SHA24/078002

CARDIAC INTENSIVIST THINK LIKE AN ENDOCRINOLOGIST? ENDOCRINE AXIS AFTER CARDIAC SURGERY DR.HANAN ABUHASSAN,MBBS,DCH(IRD),CABP SENIOR CONSULTANT HEAD OF PEDIATRIC CARDIAC INTENSIVE CARE UNITS PRINCE SULTAN CARDIAC CENTER PRINCE SULTAN MILITARY MEDICAL CITY

ENDOCRINE AXIS AFTER CARDIAC SURGERY

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The past several years have seen an increased appreciation of the potential role of the endocrine system in the recovery process following surgery for congenital heart disease.

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Many of the hormonal changes following cardiac surgery are adaptive and necessary.

ENDOCRINE AXIS AFTER CARDIAC SURGERY

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Cardiopulmonary bypass increases "stress" hormones by the duration of bypass and technique been used .

ENDOCRINE AXIS AFTER CARDIAC SURGERY Surgery evokes a series of hormonal and metabolic changes commonly referred to as the stress response There is increased secretion of pituitary hormones and activation of the sympathetic nervous system.

ENDOCRINE AXIS AFTER CARDIAC SURGERY HORMONAL CHANGES DURING SURGERY Pituitary

Adrenal

Increased secretion

Growth hormone Catecholamine (GH) Adrenocorticotrophi Cortisol c hormone (ACTH) β-Endorphin Aldosterone Prolactin Arginine vasopressin (posterior pituitary) (AVP)

Unchanged secretion

Thyroid stimulating hormone (TSH) Luteinizing hormone (LH) Follicle stimulating hormone (FSH)

Decreased secretion

Pancreatic

Others

Glucagon

Renin

Insulin

Testosterone Oestrogen Tri-iodothyronine (T3)

ENDOCRINE AXIS AFTER CARDIAC SURGERY 

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it remains unclear which factors hypothermia Hemodilution by content of prim solution decreased perfusion of endocrine glands denaturation of hormones by foreign surface of CPB machine

ENDOCRINE AXIS AFTER CARDIAC SURGERY THYROID The developing heart normally undergoes thyroid promoted maturation of physiologic and metabolic processes, which can increase cardiac contractile function and reserve. It

remains unresolved whether the hormone responses in the euthyroid sick syndrome represent part of an adaptive response, which lowers tissue energy requirements in the face of systemic illness, or a maladaptive response, which induces damaging tissue hypothyroidism.

ENDOCRINE AXIS AFTER CARDIAC SURGERY

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Response of free T3 concentration to cardiovascular surgery in 14 patients. T3 declined during cardiopulmonary bypass (CPB) and then declined further during the first 24 hours after operation. Concentrations of free T3 during cardiac surgery in 14 patients. Concentrations were measured preoperatively (Pre), after administration of heparin (Hep), after initiation of CPB (CPB), at the nadir of hypothermia (Hypo), after rewarming (Warm), and at 2 (2 Hr), 8 (8 Hr), and 24 hours (24 Hr) after CPB. Statistical comparisons were made between the preoperative and subsequent measurements. (From Holland FW II, Brown PS Jr, Weintraub BD, et al. Cardiopulmonary bypass and thyroid function: a "euthyroid sick syndrome."Ann Thorac Surg 1991;52:46–50, with permission.)

ENDOCRINE AXIS AFTER CARDIAC SURGERY

These thyroid hormone changes may be mediated in part by cytokines or other inflammatory mediators acting at the level of the •hypothalamus and pituitary • the thyroid gland •the hepatic deiodinase system, •binding of thyroxine to thyroid binding globulin.

