Pulmonary, Renal and Neurosonographic recovery in children on ECLS support – “The ECLS Study”

When a child is critically ill and admitted to the intensive care unit because of a life-threatening condition, children often develop heart or lung failure and reach maximum conventional treatment. In this group of children mortality exceeds >80% in these situations, Extracorporeal Membrane Oxygenation or also referred to as Extracorporeal Life Support, (ECLS) has become the standard rescue treatment for neonates and children.

The Pulmonary, Renal and Neurosonographic recovery in children on ECLS study is a complex single site study that will investigate measurements and indicators that point to lung recovery and blood flow to the brain and kidneys, in patients requiring ECLS. The study will use Electrical Impedance Tomography (EIT) and other parameters of respiratory mechanics. It also aims to identify the typical ultrasound characteristics of major vessels, particularly the middle cerebral arteries (MCA) and renal arteries.

Information for parents and guardians of our patients

Why are we conducting the ECLS Study?

We are doing this study to determine which lung function measures indicate lung recovery for patients on ECLS. We are also trying to determine the way that blood flows around the body for patients on ECLS, particularly to the brain and kidneys. Based on the data we collect from this study, we may be able to improve ventilation strategies for children on ECLS, and thereby improve their outcomes.

What is ECLS?

Extracorporeal Life Support (ECLS). Used to determine which lung function measures indicate lung recovery for patients on ECLS. To determine the way that blood flows around the body for patients on ECLS, particularly to the brain and kidneys.

How is the study being achieved?

All children that require ECLS support are eligible for this study. The study requires the daily capture of lung function data. To do this we will place small electrodes around the circumference of your child’s chest – these are soft and cause no discomfort. The electrodes are for measuring Electrical Impedance Tomography (EIT), which gives us a picture of air and blood flow in the chest. Your child may be placed on a different ventilator to facilitate the lung function testing. This is done by briefly adjusting some of the ventilator settings and recording the associated changes to the pressures in your child’s lungs. The entire process will take up to 90 minutes and will be repeated daily while your child is on ECLS and on the first day after your child comes off ECLS support. Your child will be carefully monitored throughout. Ultrasound will also be used to measure the blood flow of the arteries in the brain and in the body, this will be done daily for five days and then once after they come of ELCS. This will take roughly 30 mins and involve placing the ultrasound transducer / camera onto the top and/or side of the head, and on the abdomen. ECLS patients often have routine monitoring with ultrasound during their treatment anyway. This study will not interfere at all with any of your child’s care.

Are there any risks or discomforts?

The above testing and measurements does not interfere at all with any of your child’s care, and should not cause them any discomfort or distress. Additionally, as the testing is only done once per day, we can ensure it is done at a time convenient for your child and the PICU medical team.

EIT has been used in numerous neonatal and paediatric studies and has been shown to be safe. There are no known hazards associated with the use of EIT. Also, the EIT monitoring does not interfere with any other routine clinical monitoring equipment.

Ultrasound is commonly used on patients in PICU as it does not involve ionising radiation like x-rays and is considered to be safe. The scans will be as short as possible to only get the information we need for the study, and the ultrasound machine is not known to interfere with any of the other monitoring equipment.

What are the potential benefits?

This study may not have any direct benefits to your child. However, as the aim of this study is to enable early identification of non-responders or non-recovering lungs, this may allow for changes in existing standard care, which may shorten recovery time for future patients on ECLS. The aim of the ultrasound component of the study is to better understand the effects that ECLS has on the way blood moves around the body, particularly in the brain and in the kidneys. This will ideally help us to better understand when there is a problem with blood flow and potentially identify factors that may improve the standard of care.

Consent

Our study is a strictly observational survey within the established clinical routine and does not impose any risk or relevant burden to included paediatric patients. Consent will be sought from parents or legal guardians of eligible participants using parent information sheet and consent form. Anonymity and confidentiality is assured. All data will be de-indentified.

