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Haemodynamic effects of prophylactic post-operative hydrocortisone following cardiopulmonary bypass in neonates undergoing cardiac surgery

Published online by Cambridge University Press:  23 March 2023

Lily M. Landry Open the ORCID record for Lily M. Landry [Opens in a new window] ,
Viswanath Gajula ,
Jarrod D. Knudson  and
Christopher L. Jenks
Lily M. Landry*
Affiliation:
Department of Pediatrics, Division of Pediatric Cardiology, University of Mississippi Medical Center, Jackson, MS, USA
Viswanath Gajula
Affiliation:
Department of Pediatrics, Division of Pediatric Critical Care, University of Mississippi Medical Center, Jackson, MS, USA
Jarrod D. Knudson
Affiliation:
Department of Pediatrics, Division of Pediatric Critical Care, University of Mississippi Medical Center, Jackson, MS, USA
Christopher L. Jenks
Affiliation:
Department of Pediatrics, Division of Pediatric Critical Care, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
*
Author for correspondence: L. M. Landry, MD, Department of Pediatric Critical Care, Baylor College of Medicine/Texas Children’s Hospital, 6651 Main Street, Houston, TX 77030, USA. Tel: 832-824-1000. E-mail: Lmm07c@gmail.com
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Abstract

Multiple studies have endeavoured to define the role of steroids in paediatric congenital heart surgery; however, steroid utilisation remains haphazard. In September, 2017, our institution implemented a protocol requiring that all neonates undergoing cardiac surgery with the use of cardiopulmonary bypass receive a five-day post-operative hydrocortisone taper. This single-centre retrospective study was designed to test the hypothesis that routine post-operative hydrocortisone administration reduces the incidence of capillary leak syndrome, leads to favourable postoperative fluid balance, and less inotropic support in the early post-operative period. Data were gathered on all term neonates who underwent cardiac surgery with the use of bypass between September, 2015 and 2019. Subjects who were unable to separate from bypass, required long-term dialysis, or long-term mechanical ventilation were excluded. Seventy-five patients met eligibility criteria (non-hydrocortisone group = 52; hydrocortisone group = 23). For post-operative days 0–4, we did not observe a significant difference in net fluid balance or vasoactive inotropic score between study groups. Similarly, we saw no major difference in secondary clinical outcomes (post-operative duration of mechanical ventilation, ICU/hospital length of stay, and time from surgery to initiation of enteral feeds). In contrast to prior analyses, our study was unable to demonstrate a significant difference in net fluid balance or vasoactive inotropic score with the administration of a tapered post-operative hydrocortisone regimen. Similarly, we saw no effect on secondary clinical outcomes. Further long-term randomised control studies are necessary to validate the potential clinical benefit of utilising steroids in paediatric cardiac surgery, especially in the more fragile neonatal population.

Keywords

hydrocortisonecardiopulmonary bypassclinical outcomescongenital heart surgeryinflammation
Type
Original Article
Information
Cardiology in the Young , Volume 33 , Issue 12 , December 2023 , pp. 2504 - 2510
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Creative Commons
Creative Common License - CCCreative Common License - BY
This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted re-use, distribution and reproduction, provided the original article is properly cited.
Copyright
© The Author(s), 2023. Published by Cambridge University Press

Neonates that are undergoing cardiac surgery with the use of cardiopulmonary bypass carry the highest risk of developing post-operative complications, including myocardial dysfunction and low cardiac output syndrome.Reference Kozik and Tweddell1,Reference Robert, Borasino and Dabal2 Cardiopulmonary bypass provokes a systemic pro-inflammatory response that is characterised by the release of many neurohumoral substances that ultimately lead to capillary leak and multiorgan dysfunction.Reference Kozik and Tweddell1,Reference Fudulu, Lightman and Caputo3–Reference Seghaye5 This inflammatory response, which involves a series of complement activation, cytokine release, and endothelial cell activation, is significantly exaggerated in neonates due to their higher metabolic demands, reactive pulmonary vasculature, and immature organ systems.Reference Kozik and Tweddell1,Reference Bronicki, Flores and Loomba6–Reference Hall, Smith and Rocker8

