Hypothalamic-Pituitary-Adrenal Axis

The hypothalamic-pituitary-adrenal axis involves release of catecholamines, sex steroids, glucocorticoids and mineralocorticoids from the adrenal gland under control of the hypothalamus and pituitary gland.Reference Trimarchi⁵ Many types of stress cause the hypothalamus to secrete corticotropin-releasing hormone. Corticotropin-releasing hormone stimulates the anterior pituitary gland to secrete adrenocorticotropic hormone, often termed “ACTH”, which then stimulates the adrenal cortex to secrete glucocorticoids such as cortisol. Adrenocorticotropic hormone has little control over secretion of aldosterone, the other major steroid hormone from the adrenal cortex.

The haemodynamic alterations of adrenal insufficiency, due predominantly to deficiency of cortisol, can present as vasomotor paralysis or shock.Reference Trimarchi⁵ Adrenal insufficiency is associated with decreased myocardial contractility, vasodilatation, and capillary leak. Critical illness typically results in increased cortisol levels of up to six times baseline and loss of the diurnal variation.Reference Cooper and Stewart^6–Reference Sarthi, Lodha, Vivekanandhan and Arora¹⁰ The appropriate basal level of cortisol in critically ill patients has been controversial, with proposed values for normal basal cortisol ranging from 6–34 micrograms per decilitre.Reference Cooper and Stewart^6, Reference Oelkers^7, Reference Annane, Sebille and Charpentier^11–Reference Rady, Johnson, Patel, Larson and Helmers¹³ The discrepant definitions of adrenal insufficiency have yielded highly variable estimates of the incidence of adrenal dysfunction in the critically ill.Reference Cooper and Stewart^6, Reference Pizarro, Troster, Damiani and Carcillo¹⁴ For example, the reported incidence of adrenal dysfunction in sepsis ranges from 17–54%.Reference Cooper and Stewart^6, Reference Pizarro, Troster, Damiani and Carcillo^14–Reference Soni, Pepper and Wyrwinski²⁰ Adrenal dysfunction in critical illness is associated with increased duration and requirement for inotropes and/or vasopressors, and worsened clinical outcomes.Reference Pizarro, Troster, Damiani and Carcillo^14, Reference Hatherill, Tibby, Hilliard, Turner and Murdoch¹⁵ Annane and colleagues classified adult patients with septic shock into three prognostic groups based on adrenal function, with the worst mortality in patients with elevated basal cortisol and a poor response to adrenocorticotropin hormone stimulation.Reference Annane, Sebille and Charpentier^11, Reference Annane, Sebille, Troche, Raphael, Gajdos and Bellissant^12, Reference Annane²¹

Observations in children with septic shockReference Pizarro, Troster, Damiani and Carcillo¹⁴ and children with congenital cardiac diseaseReference Sajan, Dent, Schwartz and Nelson²² are consistent with these findings. The integrity of the hypothalamic-pituitary-adrenal-axis during critical illness is typically assessed by the cosyntropin stimulation test.Reference Rothwell, Udwadia and Lawler¹⁹ In response to cosyntropin stimulation, it is generally accepted that a cortisol increase of less than 9 micrograms per decilitre, is inappropriate and associated with worse outcomes.Reference Annane, Sebille, Troche, Raphael, Gajdos and Bellissant¹² The appropriate basal level of cortisol in critically ill patients is controversial, however, with proposed values for normal basal cortisol ranging from 6–34 micrograms per decilitre.Reference Cooper and Stewart^6, Reference Oelkers^7, Reference Annane, Sebille and Charpentier^11–Reference Rady, Johnson, Patel, Larson and Helmers¹³ These discrepant definitions of adrenal insufficiency have yielded highly variable estimates of the incidence of adrenal dysfunction in critical illness. Although the data in children are limited, existing evidence suggests that a basal cortisol level of 16 micrograms per decilitre or more reflects an appropriate stress response in critically ill paediatric patients.Reference Pizarro, Troster, Damiani and Carcillo^14, Reference Sajan, Dent, Schwartz and Nelson²² The “expected” adrenal response to critical illness is thus defined as an adequate basal cortisol, greater than 16 micrograms per decilitre, and an appropriate cosyntropin response of a cortisol level increase of greater than 9 micrograms per decilitre. We have used the term activated adrenal response to describe this adrenal response. Using the above reference values, adrenal activity can thus be classified into one of the following four groups:

• • Activated adrenal response: an adequate basal cortisol of greater than 16 micrograms per decilitre, with an appropriate response to cosyntropin stimulation manifested by a change in cortisol of greater than 9 micrograms per decilitre.