Information for participating study centres

Background on the ECLS Trial

Extracorporeal life support (ECLS) is an established treatment for paediatric and neonatal patients with potentially reversible lung and/or heart failure. The technical principle is similar to extracorporeal circulation during cardiopulmonary bypass surgery but is adapted to long term use. In principle, ECLS is offered to patients with cardiac, respiratory or combined cardio-respiratory failure. There are several forms of ECLS, the two most common are veno-arterial (VA) and veno-venous (VV) ECLS. VA ECLS can provide acute support in cardiogenic shock, cardiac arrest and in severe respiratory failure with right heart failure. VV ECLS supports patients in severe respiratory failure only. During ECLS therapy, aggressive mechanical ventilation is avoided to prevent ventilator-induced lung injury, with the aim to rest the lung. Most ECLS centres ventilate their patients with a higher positive end-expiratory pressure (PEEP) of 10 to 14 cmH2O and a low respiratory rate to prevent deterioration of pulmonary function on VA or VV ECLS and give diseased lungs the opportunity to heal. Data has shown that a higher PEEP (12-14 cmH2O) is associated with a shorter duration of ECMO therapy, higher dynamic lung compliance, better radiographic scores and fewer complications, compared to a lower PEEP strategy (3-5 cmH2O) [1,2]. Recent reports in adult patients undergoing ECLS treatment for severe respiratory distress show that ultra-protective ventilation is associated with improved outcome [14]. There is also a general trend, in conventional ventilation for severe respiratory disease, to use an open lung strategy with higher PEEP. Despite this, an open lung strategy is often neglected in ECLS patients, despite the potential benefit. The Queensland Children’s Hospital (QCH) Paediatric Intensive Care Unit (PICU), follows a ventilation standard which is defined for patients during full VA and VV ECLS therapy and during the weaning process. This standard has clearly defined aims for pCO2 and SpO2 in both sequential and parallel circulation. These ventilation standards are not evidence based and have no scientific backup, as there is no scientific data available on ventilation distribution and the pulmonary recovery of patients on ECLS. So far, management of therapy is mainly based on changes in measured tidal volumes and imaging results (chest-X-ray, computed tomography of the lung). Therefore, identification of non-responders and information for decisions on further treatment is insufficient. Despite the fact that we measure lung function routinely in these patients, we do not have any evidence that any of these measurements are predictive of outcome or recovery, nor do we have any evidence that an open lung strategy, in combination with ultra-protective ventilation has any impact on outcome.

VA and VV ECLS have a variety of potential cannula placement sites, and subsequently a variety of potential influences on patient haemodynamics. Ultrasound, particularly Doppler and Pulsed Wave (PW) ultrasound, have a well-established role in the qualitative and quantitative evaluation of haemodynamics. The range of vessels that can be reliably interrogated using ultrasound is dependent on the ability to confidently visualise them through acoustic windows. In cranial ultrasound or neurosonography, the open fontanelles provide such a window to assess the intra-cranial structures and also the major intra-cranial blood vessels. Cranial ultrasound, without dedicated vascular ultrasound assessment, is routine in all neonates on ECLS in order to monitor for intra-cranial haemorrhage (ICH)1,2. In older children whose fontanelles have closed and no longer permit the transmission of ultrasound through the skull, intra-cranial vessels can still be reliably assessed through the relatively thin bone of the temporal plate. A recent study of 18 children on ECLS3 indicated that there was a potential relationship between the observed cerebral blood flow velocities and the occurrence of ICH and recommended further study.

Renal function is often adversely affected by ECLS, with a potential consequence of renal haemodynamic compromise being acute kidney injury (AKI), evolving into chronic renal disease and potentially end-stage renal disease and an increased mortality rate4. Ultrasound of the kidneys and abdominal arterial blood supply in ECLS patients would provide a baseline study to determine any pathological variation from what should normally be encountered on the various forms of ECLS. There is also scope to compare the quantitative value of the arterial velocities, their resistivity and pulsatility, with clinical indicators such as urine output and determine any relationship. Kilburn et al (2016) suggested that Doppler ultrasound could be of potential benefit in investigating AKI in ECLS patients and note the lack of available data to date5. The ability to better tailor renal treatment during ECLS could lead to reduced renal disease in this patient cohort.

Specifics of study

Study Aim

The study aims to establish a baseline of ultrasound waveforms from which pathological variations can be identified whilst undergoing ECLS.

Study design

  1. Pulmonary function tests including measures of EIT will be performed on a daily basis whilst the patient is on ECLS and preferentially one day after weaning off ECLS.
  2. Cranial and/or trans-cranial Doppler ultrasounds and abdomincal artery ultrasounds will be performed daily for the first five days of ECLS treatment and then as clinically indicated.

Our project is a single-center survey including patients from the Queensland Children’s Hospital (QCH).

