SCCM Resource Library-Plenary: Cultivating Leadership From Within (Norma J. Shoemaker Honorary Lecture)

Plenary: Cultivating Leadership From Within (Norma J. Shoemaker Honorary Lecture)

Video Transcription

Thank you for the invitation. I'm here to present the results of a study that we just published with my colleague Tommaso  Fusali and another larger group in critical care medicine on the effects of prone position in COVID-19 RDS. We studied this with CT and electrical impedance tomography.  These are my conflict of interest, not really relevant for this talk. Changes in ventilation are what we are used to, and over-distention, superimposed pressure,  edema, makes the ventilation distribution highly heterogeneous. But the other side of the coin is perfusion, which is by similar mechanism, heterogeneous as well.  You have compression, you have occlusion, so the perfusion and the ventilation are independently  sometimes heterogeneous, and the combination of the two may be even more heterogeneous.  So there is a conceptual framework, pathophysiological framework that indicates that the more heterogeneous  is the lung, the more processes make the patient severe, the more the VQ mismatch will be high.  So lung collapse, airway closure, ventilation heterogeneity, over-distention, vascular occlusion, all can increase VQ mismatch, and all are correlated with the severity of RDS.  So VQ mismatch, if we can measure VQ mismatch at the bedside, may be an accurate marker of RDS severity, a mechanism of additional injury, and may be a target for personalized  intervention. Let's start from the first point. Briefly, low PF ratio is correlated with the RDS outcome. We all know this. And low PF ratio usually comes from high shunt.  So the more you have a mismatch in the direction of perfused non-ventilated unit, shunted perfusion, the more the higher is the mortality.  But also wasted ventilation is correlated with the mortality of RDS. This is a study from 2002, and we see that the more the dead space of wasted ventilation,  non-perfused units, the more it increases, the more increases the mortality of RDS. We now have ventilatory ratio, which is really a mix of dead space mostly, but also shunt.  Because if you have high shunt, the venous PCO2 will directly pass to the arterial PACO2, increasing it without any gas exchange.  So ventilatory ratio is the amount of ventilation that you need to have the actual PCO2 as compared to the ideal ventilation to have normal PCO2.  So the more severe is the gas exchange, but impairment, the higher the ventilatory ratio. And if you have a ventilatory ratio above two, there are at least one to a couple of  large studies, but also many others smaller, showing a correlation with the outcome of RDS.  With the electrical impedance tomography, you can measure the distribution of ventilation. And now with a saline bolus of 5% saline, with a bolus of 5% saline of 10 ml, you can  measure perfusion, the distribution of perfusion within the thorax. With my colleague Elena Spinelli, we published this paper showing that the less is the  mismatching, the higher is the VQ mismatch, number of units non-matched, either unmatched ventilation, wasted ventilation, or unmatched perfusion, wasted perfusion.  If you sum this up, this is clearly correlated and predicts outcomes. So the more the mismatch, the more severe the patient, the worse is the outcome.  Is this correlated with some additional injury or is just a marker? Well, there are very initial data from the lab showing that if you close an artery, a  pulmonary artery, and you let the dog breathe for five days, you have acute lung injury. So the large dead space fraction induces lung injury, something like a dead space CD, this  was. We investigated this more deeply last year. We published in the Blue Journal, this paper showing that if you occlude the left pulmonary artery, you have bilateral lung injury.  This is prevented by inhalation of CO2, restoring normal hypocapnia, alveolar capnia, because if you have a ligated region, if you have a dead space there, you will have hypocapnia,  which is injurious for the lung. And the addition of CO2 restored normal capnia and prevented the injury as seen by all  these markers. But the addition of CO2 was useful to understand the mechanism because ligation of one side, so large dead space fraction, moves the ventilation to the rest of  the lungs, which are over-distended. So the rest of the lung, in this case, the right lung, the non-ligated develops some kind  of VD. And also the presence of occluded perfusion, pulmonary perfusion, increases inflammation, which may lead to regional injury.  So we have bilateral lung injury with ligation of just one side. So dead space VD is VD to the part with the space, but also with the rest, to the rest  of the lung. And what about protection by CO2? CO2 is increased when you deliver CO2 by inhalation, but it also increases when you decrease tidal volume or you increase dead space.  So we just finished this paper with the study with the ligation of the left pulmonary artery and we increased the CO2 to protect the lung with alternative methods, but only inhaled  CO2 fully protected the lungs, meaning that the restoring normocapnea is protective. Or the other side of the coin is that having alveolar hypocapnea is highly dangerous for  the lungs. So dead space may cause additional injury and not be only just a marker of severity of the patient. The other mechanism may be shunt.  We induced shunt by ventilated only one lung. This is electrical impedance tomography. And you see this connection and then ventilation again with just one lung ventilated, in  this case, the right one. And ventilated the right lung, which is fully ventilated, aerated, and the other is  collapsed. So the other is our model of shunt, you have a part of the lung collapsed, the other ventilated, led to injury of both regions and decrease in tidal volume of the  ventilated side protected also the other lung. So having shunt, so wasted perfusion, non-ventilated region of the lung, may be itself a cause of additional injury.  So ventilation permutation mismatch may be a synthesis of ARDS mechanism of severity, a sensitive marker of ARDS outcome, but also specific mechanism of VD.  