ENDOCRINE AXIS AFTER CARDIAC SURGERY 

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Burger A (1976) Effect of amiodarone on serum triiodothyronine, reverse triiodothyronine, thyroxin, and thyrotropin. A drug influencing peripheral metabolism of thyroid hormones. J Clin Invest 58:255–259 Allen DB, (1989) Thyroid hormone metabolism and level of illness severity in pediatric cardiac surgery patients. J Pediatr 114:59–62 Murzi B, (1995) Thyroid hormones homeostasis in pediatric patients during and after cardiopulmonary bypass. Ann Thorac Surg 59:481–485 Bettendorf M (1997) Transient secondary hypothyroidism in children after cardiac surgery. Pediatr Res 41:375–379 Brogan TV, Bratt (1997) Thyroid function in infants following cardiac surgery: comparative effects of iodinated and noniodinated topical antiseptics. Crit Care Med 25:1583–1587

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Ririe DG, 1998) Effects of cardiopulmonary bypass and deep hypothermic circulatory arrest on the thyroid axis during and after repair of congenital heart defects: preservation by deep hypothermia? Anesth Analg 87:543–548 Chowdhury D, (1999) Usefulness of triiodothyronine (T3) treatment after surgery for complex congenital heart disease in infants and children. Am J Cardiol 84:1107–1109 A1110 Portman MA, (2000) Triiodothyronine repletion in infants during cardiopulmonary bypass for congenital heart disease.

J Thorac Cardiovasc Surg 120:604–60 Martino E, (2001) The effects of amiodarone on the thyroid.

Endocr Rev 22:240–254 Bartkowski R, (2002) Thyroid hormones levels in infants during and after cardiopulmonary bypass with ultrafiltration.

Eur J Cardiothorac Surg 22:879–884

ENDOCRINE AXIS AFTER CARDIAC SURGERY Plumpton

K, (2005) Identifying infants at risk of marked thyroid suppression post-cardiopulmonary bypass. Intensive Care Med 31:581 Mackie AS, (2005) A randomized, double-blind, placebo-controlled pilot trial of triiodothyronine in neonatal heart surgery. J Thorac Cardiovasc Surg 130:810–816 Kovacikova L, (2005) Thyroid function and ioduria in infants after cardiac surgery: comparison of patients with primary and delayed sternal closure. Pediatr Crit Care Med 6:154–159 Portman MA, 2008) Abstract 2596: triiodothyronine for infants and children undergoing cardiopulmonary bypass (TRICC) study: safety and efficacy. Circulation 118:S749–750 Cardiopulmonary Bypass and Serum Thyroid Hormone Profile in Pediatric Patients with Congenital Heart Disease Sachinfirst published online: 22 MAY 2012

Endocrine Axis after Cardiac Surgery 

Cardiopulmonary bypass and open heart operations result in a low T3 state and are often complicated by significant cardiovascular dysfunction similar to that observed in clinical hypothyroidism.

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SES develop in postoperative cardiac children regardless of the procedure complexity.

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The most common pattern is a decrease in total and unbound triiodothyronin (T3) with normal levels of thyroid stimulating hormone (TSH) and thyroxin (T4) SES type 1.

ENDOCRINE AXIS AFTER CARDIAC SURGERY

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showed that when a larger amount of T3 is removed by ultra filtration, patients show a prolonged recovery.

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Elevated serum level of steroid as part of stress may influence the de iodinase activity.

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Dopamine infusion induce partial hypopituitrism.

ENDOCRINE AXIS AFTER CARDIAC SURGERY

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The concentration of plasma selenium in children undergoing cardiopulmonary bypass decreases significantly, resulting in diminished de iodinase activity and a subsequent reduction in the conversion of T4 to T3 hypothyroidism

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that neonates undergoing more lengthy procedures may benefit from T3 replacement, with improved cardiac output and more favorable intensive care unit (ICU) acuity scores.

ENDOCRINE AXIS AFTER CARDIAC SURGERY

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that younger children (less than three months of age) with longer CBP time (greater than 120 minutes) showed prolonged ventilation after CBP and lower free T3 levels Amiodarone administration known affect thyroid homeostasis by competitive inhibition of 5monodeiodinase which convert T4 to T3 and reverse T3 to T2 also by direct effect of high iodine content.