• • Absolute adrenal insufficiency: an inadequate basal cortisol of less than 16 micrograms per decilitre, with an inappropriate response to cosyntropin stimulation manifested by a change in cortisol of less than 9 micrograms per decilitre.

• • Relative adrenal insufficiency: an adequate basal cortisol of greater than 16 micrograms per decilitre, with an inappropriate response to cosyntropin stimulation manifested by a change in cortisol of less than 9 micrograms per decilitre.

• • Insufficient basal cortisol: an inadequate basal cortisol of less than 16 micrograms per decilitre, with an appropriate response to cosyntropin stimulation manifested by a change in cortisol of greater than 9 micrograms per decilitre.

The categories above delineate the various adrenal responses to critical illness. Existing evidence suggests that steroid treatment may be more beneficial in certain subsets of adrenal response than in others. There is uniform agreement that patients manifesting absolute adrenal insufficiency require glucocorticoid supplementation and possibly mineralocorticoid supplementation as well. Although conflicting data exist, previous studies in adult patients with sepsis support steroid treatment in patients with both relative adrenal insufficiency and insufficient basal cortisol.Reference Annane, Sebille and Charpentier^11, Reference Annane, Sebille, Troche, Raphael, Gajdos and Bellissant^12, Reference Annane²¹

Much of the data on the hypothalamic-pituitary-adrenal axis in critical illness stems from research in patients with sepsis. With increasing recognition of adrenal dysfunction in sepsis and/or septic shock in both adult and paediatric patients, it has become evident that adrenal dysfunction has prognostic implications. Of note, the adrenal response may change during the course of an illness.Reference Oppert, Reinicke, Graf, Barckow, Frei and Eckardt²³ For example, a patient may demonstrate an activated adrenal response early in an illness that subsequently shifts to absolute or relative adrenal insufficiency. In patients treated with hydrocortisone with or without fludrocortisone, studies suggest that inotrope requirements fall most rapidly in patients with an inappropriate cosyntropin response or those with insufficient basal cortisol.Reference Annane, Sebille and Charpentier^11, Reference Oppert, Reinicke, Graf, Barckow, Frei and Eckardt^23, Reference Oppert, Schindler and Husung²⁴ In other groups of patients requiring inotropes for more than 48 hours, steroid administration may lead to the earlier cessation of inotropes and greater reversal of shock.Reference Bollaert, Charpentier, Levy, Debouverie, Audibert and Larcan^25, Reference Briegel, Forst and Haller²⁶ This may explain the correlations between adrenal dysfunction and catecholamine refractory shock in patients with sepsis.Reference Sarthi, Lodha, Vivekanandhan and Arora^10, Reference Hatherill, Tibby, Hilliard, Turner and Murdoch¹⁵

Cortisol is secreted from the adrenal cortex regulated by corticotropin and corticotropin-releasing hormone in response to physiologic stress. Cortisol has a plethora of functions:

• • it regulates vascular smooth muscle toneReference Hallman, Peltoniemi and Saarela²⁷

• • maintains endothelial integrityReference Lamberts, Bruining and de Jong^28, Reference Seri, Tan and Evans²⁹ and

• • potentiates the actions of catecholamines.Reference Annane^21, Reference Lamberts, Bruining and de Jong²⁸

In addition to these vascular effects, cortisol also has the following functions:

• • modulates inflammation

• • conserves sodium and water, and

• • increases glucose levels.Reference Trimarchi⁵

The mineralocorticoid named aldosterone is secreted by the adrenal gland in response to hypotension, hyperkalemia, hyponatremia, and adrenocorticotropin hormone stimulation. Aldosterone induces potassium secretion and sodium and water retention by the kidneys.Reference Trimarchi⁵ The classic symptoms of adrenal crisis resulting from mineralocorticoid deficiency, and thus treated with fludrocortisone acetate, include hyponatremia, hyperkalemia and hypovolemia.Reference Trimarchi^5–Reference Oelkers⁷ Acidosis, hypercalcemia, and hypoglycemia may also occur. The haemodynamic alterations of adrenal insufficiency, due predominantly to cortisol deficiency, can present as vasomotor paralysis or shock.Reference Trimarchi⁵ Adrenal insufficiency is associated with decreased myocardial contractility, vasodilatation, and capillary leak.

Various insults and altered neurohumoral mechanisms may impair the hypothalamic-pituitary-adrenal -axis during critical illness, either resulting from diminished release of corticotropin and corticotropin-releasing hormone or from diminished responsiveness of the adrenal gland to these regulatory hormones. Commonly used pharmacologic agents can alter adrenal function, such as narcotics, ketamine, etomidate, ketoconazole, rifampin and phenytoin.Reference Donmez, Kaya, Haberal, Kutsal and Arslan^30, Reference Absalom, Pledger and Kong³¹ Pathophysiologic insults that can alter hypothalamic, pituitary, or adrenal function include cytokines, inflammatory mediators, hypoxia, reperfusion injury, and/or adrenal haemorrhage.Reference Chrousos³² Waterhouse-Friderichsen syndrome is massive haemorrhage into the adrenal glands, and is usually bilateral. Various cytokines can suppress the pituitary response to hypothalamic corticotropin-releasing hormone or induce systemic or tissue specific corticosteroid resistance.Reference Cooper and Stewart^6, Reference Marik and Zaloga¹⁷ Cortisol levels are reduced after cardiac surgery, which may result from the systemic inflammatory response and cytokine release induced by cardiopulmonary bypass.Reference Henzen, Kobza, Schwaller-Protzmann, Stulz and Briner³³ Finally, developmental factors may modulate adrenal function.

Thyroid function

The hypothalamus secretes thyrotropin-releasing hormone, which stimulates the pituitary gland to secrete thyroid-stimulating hormone, which catalyzes the conversion of thyroglobulin to thyroxine, commonly known as “T₄”. Thyroxine is then cleaved to form the active hormone triiodothyronine, commonly known as “T₃”. Triiodothyronine increases basal metabolic rate and stimulates growth in tissues by increasing activity of sodium-potassium-adenosine triphosphate pumps.Reference Trimarchi⁵ From a cardiac standpoint, thyroid hormones increase contractility, cardiac output, and ejection fraction.Reference Dimmick, Badawi and Randell^34, Reference Klein and Ojamaa³⁵ Although triiodothyronine improves diastolic function and increases intracellular calcium levels via the sodium-calcium exchanger, it may also increase myocardial oxygen consumption.Reference Dimmick, Badawi and Randell^34–Reference Klein and Ojamaa³⁷ In peripheral vasculature, thyroid hormones reduce systemic vascular resistance and increase pulse pressure.Reference Klein and Ojamaa³⁵ Thyroid hormones have been shown to potentiate the effects of catecholamines.Reference Klein and Ojamaa^37, Reference Moruzzi, Doria and Agostoni³⁸

Hypothyroidism is associated with decreases in triiodothyronine, thyroxine, and reverse triiodothyronine with high levels of thyroid stimulating hormone. Symptoms of hypothyroidism include bradycardia, pericardial effusions, hypertension and a narrowed pulse pressure, and myxedema.Reference Klein and Ojamaa³⁵ Studies have also shown decreases in cardiac output and cardiac contractility, as well as decreased diastolic relaxation and diastolic filling. There have also been rare incidences of increased QT interval leading to Torsades. Chronic hypothyroidism, including subclinical hypothyroidism, has been associated with accelerated atherosclerosis, hypercholesterolemia, coronary artery disease, and an increased relative risk of death from cardiovascular causes.Reference Singh, Duggal, Molnar, Maldonado, Barsano and Arora³⁹ In those with congestive heart failure, reduction in triiodothyronine levels have been shown to be proportional to New York Heart Association class,Reference Klein and Ojamaa³⁵ mortality,Reference Chopra^40, Reference Hamilton, Stevenson and Fonarow⁴¹ morbidity,Reference Klein and Ojamaa^37, Reference Utiger⁴² poor haemodynamics, and hyponatremia.Reference Hamilton, Stevenson and Fonarow⁴¹