Corticosteroids are potent anti-inflammatory agents that have been strategically utilised in paediatric cardiac surgery to blunt this inflammatory response.Reference Pasquali, Hall and Li9–Reference Fudulu, Schadenberg and Gibbison13 Multiple studies have demonstrated that corticosteroids are significantly effective in reducing post-bypass inflammation through gene modification resulting in the upregulation of anti-inflammatory cytokine (Interleukin-10) synthesis and the downregulation of pro-inflammatory cytokine (tumor necrosis factor-alpha, interleukin-1 beta, interleukin-6, and interleukin-8) synthesis, nitric oxide synthesis, and complement activation.Reference Hall, Smith and Rocker8,Reference Bronicki and Hall10,Reference Celik, Gormus and Okesli14 Despite what we know about corticosteroids and their effects on inflammation, there remains a considerable degree of uncertainty regarding their impact on post-operative clinical outcomes.Reference Fudulu, Lightman and Caputo3,Reference Bronicki, Flores and Loomba6,Reference Fudulu, Gibbison and Upton12,Reference Fudulu, Schadenberg and Gibbison13,Reference Checchia, Bronicki and Costello15–Reference Scrascia, Rotunno and Guida17

Several randomised control trials have sought to assess the effects of corticosteroids on short-term and longer-term clinical outcomes in paediatric patients that have undergone cardiac surgery.Reference Robert, Borasino and Dabal2,Reference Bronicki, Flores and Loomba6,Reference Scrascia, Rotunno and Guida17–Reference Gibbison, Villalobos Lizardi and Avilés Martínez30 Recent meta-analyses by Gibbison et. al and Bronicki et. al found evidence to suggest that corticosteroids reduce the duration of post-operative mechanical ventilation and favourably impact post-operative fluid balance.Reference Bronicki, Flores and Loomba6,Reference Gibbison, Villalobos Lizardi and Avilés Martínez30 They also noted that corticosteroids had minimal to no impact on mortality which was consistent with the previous literature.Reference Bronicki, Flores and Loomba6,Reference Scrascia, Rotunno and Guida17,Reference Gibbison, Villalobos Lizardi and Avilés Martínez30,Reference Pasquali, Li and He31 In lieu of these findings, it is worth noting that the patient selection criterion for the studies included in these systematic reviews were widely diverse, with several studies excluding neonates altogether.Reference Lindberg, Forsell, Jögi and Olsson20,Reference Amanullah, Hamid and Hanif22,Reference Keski-Nisula, Suominen and Olkkola25

This retrospective review was designed to test the hypothesis that routine post-operative hydrocortisone administration reduces the incidence of capillary leak syndrome in neonates who have undergone cardiac surgery with the use of cardiopulmonary bypass and leads to favourable postoperative fluid balance and less inotropic support in the early post-operative period. Additionally, we further sought to determine the impact of post-operative hydrocortisone administration on volume resuscitation, diuretic use, and various clinical outcomes including ICU length of stay, hospital length of stay, duration of mechanical ventilation, and time from surgery to initiation of enteral feeds.

Materials and method

Study design

In September, 2017, our institution implemented a standardised protocol requiring that all neonates undergoing cardiac surgery with the use of cardiopulmonary bypass receive a five-day post-operative hydrocortisone taper. This change in clinical practice was implemented in response to the published results of Robert et al’s randomised control trial that demonstrated a significant reduction in the incidence of low cardiac output syndrome with their described steroid regimen.Reference Robert, Borasino and Dabal2 Prior to this protocol change, corticosteroid use at our institution was managed independently by the attending physician on service. This retrospective chart review was conducted at a single-centre university hospital in Jackson, Mississippi. After receiving approval from the University of Mississippi Medical Center Institutional Review Board (reference #2020V0211), data were collected on all term neonates undergoing cardiac surgery with the use of cardiopulmonary bypass between 1 September, 2015 and 1 September, 2019, providing a two-year comparison.

Patient selection

Term and near-term neonates (>36 weeks gestational age) who underwent cardiac surgery with the use of cardiopulmonary bypass within the first 28 days of life were eligible for inclusion. We excluded infants < 36 weeks gestational age, infants weighing less than 2000 grams at birth, infants who were unable to separate from bypass, and infants who required long-term postoperative dialysis or long-term mechanical ventilation (home ventilator).

Data extraction

All information was collected from electronic medical records and entered into a Research Electronic Data Capture database (University of Mississippi Medical Center, Jackson, MS).Reference Harris, Taylor and Thielke32,Reference Harris, Taylor and Minor33 Data pertaining to patient demographics (sex, gestational age, age at surgery, and weight), intraoperative parameters (bypass, cross-clamp, deep hypothermic circulatory arrest, and antegrade cerebral perfusion times), and type of surgery were collected. Post-operative data, including daily net fluid balance, urine output, intravenous diuretic requirements, and daily fluid requirements, were recorded and trended for every patient beginning at the time of arrival to the cardiac ICU through post-operative day seven. A vasoactive-inotropic score, as described by Gaies et al. (See Appendix A), was used as a means of comparing total inotropic support between groups.Reference Gaies, Gurney and Yen34–Reference McIntosh, Tong and Deakyne37 Following admission to the ICU, a vasoactive-inotropic score was abstracted at three random time points per day for post-operative days zero through four. Secondary clinical outcomes included post-operative duration of mechanical ventilation, ICU length of stay, hospital length of stay, and time from surgery to initiation of enteral feeds.

