting; and a low serum uric acid concentration caused by uric acid wasting in the urine. Urine output is typically brisk. Clinical evidence of hypovolemia (or isotonic volume replacement to avoid it) is crucial, because these laboratory findings may overlap with SIADH, and the 2 disorders are managed differently.20Gutierrez O.M. Lin H.Y. Refractory hyponatremia.Kidney Int. 2007; 71: 79-82Crossref PubMed Scopus (11) Google Scholar, 33Maesaka J.K. Imbriano L.J. Ali N.M. et al.Is it cerebral or renal salt wasting?.Kidney Int. 2009; 76: 934-938Crossref PubMed Scopus (30) Google Scholar Maintaining a positive water and salt balance is the key element of therapy. Volume repletion should be achieved with isotonic saline. Severe hyponatremia may require hypertonic saline administration or oral salt supplementation. It is essential to frequently monitor therapy and adjust treatment accordingly. Administration of a mineralocorticoid, such as fludrocortisone, can also be used.31Taplin C.E. Cowell C.T. Silink M. et al.Fludrocortisone therapy in cerebral salt wasting.Pediatrics. 2006; 118: e1904-e1908Crossref PubMed Scopus (24) Google Scholar, 34Albanese A. Hindmarsh P. Stanhope R. Management of hyponatraemia in patients with acute cerebral insults.Arch Dis Child. 2001; 85: 246-251Crossref PubMed Scopus (52) Google Scholar, 35Kinik S.T. Kandemir N. Baykan A. et al.Fludrocortisone treatment in a child with severe cerebral salt wasting.Pediatr Neurosurg. 2001; 35: 216-219Crossref PubMed Scopus (21) Google Scholar Long-term therapy is not necessary, because CSW tends to resolve within 3 to 4 weeks.24Palmer B.F. Hyponatraemia in a neurosurgical patient: syndrome of inappropriate antidiuretic hormone secretion versus cerebral salt wasting.Nephrol Dial Transplant. 2000; 15: 262-268Crossref PubMed Google Scholar Diabetes insipidus (DI) is characterized by excretion of large amounts of dilute, tasteless (insipid) urine, leading to hypernatremia. The 2 most important pathophysiologic mechanisms are vasopressin (ADH) deficiency in central DI and renal vasopressin insensitivity in nephrogenic DI. Central DI is caused by a defect in secretion or synthesis of vasopressin by the neurohypophyseal system. Acquired forms of central DI are more commonly seen in the PICU. Causes of DI are summarized in Box 3.Box 3Causes of DI•Head trauma•Tumors (craniopharyngioma, meningioma, leukemia, lymphoma)•Postneurosurgical procedures•Cerebral vascular anomalies•Infections (meningitis, encephalitis)•Rheumatic disease (Wegener granulomatosis, systemic lupus erythematosus, scleroderma)•Guillain-Barré syndrome•CNS malformation•Brain death •Head trauma•Tumors (craniopharyngioma, meningioma, leukemia, lymphoma)•Postneurosurgical procedures•Cerebral vascular anomalies•Infections (meningitis, encephalitis)•Rheumatic disease (Wegener granulomatosis, systemic lupus erythematosus, scleroderma)•Guillain-Barré syndrome•CNS malformation•Brain death There exist rare genetic forms of DI with autosomal-dominant and autosomal-recessive inheritance involving the ADP-neurophysin gene, as well as an X-linked recessive form of central DI. DI can be associated with congenital CNS malformations such as holoprosencephaly, agenesis of the pituitary, and midline craniofacial abnormalities. Severe damage to the neurohypophysial system by neurosurgery or trauma often results in a typical triphasic response with an initial polyuric phase (hours to days), reflecting inhibition of ADH release caused by hypothalamic dysfunction.32Hannon M.J. Finucane F.M. Sherlock M. et al.Disorders of water homeostasis in neurosurgical patients.J Clin Endocrinol Metab. 2012; 97: 1423-1433Crossref PubMed Scopus (9) Google Scholar This response is followed by unregulated release of vasopressin from the degenerating posterior pituitary, clinically inducing SIADH (days 6–12). DI may ensue in a third phase after the posterior pituitary ADP stores are depleted. This last phase may be permanent or transient.13Adrogue H.J. Madias N.E. Hyponatremia.N Engl J Med. 2000; 342: 1581-1589Crossref PubMed Scopus (793) Google Scholar, 36Agha A. Sherlock M. Phillips J. et al.The natural history of post-traumatic neurohypophysial dysfunction.Eur J Endocrinol. 