So maybe it could be a target for personalized lung protective intervention. OK, so you have IVQ mismatch, the patient is more severe, you have a specific pattern  causing additional injury, and you may want to decrease this pattern by personalized intervention to protect the lungs of the patient and improve the outcome.  This is why we investigated the mechanism of prone position in COVID-19 ARDS. COVID-19 ARDS patients are protected by prone position, mortality decreases.  But we don't know that if given the slightly or largely, I don't want to come into this debate, but COVID-19 ARDS may have a different physiology with high compliance and severe  hypoxemia without much lung collapse. So maybe the lung protective mechanism of prone position may differ from the classical  ARDS with low compliance and large fraction of collapse inside the lungs. So we looked for specific mechanism of lung protection by prone position in COVID-19 ARDS.  So we conducted a study in the hospital of Tommaso Fusari and his colleagues, Sacco Hospital in Milan, on 21 moderate severe COVID-19 ARDS patients.  Here are the characteristics, ventilated with 10 of PEEP, very high FiO2, moderate severe,  slightly higher tidal volume because compliance was very good, around 40, very low PF ratio, around 100, high ventilatory ratio because this patient have high dead space.  Intubated and mechanical ventilated since two or three days. So at the very early phase of the COVID-19 ARDS.  The first or second session of prone position, so very early application of prone position. PEEP was 10, tidal volume already told you.  The protocol was prone in the patient in the ICU, transport to CT scan, one CT scan in prone position,  then third supine, another CT scan, back to the ICU, EIT in the supine position, then prone, EIT in the prone position.  So it was a sequence, but all the measures were performed within a couple of hours.  So the same pathophysiological condition of the lungs with the same respiratory settings and the same patient.  We measure the recruitment by CT scan and at electroma and VQ matching by EIT. Let's go to the result. This is how you assess recruitment by CT scan.  What happened when we prone the patient? So recruitment in the whole lungs was significant. There were two patients which they recruited.  But interestingly, we divided the lung regions into ventral and dorsal part, and only the dorsal part was recruited, while the ventral part was derecruited.  So originally, there was not much lung protection, maybe only in the dorsal part. And the amount of recruitment was quite small.  Moreover, compliance didn't change between supine and prone position, was perfectly the same. Already, again, indicating not much recruitment.  So recruitment, which should be one of the most prominent effects of prone position, was not so relevant here.  Instead, we measured the dynamic index of at electroma, and we showed that it decreased significantly in the dorsal region and somehow also in the ventral region.  So full lung protection for at electroma, opening and closing, which induces inflammation in the lungs.  So these lungs are highly compliant, and this may be due to high fractions of opening and closing, which are reduced by the prone position. And finally, VQ mismatch.  We showed redistribution of tidal volume to the dorsal region. We decreased the dead space, wasted ventilation in the ventral regions. You see it here.  And these may have decreased the regional over-distention and the regional risk of dead space induced VV. So to conclude, VQ mismatch may be a target for personalized intervention.  So the more the VQ mismatch, the more severe the patient. And if we understand what is the specific alteration in the patient, we can perform intervention to reduce this.  VQ mismatch may be a specific feature of COVID-19 ARDS. Prone position improves the outcome of COVID-19 ARDS.  But our study indicates that the mechanism underlying the protection of the lungs of the patient in COVID-19 ARDS may differ from the general ARDS population.  Indeed, there could be specific pathophysiologic change in lung protection by the prone position. So prone position may target specific pathophysiological feature of COVID-19 ARDS.  In particular, in the recruitment doesn't seem to play a major role.  Reduce the tele-trauma and instead reduce dead space and better VQ matching may be a relevant mechanism for COVID-19 ARDS.  So the pathophysiological framework is hypoxemic patient with high compliance. This could be an high dead space. You may have a lot of tele-trauma in the supine position.  You prone them. You decrease tele-trauma by better homogenization of lung volumes and you improve VQ matching,  especially in the ventral region because of compression of the chest wall and movement of the dead volume in the back.  So specific mechanism for COVID-19 ARDS disclosed by EAT and CT scan combined. And I end here and I thank you very much. And we will meet in the live session from what I understand.  Charles Pohl and I am currently a hospice and palliative care medicine fellow at the City of Hope Comprehensive Cancer Center in Duarte, California.  I have recently completed a pediatric critical care fellowship at the University of California, San Diego and Rady Children's Hospital.  Today, I will be presenting our investigation of complications of peripheral intravenous administration of hypertonic saline. I do not have any disclosures.  Our institution in San Diego has a rich history of administration of PIV hypertonic saline and has inspired many clinicians and investigators to promote the positive results.  Until now, this data had not yet been peer reviewed and published with many institutions restricting the use of hypertonic saline to a central line.  We believe that we could perform an investigation which would change clinical practice.  Administration of 3% hypertonic saline has historically been discouraged due to the theoretical risk of infiltration and extravasation caused by administering a vesicant into a peripheral vein.  