Lung Injury After Neonatal Congenital Cardiac Surgery Is Mild and Modifiable by Corticosteroids

Anu K Kaskinen ¹, Juho Keski-Nisula ², Laura Martelius ³, Eeva Moilanen ⁴, Mari Hämäläinen ⁴, Paula Rautiainen ², Sture Andersson ⁵, Olli M Pitkänen-Argillander ⁶

J Cardiothorac Vasc Anesth. 2021 Jul;35(7):2100-2107.  doi: 10.1053/j.jvca.2021.01.017. Epub 2021 Jan 16.  Free article

Take Home Points:

 

• Administration of intraoperative methylprednisolone and a postoperative course of stress-dose steroids to neonates undergoing congenital cardiac surgery and cardiopulmonary bypass were not associated with increased adverse postoperative events such as hyperglycemia, wound infection and sepsis.
• Compared to the placebo group, patients in the steroid group showed modest improvement in postoperative radiographic lung edema scores and in ventilator-calculated dynamic respiratory system compliance. These changes were clinically insignificant and were not associated with differences in duration of mechanical ventilation, ICU stay or other relevant measures.
• Only one patient met defined criteria for lung injury; therefore, the title of this supplemental study may be misleading.

 

 

      

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Commentary by Felipe A. Medeiros MD and Destiny F. Chau MD, Pediatric cardiac anesthesiologists at Arkansas Children’s Hospital, Little Rock, AR.  Inflammatory mediators resulting from cardiac surgery, cardiopulmonary bypass (CPB) and lung ischemia-reperfusion can lead to tissue edema and development of lung injury. Steroids are often administered intraoperatively to neonates undergoing CPB to reduce the systemic inflammatory response. Yet, steroid administration has not consistently been associated with improved postoperative outcomes. There are reports that adding a postoperative course of stress-dose steroids may prevent adrenal insufficiency and reduce low-cardiac output syndrome. The authors performed a prior randomized, double-blinded, placebo-controlled trial in neonates undergoing cardiac surgery with CPB who received low-dose intraoperative steroids followed by postoperative stress-dose steroids versus placebo. They concluded that the stress-dose steroid regimen reduced inflammatory markers and inotropic scores and was associated with improved measures of postoperative ventricular function compared to the placebo group. The stress-dose steroids also did not suppress the hypothalamic-pituitary-adrenal axis and was not associated with increased adverse events.  In this supplemental study, the authors used the same data set and aimed to evaluate the postoperative pulmonary function of neonates undergoing cardiac surgery and CPB in order to assess whether postoperative stress-dose steroids would mitigate postoperative lung injury.

 

The study was conducted between April 2012 and October 2014 in Finland. Forty neonates (28 days or less of age) undergoing congenital heart surgery were included.  Exclusion criteria were: gestational age 36 weeks or less, chromosomal anomalies, presence of pulmonary malformations, preoperative pulmonary symptomatology, preoperative steroid use and preoperative inotropic support other than milrinone.  Each patient was randomized to receive either 2 mg/kg of methylprednisolone (steroid group) or saline (placebo group) intravenously after anesthesia induction. In the steroid group, a hydrocortisone course was planned for 5 days as follows:  0.2mg/kg/h was initiated 6 h after CPB and maintained for 48 h, this dose was then decreased to 0.1mg/kg/h for the next 48 h and then further reduced to 0.05mg/kg/h for the following 24 h before termination of steroid therapy. The placebo group received a similar infusion regimen containing saline solution only.

 

The anesthetic management described by the authors in the primary study paper consisted of S-ketamine, sufentanil, pancuronium, and sevoflurane. All patients were intubated with a cuffed endotracheal tube. Three surgeons performed all the surgeries; they would commonly leave the patient’s chest open to prevent hemodynamic instability. Milrinone and levosimendan were used as the first-line vasoactive drugs with epinephrine and norepinephrine added as indicated. Inhaled nitric oxide was started after CPB separation for pulmonary hypertension. Aprotinin was used for antifibrinolysis. Postoperatively, the patients were mechanically ventilated with pressure-controlled synchronized intermittent mandatory ventilation mode. Insulin was started in the intensive care unit (ICU) if blood glucose levels were above 180 mg/dL in two repeated results.

 

The participants’ demographics, perioperative and surgical complexity characteristics were similar in both groups. Patient characteristics in the steroid and placebo groups, respectively, were (expressed as median): age 8 days vs 7 days, weight 3.37 kg vs 3.50 kg, gestational age 39.1 weeks vs 40 weeks, and male sex 73% vs 75%. Surgeries included repairs for risk adjustment in congenital heart surgery-1 (RACHS-1) lesions, ventricular septal defects, tetralogy of Fallot, transposition of the great arteries, total anomalous pulmonary veins, hypoplastic aortic arch, and truncus arteriosus. Median times were comparable between the steroid and placebo groups: CPB (175 vs 167 min), aortic cross clamp (98 vs 86 min) and anterograde cerebral perfusion (55 vs 48 min), respectively; anterograde cerebral perfusion was performed in 45% of the steroid vs 40% of the placebo group patients. Preoperative mechanical ventilation was used in 15% vs 5% of the steroid and placebo groups. Fluid balance on POD 1 at noon were similar between groups (+42 vs +62 ml/kg, steroid and placebo groups).

