Critical Illness-Related Corticosteroid Insufficiency (CIRCI) After Pediatric Cardiac Surgery

Background

Low cardiac output syndrome (LCOS) after cardiopulmonary bypass (CPB) in pediatric patients is a multifactorial manifestation of hemodynamic changes occurring within the first 6 to 18 h after cardiac surgery. Pediatric patients with congenital heart disease may develop critical illness-related corticosteroid insufficiency (CIRCI) after CPB and deep hypothermic circulatory arrest (DHCA) with an incidence as high as 33% in neonates.^1–4 CIRCI may contribute to postoperative hemodynamic instability and capillary leak. ³ CIRCI has been studied mostly in critically ill patients with trauma and septic shock. There is an extreme paucity of data on CIRCI after CPB, and the current limited literature does not support the routine use of corticosteroids before or after CPB.^5,6 However, a few small studies have demonstrated lower cortisol levels and blunted Adrenocorticotropic Hormone (ACTH) response in a subgroup of patients with fluid- and catecholamine-refractory hypotension with dramatically improved hemodynamics after the administration of exogenous steroids.^3,7 Unfortunately, optimal identification of this subset of patients is difficult, and a single diagnostic and therapeutic approach remains elusive. The optimal timing and efficacy of preoperative or postoperative corticosteroid administration is also unclear. We review and analyze the available literature on CIRCI, specifically in the setting of pediatric cardiac surgery, and suggest diagnostic and therapeutic algorithms to help identify high-risk patients.

Methods

A systematic review of the literature was performed to identify published articles where pediatric patients (less than 18 years of age) received corticosteroids before cardiac surgery requiring CPB (Figure 1). Published papers were identified by searching Ovid Medline, Embase, World Health Organization Library Information System, and Cochrane Database. A combination of MeSH and non-MeSH terms including “bypass, cardiopulmonary,” “cortisol,” “pediatric,” “congenital heart disease,” “congenital heart surgery,” and “cardiac surgery” and “pediatric cardiac surgery” were used. Expert opinion was used to identify sentinel papers addressing the various aspects of CIRCI including pathophysiology, biochemistry, clinical diagnosis, management, and outcome effects. Full texts and reference lists of all included papers were scanned.

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Figure 1.

Serum cortisol levels (TOP) and serum adrenocorticotropic hormone (ACTH) levels (BOTTOM) in patients with cardiopulmonary bypass (CPB), deep hypothermic circulatory arrest (DHCA) with no preoperative steroids, and DHCA with preoperative steroids. Reprinted with permission from Gajarski et al. ¹⁴

Pathophysiology

The pathophysiology of CIRCI after pediatric heart surgery is poorly understood. Proposed mechanisms include the following:^1,6–10

Lower basal circulating cortisol levels after CPB due to ultrafiltration, hemodilution/blood products.

Normal ACTH and Cortisol Response after Cardiac Surgery: Several studies have investigated the levels of ACTH and cortisol after cardiac surgery. It has been observed that both ACTH and cortisol levels reach their highest point within the first 2 h after surgery and then gradually decrease over the following hours. The trend of ACTH levels closely mirrors that of cortisol levels.^10,13–17

Both CPB and DHCA resulted in significantly higher peak levels of ACTH and cortisol compared with control subjects. After the initial peak, the levels of both hormones steadily declined over the next 12 to 24 h.^10,13,14,17

In patients who underwent DHCA, both ACTH and cortisol levels continue to decrease steadily, reaching their lowest point between 18 and 24 h. Notably, cortisol response to exogenous ACTH is blunted after DHCA with profound peak-to-trough declines despite paradoxically elevated endogenous ACTH levels. These effects are exaggerated in patients who have received perioperative steroids. ¹⁴ These findings suggest a possible supraphysiological need after arrest and/or dysregulation of the HPA feedback loop with DHCA and perioperative steroids as important modifying factors. However, other studies have indicated that ACTH levels are low after perioperative corticosteroid use due to the natural negative feedback loop.^3,4,7,18 These conflicting observations may be attributed to numerous factors, including differences in preoperative corticosteroid regimens, surgical elements, and variations in the timing and dosage of steroid administration.

