Congenital Heart Anesthesia Intensive Care

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

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.     [caption id="attachment_13834" align="alignleft" width="300"] Felipe Medeiros[/caption] [caption id="attachment_13835" align="alignleft" width="225"] Destiny F. Chau, M.D.[/caption]                                    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:   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.   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


Predictors of Increased Lactate in Neonatal Cardiac Surgery: The Impact of Cardiopulmonary Bypass.

Predictors of Increased Lactate in Neonatal Cardiac Surgery: The Impact of Cardiopulmonary Bypass. Nasr VG, Staffa SJ, Boyle S, Regan W, Brown M, Smith-Parrish M, Kaza A, DiNardo JA.J Cardiothorac Vasc Anesth. 2021 Jan;35(1):148-153. doi: 10.1053/j.jvca.2020.06.009. Epub 2020 Jun 10.PMID: 32620493   Take Home Points   High lactate levels are known to correlate with hypoperfusion and tissue hypoxia. Rate of increase of lactate during cardiac surgery has been previously identified as a risk factor for morbidity and mortality in cardiac surgery in children. In this study, three additional predictors were found to be associated with changes in lactate concentration during cardiopulmonary bypass in neonates: Circulatory arrest time Time of mean arterial pressure < 25 mmHg. Time of mean arterial pressure 35 – 39 mmHg. The first two variables were positive predictors, while the third was negatively correlated with change in lactate.   Lori Riegger                                            Commentary by Lori Q. Riegger MD, Associate Professor of Anesthesiology, Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, Michigan:  Lactate levels are used as an important biomarker for oxygen delivery, with high lactate levels classically corresponding to decreased systemic perfusion and tissue hypoxia.1 Several studies have demonstrated associations between hyperlactatemia and postoperative morbidity and mortality after pediatric cardiac surgery. Peak lactate levels were higher in nonsurvivors of congenital heart surgery,2 and the “lactime,” or the time in which the lactate level is > 2 mmol/L, has been demonstrated to correlate with mortality as well as postoperative ventilator days and hospital days.3 Over the first 24 hours after cardiac surgery, an increased rate of lactate by 0.6 mmol/L/h has been shown to increase the risk of death, need for extracorporeal support (ECMO), and dialysis.4  While a change > 2 mmol/L from the last lactate on cardiopulmonary bypass (CPB) to the first lactate in the cardiac intensive care unit has been identified as a risk factor for morbidity after cardiac surgery in children.5 This current study aimed to examine factors which predict hyperlactatemia during CPB in neonates.   This retrospective study examined 376 neonates from July 2015 to December 2018 who underwent cardiac surgery with cardiopulmonary bypass (CPB). Lactate measurements were collected at several time points during the surgery (pre-bypass, initiation of CPB, at the end of CPB, at the end of the operating room time and first in the cardiac intensive care), and changes were examined using nonparametric Wilcoxon signed rank for paired data. The changes in lactate from one point to the next were computed for analysis.   The cohort was 60% male, and the median age was 5 days with a range of 1-30 days. Fifty-nine percent had two ventricles while the remaining had single ventricle physiology, and 68% of the study group were a STAT category 4 or 5. One quarter of the patients were premature, 27% had preoperative endotracheal tubes, 4% required postoperative ECMO within 48 hours, and 3% did not survive postoperatively. Significant increases in lactate were noted both in the time from pre-CPB to end of CPB (p < 0.001) and from the beginning to the end of CPB (p < 0.001). Median time before CPB was 162 minutes (IQR 142 - 181), median CPB time was 150 minutes (IQR 112 - 190), and the median time after CPB was 112 minutes (IQR 95 – 138). The median CPB temperature target was 24°C (IQR 18-28). Mean inotrope score was 2.23 (IQR 0 – 5.18) pre-CPB and 4.79 (IQR 2.98 – 8.03) post-CPB.   