ENDOCRINE AXIS AFTER CARDIAC SURGERY

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Prolong chest tube drainage will lead to decrease thyroid binding globulin which lead to hypothyroidism.

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demonstrated a prolonged decrease in thyroid hormones for five to seven days

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This recognition has prompted a number of investigators to study the effects of T3 administration to patients in the perioperative period

ENDOCRINE AXIS AFTER CARDIAC SURGERY 

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Open sternotomy and delayed sternal closure (DSC) is a surgical technique that has been used in children for the past 20 years that facilitates postoperative recovery in the intensive care unit showed a correlation between low T3 and T4 levels and survival in 10 infants of less than 5 kg body weight.

In the two patients that died in this small series, no increase in T3 and T4 or TSH was found after a trough was reached at 48 to 72 hours after surgery.

ENDOCRINE AXIS AFTER CARDIAC SURGERY

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prophylactic administration of TT4 for improving outcomes needs to be studied further.

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The small number of controlled trials performed to date have shown conflicting results on the cardiovascular effects of tri iodothyronine infusion post surgery.

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Multiple lines of evidence have suggested that T3 can act acutely as a positive inotrope and vasodilator agent.

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none has had the statistical power to address the question of altered mortality.

ENDOCRINE AXIS AFTER CARDIAC SURGERY

ENDOCRINE AXIS AFTER CARDIAC SURGERY Glucocorticoids A similar rationale exists for the use of glucocorticoids  Cortisol is essential for maintaining vascular tone and may affect myocardial function Particularly in premature and stressed term neonates.  A relative adrenal insufficiency may develop as a result of the effects of inflammation on an immature hypothalamus–pituitary axis  the definition of a relative adrenal insufficiency remains unclear.  a normal or near normal cortisol level in a critically ill patient is indicative of an inadequate hypothalamus– pituitary axis response Management of the postoperative pediatric cardiac surgical patient Anthony C. Chang, Crit Care Med 2011 Vol. 39, No. 8

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Bourbon, et al., “The effect of methylprednisolone treatment on the cardiopulmonary bypass-induced systemic inflammatory response,” European Journal of Cardio-thoracic Surgery, vol. 26, no. 5, pp. 932–938, 2004.

Gessler, et al., “Administration of steroids in pediatric cardiac surgery: impact on clinical outcome and systemic inflammatory response,” Pediatric Cardiology, vol. 26, no.

5, pp. 595–600, 2005 P. Whitlock, et al., “Clinical benefit of steroid use in patients undergoing cardiopulmonary bypass: a metaanalysis of randomized trials,” European Heart Journal, vol. 29, no. 21, pp. 2592–2600, 2008 A. Bronicki, “Dexamethasone reduces the inflammatory response to cardiopulmonary bypass in children,” Annals of Thoracic Surgery, vol. 69, no. 5, pp. 1490–1495, 2000

ENDOCRINE AXIS AFTER CARDIAC SURGERY 

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Schroeder, et al: Combined steroid treatment for congenital heart surgery improves oxygen delivery and reduces post bypass inflammatory mediator expression. Circulation 2003; 107: 2823–2828 Checchia PA, et al: Dexamethasone reduces postoperative troponin levels in children undergoing cardiopulmonary bypass. Crit Care Med 2003; 31:1742 Malagon I, et al: Effect of dexamethasone post operative cardiac troponin T production in pediatric cardiac surgery. Intensive Care Med 2005; 31:1420– 1426

ENDOCRINE AXIS AFTER CARDIAC SURGERY 

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the immature pituitary–adrenal axis in neonates may respond differently Suppression of the pituitary–adrenal axis by a preoperative bolus of methylprednisolone may be one reason for the low cortisol levels observed after operation.

Another potential reason is the ultrafiltration used during cardiopulmonary bypass, which may remove glucocorticoids from the circulation.

The third potential reason is, that the pituitary–adrenal axis may be affected as a part of systemic inflammation or organ dysfunction.

ENDOCRINE AXIS AFTER CARDIAC SURGERY

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Peak serum cortisol was unrelated to CPB time and did not predict the level of inotrope support.