Sample size

Sample size: 40-70 patients (55% cardiac, 45% respiratory ECLS)

Outcomes, Significance and Innovation

Purpose of the study

The purpose of this pilot study is twofold; one to describe the pulmonary recovery in patients requiring ECLS support, measured with Electrical Impedance Tomography (EIT) and other parameters of respiratory mechanics. Secondly to identify the typical ultrasound characteristics of major vessels, particularly the middle cerebral arteries (MCA) and renal arteries, in patients requiring ECLS.

Primary Outcomes

The primary outcomes are to explore which lung function parameter identifies responders of ECLS treatment (lung recovery). Based on the findings a potential interventional trial will be conducted investigating whether a different ventilation strategy on ECLS may improve outcome. Furthermore, the study aims to establish a baseline of ultrasound waveforms from which pathological variations can be identified whilst undergoing ECLS.

Secondary Outcomes

The secondary outcome is to establish a potential relationship between abdominal artery haemodynamics and renal function in order to reduce the incidence of AKI, and to further investigate the relationship between increased MCA resistivity and ICH in ECLS patients.

Initial stage
A secondary extensive literature search will be undertaken and all studies reporting

  1. ventilation settings and outcomes of patients treated
  2. ultrasound waveform properties and values in intra-cranial and renal arteries

of paediatric patients on ECLS will be analysed. Additionally, the ELSO database (Extracorporeal Life Support Organization) will be searched and a questionnaire sent out to determine the prevalence of different ventilation strategies among adult and paediatric ECLS centres.

Inclusion Criteria
Any neonate, infant, or child up to 18 years of age with necessity of ECLS support.

All eligible patients receiving ECLS therapy, both cardiac and respiratory, in the QCH PICU will be included. Patients will be identified by either the ECLS Consultant, CNC ECLS or PICU research team member.

Exclusion Criteria
None

Potential risks
The study is a prospective observational study. The applied pulmonary function tests are part of our standard clinical practice and do not impose any additional risks to the patients. The ultrasound investigations are part of our standard clinical practice and do not impose any additional risks to the patients. Data will be entirely de-identified. The only change to the existing standard protocol is

  1. the additional use of EIT. EIT is a non-invasive procedure, free of discomfort and risk, which has been shown in numerous reports, trials and local experience in neonates, infants and older children [6-13]. In the past we have successfully used EIT for clinical purposes in patients on ECLS therapy to assess the biological course of lung disease.
  2. the additional use of TCD and routine recording of renal, aortic and CFA waveforms. Ultrasound has demonstrated no harm and will be only employed for the shortest possible time to achieve the examination outcomes using pre-determined manufacturers settings for TCD.

Potential benefits of the study
This study is an observational study. Additionally, we aim to investigate variables which allow early identification of non-responders or non-recovering lungs as well as variables which allow early identification of potential ICH or AKI. These patients could benefit from an early change of the existing standard.

Data Collection Methods
Streamlined data collection instruments and procedures will be used. All data will be collected by the Research Nurse onto the case report form (CRF) directly from the source data. Data will be entered into the electronic data platform REDCapTM (Research Electronic Data Capture, Vanderbuilt) Version 6.10.6.

eCRF
REDCap is a secure, web-based application for building and managing online databases and surveys. The ECLS Study uses REDCap for electronic data collection. If you have any concerns or questions please contact the Study Co-Ordinators

Tara Williams
e: Tara.Williams@health.qld.gov.au
t: 07 3069 7480

Kerry Johnson
e: Kerry.Johnson3@health.qld.gov.au
t: 07 3069 7478

REDCap Weblink: redcap.health.uq.edu.au

Collaborators and sponsors

Our Collaborators include:

The University of Queensland
PREDICT (Paediatric Emergency Departments International Collaborative group)
PSG (Paediatric Study Group)
ANZICS (Australia and New Zealand Intensive Care Society)