Univariate median regression analysis of predictor variables and lactate change from CPB start to end was performed. Variables with p < 0.1 were added to the multivariate model stepwise and this revealed several independent predictors of change in lactate from CPB start to end, including circulatory arrest time per 30 min (coefficient 1.216; 95% CI 0.754-1.678; p < 0.001), duration of MAP < 25 mmHg per 30 min (coefficient 0.423; 95% CI 0.196-0.651; p < 0.001), and duration of MAP 35-39 mmHg per 30 min (coefficient -0.246; 95% CI -0.397—o.095; p=0.001). The authors note that circulatory arrest as well as hypotension on CPB are times when oxygen delivery to the tissues is limited even in the setting of adequate oxygen carrying capacity. Hence, the predictors found were not unexpected. Interestingly, they found that higher MAP (35-39 mmHg) was a negative predictor for increases in lactate. It may be that a MAP between 25-35 mmHg is pivotal for optimum oxygen delivery while on CPB. Future studies would be needed to determine this, potentially again using lactate as a surrogate. They also note that neither the use of regional antegrade cerebral perfusion nor the target temp of 24°C were found to be associated with high lactate levels. Additionally, they did not find that the age of the blood transfused influenced lactate levels, although they postulate that this may be due to their institutional practice of only using blood < 7 days old for neonates. In this study, the authors note that every 30 minutes of circulatory arrest led to an increase of 1.216 mmol/L of lactate and every 30 minutes of MAP < 25 mm Hg led to an increase of 0.423 mmol/L lactate, emphasizing the need to minimize circulatory arrest and hypotension in order to decrease hyperlactatemia and the potential adverse events associated with it.   What does this mean for us?   Multiple studies involving children requiring cardiac surgery with CPB have demonstrated the relationship between high lactate levels (including peak level, change in lactate over time, length of time above a certain level) and increases in morbidity including ECMO, need for dialysis, cardiac arrest as well as mortality. This, in turn, has led to an emphasis on goal directed therapy to improve tissue perfusion to vital organs, including heart, brain and kidneys using a variety of monitoring and therapeutic modifications.   In particular, using near infrared spectroscopy monitoring to assess the regional oxygenation saturation (rSO2) during CPB may allow optimization of oxygen delivery and perfusion by focusing attention on ideal hemoglobin, MAP, pump blood and gas flow, temperature management, and pH strategies. There is evidence that a low somatic-cerebral rSO2 gradient is associated with increases in lactate concentrations and hence, the use of infra-red spectroscopy technology may become another useful monitoring tool for the adequacy of oxygen delivery during CPB. 6   Although any laboratory number needs correlation with the clinical scenario, the identification of these three risk factors for high lactate during neonatal CPB should lead to an increased awareness of the length of time of circulatory arrest as well as the necessity of circulatory arrest when antegrade cerebral perfusion is an option. This study also supports increased vigilance regarding adequate MAP during CPB to ensure sufficient tissue perfusion. Serial lactate assessments are easily measured and may demonstrate a clinical trajectory associated with deleterious outcomes. Predictors for hyperlactatemia in children undergoing CPB identified in the current study, may allow an earlier treatment response and a change in overall strategy to decrease this biomarker and its undesirable associations.   Future studies, ideally ones involving multiple centers, are warranted to confirm similar findings at other institutions, determine if there are other risk factors, and assess whether modification of these risk factors can improve clinical outcomes in this vulnerable patient population.   References Stephens EH, Epting CL, Backer CL, et al. Hyperlactatemia: An update on postoperative lactate. World J Pediatr Congenit Heart Surg. 2020;11(3):316-24 Cheung PY, Chui N, Joffe AR, et al. Postoperative lactate concentrations predict the outcome of infants aged 6 weeks or less after intracardiac surgery: A cohort follow-up to 18 months. J Thorac Cardiovasc Surg. 2005;130(3):837-43 Kalyanaraman M, DeCampli WM, Campbell AI, Bhalala U, et al. Serial blood lactate levels as a predictor of mortality in children after cardiopulmonary bypass surgery. Pediatr Crit Care Med. 2008;9(3):285-9 Schumacher KR, Reichel RA, Vlasic JR, et al. Rate of increase in serum lactate level risk-stratifies infants after surgery for congenital heart disease. J Thorac Cardiovasc Surg. 2014; 148: 589-95 Kanazawa T, Egi M, Shimizu K, et al, Intraoperative change of lactate level is associated with postoperative outcomes in pediatric cardiac surgery patients: Retrospective observational study. BMC Anesthesiol. 2015;15:29 Bojan M, Bonavelio E, Dolcino A, et al. Somatic and cerebral near infra-red spectroscopy for the monitoring of perfusion during neonatal cardiopulmonary bypass. Interact Cardiovasc Thorac Surg. 2019;29:955-9.       Congenital Heart Anesthesia and Intensive Care Section Editors Rania Abbasi – Indianapolis, IN Nischal Gautam – Houston, TX