Pre-operative and intraoperative management

All patients received a routine single dose of intraoperative intravenous methylprednisolone (20 mg/kg/dose with a maximum dose of 200 mg). Pre-operative steroids were not routinely administered at our institution. The cardiopulmonary bypass circuit prime consisted of plasmalyte, Heparin, packed red blood cells, fresh frozen plasma, 0.45% normal saline, sodium bicarbonate, calcium chloride, and mannitol. For arch reconstructions, patients were cooled to 25 degrees Celsius and given a dose DelNido cardioplegia. Intermittent ultrafiltration was used to remove extra fluid volume, and zero-balance ultrafiltration was used after antegrade cerebral perfusion to reduce any lactate created during lower body circulatory arrest. We used blood to increase the hematocrit to desired levels upon rewarming and post-clamp (above 24 degrees Celsius), calcium was administered to achieve normal levels.

Post-operative management

Prior to September, 2017, post-operative steroid administration was at the discretion of the attending physician. Some patients did receive hydrocortisone; however, the dose, duration of therapy, and patient selection criteria were highly variable. Patients who were intubated for prolonged periods of time or patients with known airway difficulties typically received a prophylactic four-dose series of dexamethasone to prevent post-extubation airway oedema and extubation failure. This standard of practice was the same for both the pre-protocol and post-protocol groups. All doses of hydrocortisone given in the post-operative period were recorded for both the pre-protocol and post-protocol groups.

Hydrocortisone protocol

Beginning 7 September, 2017, all neonates undergoing cardiac surgery with the use of cardiopulmonary bypass received a bolus of intravenous hydrocortisone (4 mg/kg) upon returning to the cardiac ICU, followed by a bolus regimen that was tapered over five days as follows: 1 mg/kg every 6 hours × 48 hours, 1 mg/kg every 8 hours × 24 hours, 1 mg/kg every 12 hours × 24 hours, then stopped.

Statistical methods

The Statistical Product and Service Solutions (IBM SPSS statistics for windows version 27 Armonk, NY: IBM Corp) was used to analyse the data. For normally distributed data, a two-tailed independent t-test was used to analyse continuous variables between the groups. A Fischer exact test was used for categorical values and dichotomous response variables. For non-normally distributed data, the Wilcoxon rank sum test was used. To evaluate the statistical dispersion, the interquartile range was utilised. An alpha of 0.05 was used to determine significance. The 95% confidence intervals were calculated when appropriate.

Results

Between 1 September, 2015 and 1 September, 2019, ninety-seven neonates underwent cardiac surgery with the use of cardiopulmonary bypass. Of these ninety-seven patients, seventy-five (77%) met eligibility criteria. The non-hydrocortisone group consisted of fifty-two patients (69%), all of whom had undergone surgery prior to September, 2017 and did not receive a standardised post-operative hydrocortisone tapered regimen. Several patients in this group did receive several doses of hydrocortisone; however, the amount of hydrocortisone used in this group was significantly less (p < 0.001) (see supplemental materials). The hydrocortisone group consisted of twenty-three patients (31%), all of whom had undergone cardiac surgery after September, 2017 and received a five-day long tapered hydrocortisone regimen in the immediate post-operative period. All patients in hydrocortisone group completed a full five days of therapy.

A demographic comparison of the groups is shown in Table 1. The study groups were statistically homogenous with no major differences in sex, age, weight, or intraoperative risk factors. The average gestational age for both groups was around 38 weeks and the average age at time of surgery was between eight and nine days old. The major types of surgeries that were performed are listed in Table 1. Surgeries listed as “Other” included the following procedures: unifocalisation procedure, pericardial tumor resection, Yasui procedure, right ventricular outflow augmentation, pulmonary valvectomy and main pulmonary artery plication, and right pulmonary artery reimplantation.

Table 1. Descriptive Statistics and Clinical Outcomes

Note. – Data are shown as n (%), mean + standard deviation [range]. ACP = antegrade cerebral perfusion; ASO = arterial switch operation; AV = aortic valve; BT = Blalock-Taussig; CPB = cardiopulmonary bypass; DHCA = deep hypothermic circulatory arrest; DKS = Daymus–Kaye–Stansel procedure; LOS = length of stay; MV = mitral valve; PA = pulmonary artery; RV-PA = right ventricle to pulmonary artery; STAT = The Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery; TAPVR = total anomalous venous return.