A subset of patients with elevated ACTH/cortisol ratios seemed to have a clinical status consistent with adrenal insufficiency and may be a target group for early postoperative steroid therapy.

Adrenocortical response in infants undergoing cardiac surgery with cardiopulmonary bypass and circulatory arrest Pediatric Critical Care Medicine: January 2010 - Volume 11 - Issue 1 - pp 44-51

ENDOCRINE AXIS AFTER CARDIAC SURGERY

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Studies in children found the administration of glucocorticoids before bypass significantly reduced the pro inflammatory factors .

Augmented the compensatory anti inflammatory responses to bypass .

Reduced the extent of myocardial injury Improved the postoperative course The use of hydrocortisone in neonates with low cardiac output syndrome after cardiac surgery normalized cardio vascular status and decreased inotropic requirements .

ENDOCRINE AXIS AFTER CARDIAC SURGERY

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A majority of pediatric cardiac centers use glucocorticoids to ameliorate the inflammatory response to bypass

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Checchia PA, Bronicki RA, Costello JM, et al: Steroid use before pediatric cardiac operations using cardiopulmonary bypass: An international survey of 36 centers.

Pediatr Crit Care Med 2005; 6:441–444

ENDOCRINE AXIS AFTER CARDIAC SURGERY

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Two prospective studies failed to demonstrate benefit from the use of glucocorticoids however they limited enrollment to older children .

Lindberg L, et al: Effects of dexamethasone on clinical course, C-reactive protein, S100B protein and von Willebrand factor antigen after paediatric cardiac surgery. Br Anaesthesia 2003; 90:728–732 Varan B, Tokel K, Mercan S, et al: Systemic inflammatory response related to cardiopulmonary bypass and its modification by methylprednisolone: High dose versus low dose. Pediatr Cardiol 2002; 23:437–441

ENDOCRINE AXIS AFTER CARDIAC SURGERY

ENDOCRINE AXIS AFTER CARDIAC SURGERY Insulin 

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Carbohydrate metabolism is regulated by insulin, glucagon, cortisol, growth hormone, and epinephrine, the concentrations of which are generally perturbed during and after CPB. After onset of CPB, blood glucose concentrations rise steadily .

Despite marked hyperglycemia, insulin concentrations decline from their control values during hypothermic bypass

ENDOCRINE AXIS AFTER CARDIAC SURGERY 

The decreased insulin response after surgery might be due to the fact that critically ill children seem to be more vulnerable than adults to beta-cell dysfunction.

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These changes may be induced by multiple factors such as hypothermia, vasopressors, elevations of proinflammatory cytokines, and use of glucocorticoids.

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Hyperglycaemia results from beta-cell dysfunction in critically ill children with respiratory and cardiovascular failure: a prospective observational study. Crit Care. 2009;

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Lambillotte JC. Direct glucocorticoid inhibition of insulin secretion: an in vitro study of dexamethasone effects in mouse islets. J Clin Invest. 1997;99:414–423

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Benzing G. Glucose and insulin changes in infants and children undergoing hypothermic open heart surgery. Am J Cardiol. 1983;52:133–136

ENDOCRINE AXIS AFTER CARDIAC SURGERY

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Hyperglycemia is a regular phenomenon in critically ill children after surgical repair or palliation of congenital heart defects.

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Some studies have shown an association of hyperglycemia with increased postoperative morbidity and mortality in these children.

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Falcao G. Impact of postoperative hyperglycemia following surgical repair of congenital cardiac defects. Pediatr Cardiol. 2008;29:628–636

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Polito A. Association between intraoperative and early postoperative glucose levels and adverse outcomes after complex congenital heart surgery. Circulation. 2008;118:2235–2242

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Yates AR, Hyperglycemia is a marker for poor outcome in the postoperative pediatric cardiac patient. Pediatr Crit Care Med. 2006;7:351–355

ENDOCRINE AXIS AFTER CARDIAC SURGERY

ENDOCRINE AXIS AFTER CARDIAC SURGERY

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The only randomized controlled study of critically ill children showed improved short-term outcome after treatment with intensive insulin therapy targeting blood glucose levels to age-adjusted normal fasting concentrations .