Diagnosis

The 2017 Consensus Guidelines task force was unable to reach agreement on a single test to reliably diagnose CIRCI. ¹⁹ Most individual studies have attempted to combine clinical and biochemical criteria. While there are no accepted testing indications, clinical criteria center on hemodynamic instability to identify patients in whom biochemical testing for CIRCI may be helpful.^{3,4,9,18,20–22} Random serum total or free cortisol blood level, response to ACTH stimulation, and elevated ACTH/cortisol ratio are the most used tests. Clinical improvement in hemodynamics after corticosteroid initiation is the most common target for effective therapy.

Risk factors: Studies have used clinical status with screening parameters to identify patients with the highest likelihood of CIRCI. These criteria combine patient risk factors with hemodynamic status and response to resuscitation. Review of the literature demonstrates the following most common risk factors for CIRCI (Table 1):^{2,4,6,14,18,22,23}

Age <30 days

Neonatal age and surgical risk score are important risk factors. In one study, all patients who developed CIRCI were neonates with RACHS-1 category score of 4 and 5. Another large review of 46 730 children showed increased mortality with steroid use in RACHS-1 categories 1 to 2 but decreased length of stay, intensive care unit length of stay, and duration of mechanical ventilation with no effect on mortality for RACHS-1 categories 4 to 6. Multiple small placebo-controlled studies have shown decreased incidence of LCOS, improved hemodynamics, and improved renal function in neonates treated with preoperative corticosteroids.^18,22,24 Two recent meta-analyses echoed these observations, finding the most benefit in neonates and surgeries with STS risk score >3.^5,23

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Table 1.

High-Risk Factors.

Age <30 days

Risk Assessment after Congenital Heart Surgery-1 (RACHS-1) or Society of Thoracic Surgeons (STAT) risk score >3

Deep Hypothermic Circulatory Arrest (DHCA)

Preoperative steroid use (including acute perioperative, eg, preincision)

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Table 2.

Hemodynamic Instability (General Criteria) Yale New Haven Children's Hospital.

MAP < fifth percentile for age

Capillary refill time > 5 s

Cerebral NIRS < 45 points, Renal NIRS < 60, NIRS decrease > 20% not associated with discomfort or agitation and/or persistently downtrending

Urine output < 0.5 cc/kg/hour despite fluid resuscitation with more than two 10 mL/kg boluses

Increase in inotropic support with 2+ vasopressors (combination of milrinone 0.5 mg/kg/min and dopamine 5 mg/kg/min or milrinone 0.5 mg/kg/min and epinephrine 0.05 mg/kg/min or milrinone 0.5 mg/kg/min and norepinephrine 0.05 mg/kg/min)

Escalating requirement for medications despite optimization of fluid and electrolyte status

Abbreviations: MAP, mean arterial pressure; NIRS, near-infrared spectroscopy.

Treatment

Both weight-based and body surface area–based stress dosing are commonly used. Weight-based dosing suggests 0.5 to 1 mg/kg every 6 h. Body surface area–based dosing suggests 50 to 100 mg/m²/d divided four times daily. An optional one-time “loading dose” of 1 to 2 mg/kg or 50 to 100 mg/m² may be given in either regimen. There is no defined duration of treatment for CIRCI and ranges from 48 to 72 h to two weeks. Most studies in this setting have used it for three to five days.^2,3,18,22 There is not a clear indication whether a taper is or is not required. At our institution, we consult endocrinology should use of steroids extend beyond 14 days.

Steroid response is expected to be marked by increased blood pressure and urine output, decreased inotrope score, and need for volume expanders over the next 48 to 72 h as markers.