A graphical comparison of median values for our primary outcomes which included a vasoactive-inotropic score and net fluid trends for both groups (post-operative days 0–4) is depicted in Figure 1. Patients in the hydrocortisone group had a more-positive net fluid balance for post-operative days 0–1 and a more-negative fluid balance for post-operative days 2–3 in comparison to the non-hydrocortisone group. Net fluid balance was almost equal for both groups on post-operative day 4. Similarly, the median vasoactive-inotropic score for the hydrocortisone group was higher for post-operative days 0 and 1, but lower for post-operative days 3 and 4 in comparison to the non-hydrocortisone group. Individually, none of these differences were found to be statistically significant.

Figure 1. A Combined Comparison of Vasoactive-Inotropic Scores & Net Fluid Trends for Both Groups (Post-operative Days 0–4).

Note. – Data are shown as median values. HC = Hydrocortisone; NH = Non-hydrocortisone; POD = post-operative day; VIS = Vasoactive-Inotropic Score.

Intravenous furosemide and bumetanide use were similar for both groups for post-operative days 0–7; however, chlorothiazide use in the hydrocortisone group was significantly higher (almost doubled) in comparison to the non-hydrocortisone group (4.4 mg/kg/day versus 1.95 mg/kg/day; p < 002) (Table 2). Additionally, the average amount of fluid or blood product that was administered during post-operative days 0–7 was also similar for both groups (Table 3).

Table 2. A Comparison of Post-operative Intravenous Diuretic Use for Post-operative Days 0–7

Note. – Data are shown as mean values. Non-HC = non-hydrocortisone, HC = hydrocortisone.

Table 3. Comparison of Fluid Requirements and between Groups for Post-operative Days 0–7

Note. – Data are shown as median values with IQR (25, 75). HC = hydrocortisone; IQR = interquartile range; Non-HC = non-hydrocortisone.

Secondary clinical outcomes including ICU length of stay, hospital length of stay, time on the ventilator, and time from surgery to initiation of enteral feeds were similar between groups (Table 1). Overall hospital survival was also similar between groups.

Discussion

The use of prophylactic perioperative steroids in paediatric cardiac surgery has become a common practice in many programs, yet an explicit understanding of their utility remains a topic of much debate. Multiple studies have made a concerted effort to define the role of steroids and assess their impact on post-operative clinical outcomes; however, confounding variables including widely diverse dosing strategies and inclusion/exclusion criteria have made this a challenging endeavour.Reference Bronicki, Flores and Loomba6,Reference Scrascia, Rotunno and Guida17,Reference Gibbison, Villalobos Lizardi and Avilés Martínez30,Reference Graham38

There have been only two randomised control trials in the last forty years that have studied the effects of prophylactic steroid administration in neonates undergoing cardiac surgery, specifically in the post-operative period.Reference Robert, Borasino and Dabal2,Reference Ando, Park and Wada29 Both Ando et al.Reference Ando, Park and Wada29 and Robert et al.Reference Robert, Borasino and Dabal2 evaluated the impact of a five-to-seven day long tapered hydrocortisone infusion versus normal saline placebo administered after the discontinuation of cardiopulmonary bypass. Specifically, both studies sought to examine the effects of hydrocortisone on treating adrenal insufficiency that may ensue after neonatal open-heart surgery. Despite slightly differed steroid regimens, both studies demonstrated improved fluid balance and urine output with steroid treatment.Reference Robert, Borasino and Dabal2,Reference Ando, Park and Wada29,Reference Graham38 Additionally, the larger and more recent of the two studies demonstrated a significant reduction in the incidence of low cardiac output syndrome with their described steroid regimen.Reference Robert, Borasino and Dabal2,Reference Graham38

Although low cardiac output syndrome has been historically difficult to define, we used negative fluid balance as a surrogate parameter for decreased capillary leak syndrome and an indirect marker of improved cardiac output.Reference Alten and Gaies39 We also used vasoactive-inotropic score as a marker of cardiovascular dysfunction, as proposed by Gaies et al.Reference Gaies, Gurney and Yen34 Our study was unable to demonstrate a significant difference in net fluid balance with the administration of a tapered post-operative hydrocortisone bolus regimen. Additionally, we saw no major difference in vasoactive-inotropic score between treatment and non-treatment groups. Although our outcome measures and results differ considerably from the aforementioned randomised control trials, there are several differences in study design that are worth expanding on.