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Debate exists on the harm of insulin-induced hypoglycemic events.

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Joosten K, (2009) Glycaemic control in paediatric critical care. Lancet 373:1423– 1424 (author reply 1424)

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Vlasselaers D, Intensive insulin therapy for patients in paediatric intensive care: a prospective, randomised controlled study. Lancet. 2009;373:547–556.

ENDOCRINE AXIS AFTER CARDIAC SURGERY

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tight glycemic control with insulin improved outcomes in adults undergoing cardiac surgery, but these benefits are unproven in critically ill children at risk for hyperinsulinemic hypoglycemia.

Tight glycemic control can be achieved with a low hypoglycemia rate after cardiac surgery in children, but it does not significantly change the infection rate, mortality, length of stay, or measures of organ failure, as compared with standard care

Tight glycemic control versus standard care after pediatric cardiac surgery.

Agus MS,etal, N eng J med 2012 Sep 27;367(13):1208-19.

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ENDOCRINE AXIS AFTER CARDIAC SURGERY 

In this study, post-CPB and postoperative hyperglycemia were not risk factors for postoperative morbidity and mortality after infant cardiac surgery.

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Some of the postulated mechanisms include the following: hyperoxia anesthetic agents, hypothermia, insulin and catecholamine derangements, and utilization of dextrose containing solutions.

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Perioperative Hyperglycemia: Effect on Outcome After Infant Congenital Heart Surgery William M. Congenital Heart Institute, Arnold Palmer Hospital for Children, Orlando, Florida

ENDOCRINE AXIS AFTER CARDIAC SURGERY GROWTH HORMON 

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Compared the onset of predictors for postoperative complications (lactate, total T3 (tT3), total T4 (tT4) and cortisone) retrospectively with the onset of altered growth hormone (GH) concentration in a patient who had a lethal postoperative outcome and in 13 patients who were without postoperative complications for a period of 24 hours postoperatively.

Compared with the values of the patients without postoperative complications, GH values were elevated (68-fold) 1 h after surgery to 103ng/ml

and lactate was increased (12-fold) to 12.7mmol/l

at 6 h postoperatively in the patient with the lethal outcome. The other parameters measured (tT3, tT4 and cortisone) showed no rapid alteration during the first hours postoperatively.

This case report suggests that the rapid postoperative onset of raised GH concentration in plasma may be an earlier marker for postoperative complications than the 'established' predictors.

Postoperative Altered Plasma Growth Hormone Levels - A Predictor for Postoperative Complications? A Case Report 2001, Vol. 17, No. 2 , Pages 88-92

ENDOCRINE AXIS AFTER CARDIAC SURGERY

ENDOCRINE AXIS AFTER CARDIAC SURGERY Vasopressin 

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Antidiuretic hormone (ADH), secreted by the posterior pituitary gland, is a potent regulator of renal water excretion.

ADH increases renal vascular resistance, reducing renal blood flow, and stimulates the release of the von Willebrand factor, perhaps improving hemostasis during and after cardiac surgery

ENDOCRINE AXIS AFTER CARDIAC SURGERY 

Its two primary functions are to retain water in the body and to constrict blood vessels.

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The rationale behind the use of exogenous AVP in critical illness is that neurohypophyseal stores may become exhausted, leading to vasodilatory shock.

Landry DW, Oliver JA: The pathogenesis of vasodilatory shock. N Engl J Med 2001; 345:588–595

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There have been a few reports on the use of AVP in children A retrospective analysis was performed in 11 children after cardiac surgery.

All had refractory hypotension and all but two had normal or mildly depressed left ventricular function.

During the first hour of AVP, there was a significant improvement in blood pressure and the inotrope score.