Key references

  1. Keszler M, Ryckman FC, McDonald JV Jr, Sweet LD, Moront MG, Boegli MJ, Cox C, Leftridge CA A prospective, multicenter, randomized study of high versus low positive end-expiratory pressure during extracorporeal membrane oxygenation. J Pediatr. 1992 Jan;120(1):107-13
  2. Keszler M, Subramanian KN, Smith YA, Dhanireddy R, Mehta N, Molina B, Cox CB, Moront MG. Pulmonary management during extracorporeal membrane oxygenation. Crit Care Med. 1989 Jun;17(6):495-500
  3. Goh AY, Chan PW, Lum LC, Roziah M. Incidence of acute respiratory distress syndrome: a comparison of two definitions. Arch Dis Child. 1998 Sep;79(3):256-259
  4. Grant CA, Pham T, Hough J, Riedel T, Stocker C, Schibler A. Measurement of ventilation and cardiac related impedance changes with electrical impedance tomography. Critical care 2011;15(1):R37.
  5. Carlisle HR, Armstrong RK, Davis PG, Schibler A, Frerichs I, Tingay DG. Regional distribution of blood volume within the preterm infant thorax during synchronised mechanical ventilation. Intensive care medicine 2010;36(12):2101-8.
  6. Tingay D, Copnell B, Dunster KR, Grant C, Dargaville P, Schibler A. Ventilation redistribution following derecruitment during endotracheal suction. Anaesthesia and Intensive Care 2008;36(6):898
  7. Tingay D, Copnell B, Grant C, Dargaville P, Schibler A. Regional lung volume and distribution of ventilation during endotracheal tube (ETT) suction. Journal of Paediatrics and Child Health 2008;44(s1):A41.
  8. Schibler A, Yuill M, Parsley C, Pham T, Gilshenan K, Dakin C. Regional ventilation distribution in non-sedated spontaneously breathing newborns and adults is not different. Pediatric pulmonology 2009;44(9):851-8.
  9. Tingay DG, Copnell B, Grant CA, Dargaville PA, Dunster KR, Schibler A. The effect of endotracheal suction on regional tidal ventilation and end-expiratory lung volume. Intensive care medicine 2010;36(5):888-96.
  10. Armstrong RK, Carlisle HR, Davis PG, Schibler A, Tingay DG. Distribution of tidal ventilation during volume-targeted ventilation is variable and influenced by age in the preterm lung. Intensive care medicine 2011;37(5):839-46.
  11. Hough JL, Johnston L, Brauer SG, Woodgate PG, Pham TM, Schibler A. Effect of body position on ventilation distribution in preterm infants on continuous positive airway pressure. PediatrCrit Care Med 2011.
  12. Humphreys S, Pham TM, Stocker C, Schibler A. The effect of induction of anesthesia and intubation on end-expiratory lung level and regional ventilation distribution in cardiac children. Paediatricanaesthesia 2011;21(8):887-93.
  13. Pham TM, Yuill M, Dakin C, Schibler A. Regional ventilation distribution in the first 6 months of life. EurRespir J 2011;37(4):919-24.
  14. Pham T, Combes A, Roze H, Chervet S, Mercat A, Roch A, …Brochard L. Extracorporeal Membrane Oxygenation for Pandemic Influenza A(H1N1)- induced Acute Respiratory Distress Syndrome. Am J RespirCrit Care Med 2013; 187(3):276-285.
  15. Van Heijst AFJ, De Mol AC, IJsselstijn H. ECMO in neonates: Neuroimaging findings and outcome. Semin Perinatol. 2014;38(2):104–13.
  16. Bembea MM. Neuromonitoring of Neonatal Extracorporeal Membrane Oxygenation Patients Using Serial Cranial Ultrasounds*. PediatrCrit Care Med. 2013 Nov;14(9):903–4.
  17. O’Brien NF, Hall MW. Extracorporeal membrane oxygenation and cerebral blood flow velocity in children. PediatrCrit Care Med. 2013;14(3):e126-34.
  18. Villa G, Katz N, Ronco C. Extracorporeal Membrane Oxygenation and the Kidney. CardioRenal Med. 2015;6(1):50–60.
  19. Kilburn DJ, Shekar K, Fraser JF. The Complex Relationship of Extracorporeal Membrane Oxygenation and Acute Kidney Injury: Causation or Association? Biomed Res Int. 2016;2016:1–14.

Location

Centre for Children’s Health Research
Queensland Children’s Hospital Precinct
Paediatric Critical Care Research Group: KIDS THRIVE
Level 7, 62 Graham Street
South Brisbane, Qld, 4101
Australia

Study coordinators

Tara Williams
e: Tara.Williams@health.qld.gov.au
t: 07 3069 7480

Kerry Johnson
e: Kerry.Johnson3@health.qld.gov.au
t: 07 3069 7478