2005; 152: 371-377Crossref PubMed Scopus (78) Google Scholar Nephrogenic DI results from partial or complete resistance of the kidney to ADH and is caused by acquired or genetic concentrating defects of the kidneys. Genetic forms may be caused by X-linked recessive alteration of the vasopressin V2 receptor or mutations of the aquaporin-2 gene, with either autosomal-dominant or autosomal-recessive inheritance. Causes for acquired nephrogenic DI are more common and include chronic renal failure, renal tubulointerstitial diseases, medications (eg, lithium, diuretics, amphotericin B, cisplatin, rifampin), metabolic derangements (hypercalcemia, hypokalemia), sickle cell disease, or dietary abnormalities (primary polydipsia, decreased sodium intake, severe protein restriction).32Hannon M.J. Finucane F.M. Sherlock M. et al.Disorders of water homeostasis in neurosurgical patients.J Clin Endocrinol Metab. 2012; 97: 1423-1433Crossref PubMed Scopus (9) Google Scholar Untreated central DI typically presents with polyuria and polydipsia if thirst is not impaired. Moderate to severe hypernatremia can develop, especially in infants and young children who cannot independently access free water and in postoperative patients with unrecognized DI. Irritability, high-pitched cry, and hyperpyrexia can be signs of hypernatremia in infants. Symptoms can progress to lethargy, increased muscle tone, and seizures. Hyperosmolar states can be complicated by shrinkage of brain cells, leading to tearing of cerebral vessels, subarachnoid hemorrhage, and venous sinus thrombosis.32Hannon M.J. Finucane F.M. Sherlock M. et al.Disorders of water homeostasis in neurosurgical patients.J Clin Endocrinol Metab. 2012; 97: 1423-1433Crossref PubMed Scopus (9) Google Scholar Urine specific gravity is less than 1.005, and urine osmolality typically low (50–200 mOsm/L). Serum sodium concentration and serum osmolality depend on hydration status of the patient. Isotonic 0.9% saline boluses should be administered to a child presenting in shock. After reversal of shock, careful replacement of water deficits is conducted with hypotonic fluids, in conjunction with vasopressin replacement. The water deficit is calculated by the following equation: water deficit = 0.6 × body weight × ([Na]–140)/140. To reduce the risk for cerebral edema, the water deficit is corrected slowly over 48 to 72 hours, with a goal decrease in serum sodium of 10 to 12 mEq/L/d using hypotonic fluid (0.2–0.45% normal saline) or enteral water. Vasopressin replacement should be initiated for central DI. A continuous infusion of vasopressin should be started at 0.5 mU/kg/h and titrated up to achieve antidiuresis. Alert patients who can regulate their thirst may be treated with intranasal or subcutaneous 1-demino-8-D-arginine vasopressin (DDAVP). It is crucial to follow patients’ intake and output closely, and replace ongoing urine output and insensible losses in addition to the calculated water deficit to avoid iatrogenic hyponatremia. Serum sodium levels require frequent monitoring (every 2–6 hours), initially. Hyperglycemia was first recognized during episodes of stress by Thomas Willis in the seventeenth century.37Brealey D. Singer M. Hyperglycemia in critical illness: a review.J Diabetes Sci Technol. 2009; 3: 1250-1260Crossref PubMed Google Scholar With data collected in the last 2 decades, it is clear that hyperglycemia is common in nondiabetic critically ill children, with peak blood glucose and duration directly associated with worse outcome.38Srinivasan V. Spinella P.C. Drott H.R. et al.Association of timing, duration, and intensity of hyperglycemia with intensive care unit mortality in critically ill children.Pediatr Crit Care Med. 2004; 5: 329-336Crossref PubMed Scopus (174) Google Scholar Hyperglycemia is found frequently in subsets of critically ill children with specific di
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