Important in critical illness is non-thyroidal illness syndrome or euthyroid sick syndrome which presents with a low triiodothyronine level associated with a normal or low thyroxine, high reverse triiodothyronine and normal or high thyroid stimulating hormone.Reference Trimarchi^5, Reference Chopra^40, Reference De Groot⁴³ Euthyroid sick syndrome is associated with abnormal findings on thyroid function tests in the setting of a non-thyroidal illness, without pre-existing hypothalamic-pituitary and thyroid gland dysfunction. After recovery from this non-thyroidal illness, these abnormalities of the thyroid function tests should be completely reversible.

Theories explaining non-thyroidal illness syndrome include:

• • the body’s attempt to decrease metabolic demands during stress,Reference Dimmick, Badawi and Randell³⁴

• • a deficit in converting thyroxine to triiodothyronine,Reference Chopra^40, Reference Katzeff, Powell and Ojamaa^44, Reference Portman, Fearneyhough, Ning, Duncan, Rosenthal and Lupinetti⁴⁵

• • decreased serum thyroid binding capacity,Reference Chopra^40, Reference Katzeff, Powell and Ojamaa⁴⁴ and

• • decreased hypothalamic activity reflected by decreased thyrotropin-releasing hormone, as sex steroids are also decreased in severe illness.Reference De Groot⁴³

Non-thyroidal illness syndrome may be exacerbated by glucocorticoids that can decrease pituitary response to thyrotropin-releasing hormone and lead to a lower level of thyroid stimulating hormone.Reference Chopra^40, Reference De Groot⁴³ Dopamine, which is frequently used in intensive care, confounds assessment of thyroid activity since it can decrease thyroid stimulating hormoneReference Chopra^40, Reference De Groot⁴³ and induce secondary hypothyroidism.Reference Faber, Kirkegaard, Rasmussen, Westh, Busch-Sorensen and Jensen^46, Reference Bettendorf, Schmidt, Tiefenbacher, Grulich-Henn, Heinrich and Schonberg⁴⁷

It is important to assess free thyroid hormone levels since critical illness often alters serum protein levels, including thyroid binding globulin and albumin.Reference De Groot⁴³ Reduced levels of triiodothyronine have been observed in as many as 70% of hospitalized patients.Reference Chopra⁴⁰ Decreased thyroxine levels have been associated with increased mortality, and the combination of low triiodothyronine and thyroxine may carry an even worse prognosis.Reference Chopra^40, Reference Utiger^42, Reference De Groot⁴³

Research is ongoing to determine the thyroid profile of patients undergoing cardiopulmonary bypass procedures, and to assess whether thyroid hormone replacement is beneficial for these patients. Thyroid hormones including thyroid stimulating hormone, thyroxine, free thyroxine, triiodothyronine, free triiodothyronine, and thyroglobulin have been shown to decrease after cardiopulmonary bypass with increases in reverse triiodothyronine.Reference Dimmick, Badawi and Randell^34, Reference Bettendorf, Schmidt, Tiefenbacher, Grulich-Henn, Heinrich and Schonberg^47–Reference Murzi, Iervasi and Masini⁵³ This decrease in triiodothyronine has been shown to be more profound in children than adults.Reference Dimmick, Badawi and Randell^34, Reference Mainwaring, Capparelli, Schell, Acosta and Nelson⁵⁴ As discussed above, dopamine administration may contribute to these alterations.Reference Faber, Kirkegaard, Rasmussen, Westh, Busch-Sorensen and Jensen⁴⁶ In children after cardiac surgery, Bettendorf and colleagues reported plasma thyroid hormone concentrations were lowest in patients treated with dopamine, and these patients also took the longest return to normal.Reference Bettendorf, Schmidt, Tiefenbacher, Grulich-Henn, Heinrich and Schonberg⁴⁷ Lower levels of thyroid hormones postoperatively have been associated with