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Rosenzweig EB, et al: Intravenous arginine–vasopressin in children with vasodilatory shock after cardiac surgery. Circulation 1999; 100(Suppl II):II- 182–II186

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Choong K, Vasopressin in pediatric shock and cardiac arrest. Pediatr Crit Care Med 2008; 9:372–379

ENDOCRINE AXIS AFTER CARDIAC SURGERY

ENDOCRINE AXIS AFTER CARDIAC SURGERY Natriuretic Peptides.  The natriuretic peptides act primarily as counter regulatory hormones to the renin–angiotensin–aldosterone system.  Atrial and B-type natriuretic peptides are produced primarily by myocardium in response to chamber wall stress. It causes vasodilation of venous capacitance and arterial resistance vessels, and improved ventricular relaxation. 

Levin ER, Gardner DG, Samson WK: Natriuretic peptides. N Engl J Med 1998; 339:

321–328

ENDOCRINE AXIS AFTER CARDIAC SURGERY 

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Serial measurements taken before, during, and after CPB have shown that renin activity increases during and shortly after CPB . angiotensin II and aldosterone concentrations rise significantly during and shortly after bypass in patients undergoing nonpulsatile perfusion .

In neonates undergoing cardiac surgery, an increase in Btype natriuretic peptide 24 hours after surgery predicts poor postoperative outcome.

B-type natriuretic peptide levels predict outcome after neonatal cardiac surgery Jong-Hau Hsu, Department of Pediatrics, University of California, San Francisco,

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A study evaluated the safety and efficacy of nesiritide in pediatric decompensated heart failure by prospectively monitoring 55 separate infusions in 32 patients. They found results similar to those found in adults: A significant increase in diuresis; reduction in ventricular filling pressures and increase in Cardiac output.

No hypotension or arrhythmias were noted during 478 cumulative days of therapy and serum creatinine levels trended downward after therapy.

Colucci WS, et al: Intravenous nesiritide, a natriuretic peptide, in the treatment of decompensated congestive heart failure. N Engl J Med 2000; 343:246–253 Jefferies JL, et al: A prospective evaluation of nesiritide in the treatment of pediatric heart failure. Ped Cardiol 2006; 27:402–407

ENDOCRINE AXIS AFTER CARDIAC SURGERY

ENDOCRINE AXIS AFTER CARDIAC SURGERY

Calcium balance 

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Calcium balance in the newborn is regulated through the actions of PTH, vitamin D, calcitonin and the calcium sensing receptor.

Hypocalcaemia is common in the postoperative neonates. it is important to maintain adequate extracellular calcium levels in neonates and small infants.

ENDOCRINE AXIS AFTER CARDIAC SURGERY

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In Metabolic and hormonal control for low cardiac output syndrome –Use of calcium, thyroxine and insulin as Myocardial contraction and relaxation are mediated by cyclic fluctuations in cytoplasmic calcium concentration.

It is important to maintain adequate extracellular calcium levels in neonates and small infants.

Infants on long term frusemide and malnourished infants.

Our practice is to measure serial ionic calcium levels and maintain them using intravenous infusion

ENDOCRINE AXIS AFTER CARDIAC SURGERY

ENDOCRINE AXIS AFTER CARDIAC SURGERY 

conclusion

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Babies and children after cardiac surgery at a specific risk to develop abnormalities in there endocrine system.

Intervention within the endocrine system post cardiac surgery remains highly controversial.

It is difficult to differentiate between beneficial adaptations and harmful abnormalities of the hormones reactions , and to outline strategies for therapy.

There is many factors in the operating room and in the ICU management which play roles in this derangements and can be minimized .

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ENDOCRINE AXIS AFTER CARDIAC SURGERY 

Questions

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Who should receive exogenous steroid, thyroxin, insulin, vasopressin and calcium infusions ?

When should it be given timing , duration and level of the hormones?

Is modification in operation timing , thermal technique and anesthesia medication , as well as upgrading CPB machine technique and type of filtration will be the best way to prevent or reduce this iatrogenic effect on endocrine and metabolic system of these patients?

Is it time to do start national project to study the best hormonal post cardiac management for our population ?

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THANK YOU