First, our study group included neonates with very complex, critical congenital cardiac anatomy requiring higher risk surgeries. Sixty-four percent of our study participants underwent either a Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery (STAT) 4 or STAT 5 category cardiac operations. Of these operations, forty-one percent were Norwood procedures. This is similar to Robert et al.’s study, but contrasts with Ando et al’s study population, which excluded patients with single ventricle anatomy/physiology and only included neonates undergoing complete biventricular repair.Reference Ando, Park and Wada29 Additionally, none of our participants received pre-operative steroids; instead, all patients received a ubiquitous single dose of intravenous methylprednisolone in the operating room, upon induction of anesthesia. This is very different from Robert et al.’s studyReference Robert, Borasino and Dabal2, in which all patients routinely received two doses of preoperative steroids (methylprednisolone 10 mg/kg/dose at 8 hours and 1 hour prior to their surgery) and none of their patients received intraoperative steroids. Lastly, our study examined the effects of a tapered bolus regimen rather than a tapered continuous infusion. Given the long duration of action of hydrocortisone, it is unlikely that tapered bolus dosing and tapered continuous infusion are significantly different. Nonetheless, further studies are needed to determine if there are clinical effects related to preoperative steroid administration or postoperative dosing techniques.

Regarding secondary clinical outcomes, we found that post-operative bolus dose hydrocortisone administration had no impact on intensive care or hospital length of stay, duration of mechanical ventilation, hospital mortality, and time from surgery to initiation of enteral feeds. This is consistent with what was noted in several prior studies.Reference Bronicki, Flores and Loomba6,Reference Scrascia, Rotunno and Guida17,Reference Gibbison, Villalobos Lizardi and Avilés Martínez30,Reference Pasquali, Li and He31

Our study certainly has limitations; the most significant being the retrospective nature of the study, and the inability to definitively establish true cause-and-effect relationships. Furthermore, this was a single-centre study with a small sample size, limiting the overall power and statistical analysis. Additionally, there was a significant study population size difference between comparison groups which may have led to skewed results. We attribute this population difference to a change in cardiothoracic surgeons that took place in 2017 leading to fewer patient referrals and thus fewer neonatal surgeries. With a retrospective analysis, some data may be incomplete or inaccurate. The ongoing Steroids to Reduce Inflammation After Infant Heart Surgery (STRESS trial) by Hill et al.Reference Hill, Baldwin and Bichel40 studying efficacy, safety, pharmacokinetics and pharmacodynamics of methylprednisolone in 1200 infants undergoing congenital heart surgery with primary end point of mortality and length of hospital stay may help standardise the treatment regimen in near future.

In conclusion, we found that the routine administration of a tapered post-operative hydrocortisone bolus regimen in full-term neonates that had undergone cardiac surgery, including single ventricle palliative procedures, with the use of cardiopulmonary bypass had no significant impact on net fluid balance or total amount of required inotropic support in the early post-operative period. Additionally, we saw no difference in secondary clinical outcomes including duration of mechanical ventilation, length of stay, or hospital mortality. Our study demonstrates that further long-term randomised control studies are necessary to validate the potential clinical benefits and/or risks associated with the use of steroids in paediatric cardiac surgery, especially in complex neonatal surgeries. Additionally, further clinical studies looking at specific steroid combinations are needed to continue to strengthen our treatment strategies for this very fragile patient population.

Supplementary material

For supplementary material accompanying this paper visit https://doi.org/10.1017/S1047951123000537

Acknowledgements

None.

Financial support

This research received no specific grant from any funding agency, commercial, or not-for-profit sectors.

Conflicts of interest

None.

Ethical standards

This material is the authors’ own original work, which has not been previously published elsewhere. The paper is not currently being considered for publication elsewhere. The paper reflects the authors’ own research and analysis is in a truthful and complete manner.

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Figure 0

Table 1. Descriptive Statistics and Clinical Outcomes

Figure 1

Figure 1. A Combined Comparison of Vasoactive-Inotropic Scores & Net Fluid Trends for Both Groups (Post-operative Days 0–4).Note. – Data are shown as median values. HC = Hydrocortisone; NH = Non-hydrocortisone; POD = post-operative day; VIS = Vasoactive-Inotropic Score.

Figure 2

Table 2. A Comparison of Post-operative Intravenous Diuretic Use for Post-operative Days 0–7

Figure 3

Table 3. Comparison of Fluid Requirements and between Groups for Post-operative Days 0–7

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