 

The patient’s pulmonary function was assessed by several modalities at discrete time periods. The assessments include: chest x-ray (CXR) lung edema score, expiratory dynamic respiratory system compliance, oxygenation index (OI), and partial pressure arterial oxygen to fractional inspired oxygen (PaO2:FiO2) ratio. This study was powered to detect differences in CXR lung edema score and dynamic respiratory system compliance but was underpowered for oxygenation measures.  Analysis of biomarkers of inflammation in tracheal aspirates for interleukin 6 (IL-6), IL-8, resistin, and 8-isoprostane and in serum for IL-6, IL-10, and C-reactive protein were done. Blood was sampled at anesthesia induction before administration of the study drug; at 5 min and 6 h after CPB separation; and on POD 1, POD 2 and POD 3. Tracheal aspirates were sampled from 22 patients postoperatively at  4 to 6 h, 24 h, 48 h, and 72 h until extubation.

 

The results of the study:

• Postoperative lung edema scores
  • compared to preoperative values– the steroid group showed no increase while the placebo group showed slight increase.
  • comparing both groups– the steroid group showed lower lung edema scores on POD-1 to POD-3 compared to the placebo group.
  • Only one patient (in the placebo group) had lung edema scores that met criteria for lung injury.
• Dynamic respiratory system compliance– the steroid group showed better compliance up to POD-3.
• No difference between groups was found on:
  • tracheal aspirate biomarkers of inflammation and oxidative stress
  • duration of mechanical ventilation
  • oxygenation measures (not powered for this measure)
  • ICU length of stay
  • mechanical ventilation days
  • percent of patients on iNO
  • adverse postoperative events (wound infections, arrhythmias, hyperglycemia, adrenal suppression)
• Days of sternum remaining open and days of iNO use were higher in the placebo group than in the steroid group.
• Serum pro-inflammatory cytokines were lower in the steroid group compared to the placebo group (from primary study paper).

 

Based on the postoperative lung edema scores and the dynamic respiratory system compliance findings, the results suggest that postoperative lung function was fairly well preserved after congenital cardiac surgery and CPB. The administration of steroids showed a modest improvement in lung edema scores and dynamic compliance which were not clinically significant. Other relevant measures were similar between groups.

 

The results suggest that steroid administration was not associated with pulmonary outcome advantages based on the measures analyzed.  The authors speculate that the lack of improvement in pulmonary outcomes shown in this present study may stem from the low-dose intraoperative methylprednisolone used. Other published studies showing improved outcomes used larger doses. The authors chose the smallest published dose that was shown effective in children undergoing cardiac surgery. However, the results from the placebo group showing only modest postoperative increase in radiographic lung edema compared to preoperative scores may be evidence of the current advances in perfusion and perioperative cardiac surgical care, even for neonatal patients. It is also possible that this tool is not sensitive or validated to measure postoperative lung edema as evidence for lung injury in this patient population. One explanation for the higher open sternum days  concurrent with the higher days of iNO use in the placebo group is that  likely more patients with severe pulmonary hypertension were in the placebo group as compared to the steroid group. The two deaths occurred in the placebo group.

 

Limitations include that the results come from a single institution. Its small sample size underpowered the study for statistical analysis of oxygenation measures. The dynamic respiratory system compliance may be affected by secretions or other temporal external factors, such as positioning, which would affect respiratory system compliance. Additionally, there is little data provided in this supplemental study or the primary study publication on blood product transfusion and postoperative renal function. These factors impact pulmonary function and may contribute to lung injury.

 

In conclusion, this supplemental study showed that, compared to placebo, a low-dose intraoperative steroid followed by postoperative stress-dose steroids for neonates undergoing cardiac surgery and CPB   showed a modest improvement on radiographic lung edema and in dynamic respiratory system compliance with no benefits on clinical outcome measures. No adverse effects were observed.

 

 

References:

 

1. Kaskinen AK, Keski-Nisula J, Martelius L, Moilanen E, Hämäläinen M, Rautiainen P, Andersson S, Pitkänen-Argillander OM. Lung Injury After Neonatal Congenital Cardiac Surgery Is Mild and Modifiable by Corticosteroids. J Cardiothorac Vasc Anesth. 2021 Jan 16:S1053-0770(21)00052-5. doi: 10.1053/j.jvca.2021.01.017. Epub ahead of print. PMID: 33573926.

 

2. Suominen PK, Keski-Nisula J, Ojala T, et al. Stress-Dose Corticosteroid Versus Placebo in Neonatal Cardiac Operations: A Randomized Controlled Trial. Ann Thorac Surg. 2017;104(4):1378-1385. doi:10.1016/j.athoracsur.2017.01.111