Diaphragm Atrophy During Pediatric Acute Respiratory Failure Is Associated With Prolonged Noninvasive Ventilation Requirement Following Extubation.

Diaphragm Atrophy During Pediatric Acute Respiratory Failure Is Associated With Prolonged Noninvasive Ventilation Requirement Following Extubation. Glau CL, Conlon TW, Himebauch AS, Yehya N, Weiss SL, Berg RA, Nishisaki A.Pediatr Crit Care Med. 2020 Sep;21(9):e672-e678. doi: 10.1097/PCC.0000000000002385.PMID: 32433439   Take Home Points   The utility of point-of-care ultrasound (POCUS) is an active field of study in the pediatric critical care population. The authors tested whether POCUS-derived measurements of diaphragm atrophy and contractility would correlate with the need for prolonged post-extubation non-invasive ventilation in children. Increased diaphragm atrophy was associated with post-extubation non-invasive ventilation, while worsened diaphragm contractility was not. The clinical relevance of such measurements could possibly guide resource management following extubation in patients recovering from acute respiratory failure.     Richard Hubbard                     Commentary by David McMann MD, M.Ed1, and Richard Hubbard MD2 1 Assistant Professor of Pediatric Critical Care Medicine, 2 Assistant Professor of Anesthesiology, McGovern Medical School/University of Texas, Houston, Texas   Background:   In previously published work1, the authors demonstrated the feasibility of point-of-care ultrasound (POCUS) in measuring signs of diaphragm atrophy and function in mechanically ventilated children.  They tested the hypothesis that diaphragmatic atrophy occurs in mechanically ventilated children at a similar rate as those reported in adults.  Their results demonstrated a correlation between diaphragm atrophy and length of mechanical ventilation (MV) as well as finding that diaphragm contractility was strongly correlated with the spontaneous breathing fraction.  However, the clinical relevance of these measurements remained elusive.   In this newly published prospective, observational study2, the authors build on their previous work by investigating the relationship between diaphragm atrophy and contractility with the need for prolonged post-extubation non-invasive positive pressure ventilation (NIPPV). Inclusion criteria for the study was any patient <18 years old with acute respiratory failure who was mechanically ventilated for more than 24 hours. Similar to their previous study, diaphragm measurements were performed by a single intensivist on the patient’s right hemidiaphragm taken within 36 hours of intubation and within 48-hours preceding extubation.  Diaphragm thickness at end expiration was measured over several time points with decreased thickness acting as an indicator of atrophy.  Thickening fraction (as measured as the change in diaphragm thickness between inspiration and expiration) was used as a surrogate for contractility.  The primary outcome was the need for NIPPV for more than 24 hours after extubation.  As secondary outcomes, routinely practiced extubation readiness tests were correlated with ultrasound measured diaphragm atrophy in a subset of patients who underwent spontaneous breathing trials.   Results:   The final data analysis comprised 47 patients who met the inclusion-exclusion criteria. NIPPV usage following extubation was observed in 20 patients, of whom 13 required NIPPV for greater than 24 hours. The need for prolonged NIPPV was associated with longer MV times (median 143 hr. vs 82 hr.) and with increased diaphragm atrophy.  However, the thickening fraction (TF) of the diaphragm did not differ between those with or without prolonged NIPPV.  Only weak correlations between diaphragm atrophy and rapid shallow breathing index and negative inspiratory force prior to extubation were observed. There was no correlation between these measurements and TF.   What does this mean for us?   This study tested the hypothesis POCUS-derived indicators of increased diaphragmatic atrophy and worsened contractility under invasive mechanical ventilation would correlate with the use of prolonged NIPPV following extubation. The study does succeed in showing such a correlation with diaphragm atrophy.  However, this association was not found with regards to diaphragm contractility, as has been seen in the adult literature3.  Unsurprisingly, those requiring prolonged NIPPV also had much longer average lengths of time under invasive mechanical ventilation.  Based on the authors’ previous work, longer mechanical ventilation would have contributed to a greater degree of diaphragm atrophy.   Some of the significant limitations of the study were that it was conducted at a single center, and a standardized sedation and ventilator management protocol was not mentioned in the manuscript. The timing of the ultrasound was also not standardized allowing for wide differences in measurement times between individual patients.   Finally, while POCUS-derived measurements of diaphragm atrophy do correlate with the need for NIPPV, it remains unclear whether this information provides clinically relevant predictive information that cannot be derived from other sources4.  As the authors rightly point out, further study is required to demonstrate the clinical utility of this modality.   Works Cited:   1 Glau CL, Conlon TW, Himebauch AS, Yehya N, Weiss SL, Berg RA, et al. Progressive Diaphragm Atrophy in Pediatric Acute Respiratory Failure&ast; Pediatr Crit Care Me. 2018;19(5):406–11. 2 Glau CL, Conlon TW, Himebauch AS, Yehya N, Weiss SL, Berg RA, et al. Diaphragm Atrophy During Pediatric Acute Respiratory Failure Is Associated With Prolonged Noninvasive Ventilation Requirement Following Extubation. Pediatr Crit Care Me. 2020;21(9):e672–8. 3 McCool FD, Oyieng’o DO, Koo P. The Utility of Diaphragm Ultrasound in Reducing Time to Extubation. Lung. 2020;198(3):499–505. 4 Vivier E, Muller M, Putegnat J-B, Steyer J, Barrau S, Boissier F, et al. Inability of Diaphragm Ultrasound to Predict Extubation Failure A Multicenter Study. Chest. 2019;155(6):1131–9.