Suggested CIRCI Pathway

Based on review of the literature, we use the algorithm denoted in Figure 2. We chose a cutoff of total cortisol <15 µg/dL based on studies that suggested neonates >35 weeks gestation with shock had cortisol levels <15 µg/dL.^{7,11,12,26,27} Other studies found the median cortisol concentration after CPB was 12 µg/dL,^3,28 and Maeda et al used a cutoff level <15 µg/dL to diagnose CIRCI.^3,20 Epinephrine infusion at alpha doses >0.1 has been used by multiple studies as a marker of significant vasopressor dependence.^3,10,21

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Figure 2.

Suggested critical illness-related corticosteroid insufficiency (CIRCI) algorithm at Yale New Haven Children's Hospital. Abbreviations: ACTH, Adrenocorticotropic Hormone; AS, aortic stenosis; ASD, atrial septal defect; ASO, arterial switch operation; AVSD, atrioventricular septal defect; CIRCI, critical illness-related corticosteroid insufficiency; DHCA, deep hypothermic circulatory arrest; DKS, Damus–Kaye–Stansel; DORV, double outlet right ventricle; LPA, left pulmonary artery; HCM, Hypertrophic cardiomyopathy; MAPCA, major aortopulmonary collateral arteries; NIRS, near- infrared spectroscopy; PA, pulmonary artery; RPA, right pulmonary artery; TAPVR, total anomalous pulmonary venous return; TOF, tetralogy of Fallot; VSD, ventricular septal defect.

Short-Term and Long-Term Implications of Corticosteroid Use

The short- and medium-term implications of corticosteroids after congenital heart surgery continue to be fiercely debated. ⁸ Pasquali et al studied 46 730 pediatric patients who received cardiac surgery across 38 different centers across the United States. ⁶ Corticosteroids in all patients not adjusted for age, weight, or severity of illness, were independently associated with longer length of stay, greater bacterial infection rates (mediastinitis, surgical wound infection, or sepsis requiring >7 days antibiotics), and greater postoperative use of insulin. There was no difference in duration of mechanical ventilation or overall mortality. However, adjusting for RACHS-1 categories 1 to 2 demonstrated increased morbidity and mortality with the use of corticosteroids, and it is likely that the risk versus benefit of corticosteroids shifts in lower-risk cardiac surgeries toward relatively greater risk. ⁶ This observation is supported by a recent meta-analysis looking at studies with Society of Thoracic Surgeons STAT risk categories >3 which concluded that corticosteroids improved postoperative fluid balance and shortened the duration of mechanical ventilation. Despite no impact on mortality, steroids tended to be beneficial in neonates and highly complex surgeries. ²³ A 2020 Cochrane review (13 studies) and a more recent meta-analysis (10 trials) on the topic both concluded that prophylactic corticosteroids probably reduce the length of postoperative hospital length of stay but likely do not alter mortality or overall morbidity after congenital cardiac surgery.^5,29

Limitations and Future Directions

Our report, however, has limitations. Source studies consist of a limited number of randomized control trials (RCTs) that are exclusively single-center works with small sample sizes. Consequently, these studies may not accurately represent the diverse population of patients undergoing congenital heart surgery, given that LCOS is a multifaceted condition influenced by a myriad of surgical and nonsurgical factors. Drawing conclusions from source studies is also difficult due to the highly variable clinical and biochemical criteria used to diagnose and/or treat CIRCI. Future directions should include clinical and biochemical studies. Large, multicenter RCTs with appropriately diverse cohorts, robust outcome measures, and uniform diagnostic criteria are required to address bedside utility of steroids in treating CIRCI. More experimental bench research examining the HPA axis response in highly stressed situations is required to help test some of the hypothesis underlying the pathophysiology of CIRCI.

Conclusion

Critical illness-related corticosteroid insufficiency is a clinical syndrome marked by low cortisol levels in the setting of LCOS after CPB. The pathophysiology is poorly understood but involves supraphysiologic need and/or HPA axis dysregulation post-CPB. The administration of corticosteroids in patients with hemodynamic instability improves hemodynamics, reduces duration of mechanical ventilation, and reduces hospital length of stay in neonates and high-complexity surgeries without altering overall mortality. However, lower risk surgeries may not benefit as much, and complications may include postoperative hyperglycemia and higher infection rates.