• • higher scores via the – the Pediatric Risk of Mortality Scoring System (PRISM), which is described in the tenth manuscript in this Supplement titled “Databases for assessing the outcomes of the treatment of patients with congenital and paediatric cardiac disease – the perspective of critical care”

• • increased length of mechanical ventilation

• • increased time requiring supplemental oxygen

• • increased intensive care unit length of stay, and

• • increased need for inotropes and Lasix.Reference Dimmick, Badawi and Randell^34, Reference Bettendorf, Schmidt, Tiefenbacher, Grulich-Henn, Heinrich and Schonberg^47, Reference Bettendorf, Schmidt, Grulich-Henn, Ulmer and Heinrich^49, Reference Dagan, Vidne, Josefsberg, Phillip, Strich and Erez⁵⁵

Conversely, patients with more favourable outcomes had higher levels of thyroid hormones than those who had complications or that died.Reference Kennedy and Butterworth⁵⁰ The nadir of thyroid hormones corresponds to the decrease in cardiac output after congenital cardiac surgery. This nadir of thyroid hormones begins soon after surgery, and may last for 48 hours. Thyroid hormones may remain at a low level for as long as 5–8 days postoperatively, and longer with more complex surgeries.Reference Bettendorf, Schmidt, Tiefenbacher, Grulich-Henn, Heinrich and Schonberg^47, Reference Kennedy and Butterworth^50, Reference Murzi, Iervasi and Masini⁵³ The cause of this decrement in thyroid hormones is unknown but may include stress induced depression of the hypothalamic-pituitary-adrenal axis, hemodilution, hypothermia, the use of dopamine or glucocorticoids, or suppression secondary to tumour necrosis factor or interleukin-6.Reference Faber, Kirkegaard, Rasmussen, Westh, Busch-Sorensen and Jensen^46, Reference Mainwaring, Healy, Meier, Nelson and Norwood^52, Reference Mainwaring, Capparelli, Schell, Acosta and Nelson⁵⁴

Replacement of triiodothyronine in patients with congenital cardiac disease who have undergone cardiac surgery is currently undergoing trials. Initial data suggest that Triostat, triiodothyronine replacement, increases cardiac index, increases systolic blood pressure, and decreases systemic vascular resistance.Reference Portman, Fearneyhough, Ning, Duncan, Rosenthal and Lupinetti^45, Reference Bettendorf, Schmidt, Grulich-Henn, Ulmer and Heinrich^49, Reference Mackie, Booth and Newburger^51, Reference Chowdhury, Ojamaa, Parnell, McMahon, Sison and Klein^56, Reference Chowdhury, Parnell, Ojamaa, Boxer, Cooper and Klein⁵⁷ The heart rate in patients increased or was unchanged but there were no serious dysrhythmias. Triiodothyronine replacement corresponded to reduced requirements of inotropes and improved balance of fluids.Reference Bettendorf, Schmidt, Grulich-Henn, Ulmer and Heinrich^49, Reference Mackie, Booth and Newburger^51, Reference Chowdhury, Ojamaa, Parnell, McMahon, Sison and Klein^56, Reference Chowdhury, Parnell, Ojamaa, Boxer, Cooper and Klein⁵⁷

Glucose homeostasis

Insulin increases glucose uptake into cells, lowers serum glucose, and stimulates the formation of glycogen, proteins and adipose.Reference Trimarchi⁵ As a counterregulatory hormone, glucagon increases serum glucose by stimulating glycogenolysis and gluconeogenesis. Hypoglycemia, defined as a glucose level less than 80 milligrams per decilitre, can be seen in paediatric patients with critical illness secondary to inadequate glycogen stores, adrenal insufficiency, and liver failure. Hypoglycaemia should be avoided as it can lead to neurologic abnormalitiesReference Kinnala, Rikalainen, Lapinleimu, Parkkola, Kormano and Kero⁵⁸.

Hyperglycaemia can occur after cardiopulmonary bypass procedures as a result of decreased insulin, insulin resistance, decreased glucose utilization with hypothermia, decreased renal elimination, increased levels of epinephrine or cortisol, and secondary to cytokines and counter-regulatory hormones.Reference Kennedy and Butterworth^50, Reference Rassias⁵⁹ Potential detrimental effects of hyperglycaemia are well documented; hyperglycaemia alters cellular immune function and is pro-inflammatory, whereas insulin has anti-inflammatory properties.Reference Rassias^59, Reference Dandona, Chaudhuri, Ghanim and Mohanty⁶⁰ Insulin can reduce cytotoxicity by shifting intracellular metabolism from utilization of free fatty acids, which can lead to toxic metabolites, to utilization of glucose.Reference Rassias⁵⁹ Van den Berghe and colleagues first reported an association of hyperglycaemia with increased morbidity and mortality in critically ill adult patients, which improved with tight glycaemic control.Reference Van den Berghe, Wilmer and Hermans^61, Reference Vanhorebeek, Ingels and Van den Berghe⁶² Findings from other studies contradict these observations, however, so the role of tight glycaemic control in critical care remains controversial, especially in paediatric and neonatal intensive care where the risk of hypoglycaemia is particularly important.Reference Branco and Tasker^63, Reference de Ferranti, Gauvreau and Hickey⁶⁴ In children with severe bronchiolitis who required mechanical ventilation, hyperglycaemia was not independently associated with mortality or morbidity.Reference Branco and Tasker⁶³ In contradictory observational studies of paediatric cardiac surgical patients, one group reported an association between hyperglycaemia and morbidity and mortality,Reference Yates, Dyke and Taeed⁶⁵ while another group observed no association between hyperglycaemia and adverse events but increased morbidity with relative hypoglycaemia.Reference Rossano, Taylor and Smith⁶⁶ No controlled trials exist in paediatrics evaluating the effect of tight glucose control with insulin, but it is evident that the adult data cannot be directly translated to paediatric practice.Reference Parker, Hazelzet and Carcillo⁶⁷ No consensus exists in the literature at present regarding perioperative glycaemic control in paediatric cardiac surgical patients.

Parathyroid function and calcium metabolism

Although calcium homeostasis is not an issue in most paediatric cardiac surgical patients, hypocalcaemia is often important in patients with suspected or known DiGeorge syndrome, which is associated with parathyroid insufficiency. Calcium concentrations are regulated by parathyroid hormone and Vitamin D after conversion to calcitriol. Calcitriol and parathyroid hormone stimulate

• • calcium mobilization from bone

• • resorption of calcium in the renal tubules, and

• • increased absorption of calcium from the gastrointestinal tract.Reference Ariyan and Sosa^68, Reference Zaloga⁶⁹

Hypocalcaemia induces secretion by the thyroid gland of calcitonin, which opposes the actions of parathyroid hormone. Critical illness can induce a state of relative hypoparathyroidism, which is exacerbated by hypomagnesaemia.Reference Ariyan and Sosa⁶⁸ Renal insufficiency can also lead to calcitriol deficiency. To assess calcium homeostasis in the intensive care unit, ionized calcium should be measured, as this is the active fraction which is not affected by alterations in serum protein concentrations. Ionized calcium levels fall with administration of heparin, which is administered in large volumes during cardiopulmonary bypass.Reference Kennedy and Butterworth⁵⁰

Decreased calcium levels can lead to reversible myocardial dysfunction causing hypotension, increased length of stay and morbidity, and increased mortality in critically ill patients.Reference Burchard, Gann, Colliton and Forster^70, Reference Carcillo and Fields⁷¹ Calcium administration increases blood pressure without affecting heart rate.Reference Zaloga⁶⁹ This effect should be balanced by the risk of destructive intracellular processes that may result from increased extracellular and cytoplasmic calcium, which may be especially relevant in patients with associated ischaemia or sepsis.Reference Zaloga⁶⁹ A retrospective review of paediatric cardiac surgical patients found that postoperative calcium supplementation was associated with mortality and morbidity, including prolonged length of stay, liver dysfunction, neurological complications, infections, and need for extracorporeal support.Reference Dyke, Yates and Cua⁷² Studies investigating control of calcium homeostasis in paediatric cardiac surgical patients are lacking, so the role of aggressive calcium replacement in patients with critical cardiac disease remains obscure.

Vasopressin

Activation of either the sympathetic nervous system or the Renin-Angiotensin-Aldosterone system causes increased release of arginine vasopressin in response to low blood pressure, decreased cardiac filling, and/or increased serum osmolarity.Reference Trimarchi^5, Reference LeJemtel and Serrano^73, Reference Treschan and Peters⁷⁴ Vasopressin acts through several receptors.Reference Holmes, Landry and Granton⁷⁵ Stimulation of V₁ receptors lead to vasoconstriction in skin, skeletal muscle, and mesenteric blood vessels, but vasodilatation at low concentrations in pulmonary, coronary and cerebral vascular beds.Reference Ali, Guglin, Vaitkevicius and Ghali⁷⁶ Stimulation of V₂ receptors leads to the transport of aquaporin to the apical membrane of the collecting ducts which increases osmotic water permeability and re-absorption without inducing kaliuresis.Reference Trimarchi^5, Reference LeJemtel and Serrano^73, Reference Treschan and Peters^74, Reference Ali, Guglin, Vaitkevicius and Ghali⁷⁶ The V_1b or V₃ receptor in the anterior pituitary also regulates hypothalamic-pituitary-adrenal axis activity during stress and resting conditions.Reference Tanoue, Ito and Honda⁷⁷ Vasopressin thus amplifies the effect of cosyntropin releasing hormone upon adrenocorticotropin hormone release.Reference Tanoue, Ito and Honda^77, Reference Aguilera and Rabadan-Diehl⁷⁸ Vasopressin and cosyntropin releasing hormone have synergistic effects upon adrenocorticotropin hormone release by the pituitary.Reference Tanoue, Ito and Honda⁷⁷

Disease states most frequently involved with vasopressin in paediatric patients include the following two entities:

• • syndrome of inappropriate antidiuretic hormone secretion, and

• • relative vasopressin deficiency.

With the syndrome of inappropriate antidiuretic hormone secretion, excess arginine vasopressin is released from the hypothalamus, which mediates free water retention by the kidney, resulting in

• • hypervolemia with a low serum osmolarity of less than 280 milliosmoles per litre

• • dilutional hyponatremia with a sodium of less than 130 milliequivalents per litre, and

• • an increased urine specific gravity.Reference Trimarchi⁵

Akin to the syndrome of inappropriate antidiuretic hormone secretion, arginine vasopressin levels are elevated in patients with congestive cardiac failure, especially those with hyponatremia.Reference LeJemtel and Serrano⁷³ This elevation has been associated with increased mortality, and trials are ongoing to evaluate the therapeutic option of vasopressin-receptor antagonists in heart failure patients to stimulate diuresis.Reference Ali, Guglin, Vaitkevicius and Ghali⁷⁶

Relative vasopressin deficiency is defined as an insufficient level of vasopressin for the patient’s clinical state. The concept of relative vasopressin deficiency in critically ill cardiac patients has only recently been introduced, so data about this condition are limited. It is diagnosed in patients with hypotension and a normal vasopressin level.Reference Holmes, Landry and Granton^75, Reference Sharshar, Blanchard, Paillard, Raphael, Gajdos and Annane⁷⁹ Vasopressin deficiency can lead to shock and may be associated with other characteristics of diabetes insipidus such as urine output greater than 4 millilitres per kilogram per hour, urine specific gravity less than 1.010 and sodium greater than 145 milliequivalents per litre.Reference Trimarchi⁵ As an adjunct for blood pressure support in sepsis, vasopressin can stabilize blood pressure and reduce the need for cathecholamines.Reference Treschan and Peters^74, Reference Sharshar, Blanchard, Paillard, Raphael, Gajdos and Annane⁷⁹ Vasopressin has been used for postoperative hypotension in paediatric cardiac surgical patients. It has been shown to increase blood pressure and decrease inotrope requirements without causing tachycardia or arrhythmias.Reference Lechner, Dickerson, Fraser and Chang^80–Reference Rosenzweig, Starc and Chen⁸²