Established risk factors for extravasation injury include the extremes of age, anatomical location of the infusion site and properties of the drug, which includes cytotoxicity, pH and osmolality.  Despite these safety concerns, there is clinical evidence to support that hypertonic saline administration through a PIV carries a low risk of complication.  Several studies evaluating adult patients have demonstrated that peripheral infusion of hypertonic saline carried a low risk of minor complications.  There is minimal data evaluating the safety of hypertonic saline administered through a PIV in pediatrics.  Two small studies showed reassuring safety profiles when hypertonic saline was administered peripherally, but no studies have evaluated patients in the pediatric critical care population.  This lack of data encouraged us to further investigate the issue, and we hypothesize that patients admitted to our children's hospital will not suffer significant morbidity following administration of hypertonic saline through a PIV.  This was a retrospective single center study at a tertiary care children's hospital.  This study was approved by the Institutional Review Board at the University of California, San Diego and Rady Children's Hospital.  Patients were identified between January 1, 2012 and January 1, 2019 if they had evidence in the electronic medical record of a peripheral IV administration of hypertonic saline.  This encompassed all available electronic medical record data at our institution at the time of query.  The primary endpoints were a PIV failure due to an infiltration or extradition injury as a complication of hypertonic saline administration.  Through our data acquisition process, bolus dose and continuous infusions of hypertonic saline were documented.  For our study, we defined a bolus dose as an administration lasting less than 60 minutes and defined a continuous infusion as an administration lasting equal to or greater than 60 minutes.  An infiltration was defined as a substance in our study, hypertonic saline, which passes through the catheter and permeates into the extravascular tissue instead of the desired endovascular space.  An extravasation injury was defined as an infiltration of medication into the soft tissues, which causes serious injury with potential for permanent harm.  Infiltration and extravasation were determined through clinical documentation by the bedside nurse and recorded as swelling, pain, edema, or permanent tissue injury at the site of administration.  Qualitative data describing the site of infiltration or extravasation was collected from documented bedside observations.  During our study time frame, a total of 1,071 patients at our center were identified through our search query as having received hypertonic saline.  545 of those patients received hypertonic saline through a central line or had incomplete documentation and therefore did not meet criteria for inclusion.  The other 526 patients were identified for inclusion in the study.  There were a total of 1,020 administrations of hypertonic saline across the 526 patients, as it was possible that a patient may receive more than one dose of hypertonic saline during the study period.  848 doses were administered as a bolus, again defined as completing within 60 minutes, with 172 doses administered as a continuous infusion, lasting greater than 60 minutes.  We then evaluated the rates of infiltration between the two groups.  The youngest patient in the study was a neonate of one day old, and the oldest was a young adult of 23 and a half. Our median age was 9.5 years.  There was no statistical significance between the age of patients who suffered a complication and those who did not. There were 216 females, 41.1%, with 310 males, 58.9%.  39 patients, 7.4%, received hypertonic saline during critical care transport.  There was no statistical significance for complication regarding patients receiving in-hospital or pre-hospital administration.  The primary indications for hypertonic administration were altered mental status, 346 patients, or 16.8%, intracranial hemorrhage, 315, or 15.3%,  concussion, 304, or 14.7%, and increased intracranial pressure, 259, or 12.5%. We collected data regarding the characteristics of the IV catheters.  We found the majority of patients received PIV placement in either the pediatric emergency department, 352 or 34.5%, or in the pediatric intensive care unit, 203 or 19.9%.  However, catheters were also placed at outside hospitals, during critical care transportation, and in other hospital locations at our children's hospital.  Catheter gauge sizes ranged from 24 to 14 gauge, with lower gauge sizes corresponding to an increased intraluminal diameter.  The majority of catheters were 22 gauge, for a total of 403, or 39.5%, or a 24 gauge, a total of 168, or 16.5%.  The majority of catheters were placed in the antecubital space, 455, or 44.6%, or in the hand, 354, or 34.7%.  But were also recorded in the forearm, foot, scalp, and external jugular vein.  Unfortunately, these characteristics could not be fitted into the statistical model due to the low frequency of complications.  Of the 843 patients who received bolus doses of hypertonic saline, there were a total of eight infiltrations, equivalent to 0.9%.  Of the 172 patients who received continuous infusions of hypertonic saline, there were a total of 13 patients with infiltrations, or 7.6%.  Looking at the data as a whole, of the 1,020 administrations of hypertonic saline, there were a total of 21 infiltrations, or 2.1%.  The overall frequency of all complications during the study period was 3.8%, a 95% confidence interval between 2.48 and 5.80.  Upon analysis using the generalized estimating equation, it was found that administrations given as a bolus of hypertonic saline were 89.1% less likely to have a complication  compared to an administration of a continuous infusion, with a p-value of less than 0.001.  Importantly, no patients in either group suffered an extravasation injury, and no patients required intervention by the wound care team, plastic surgery, or other medical interventions as a result of an infiltration injury.  There was no lasting morbidity in either group. Risk factors for complications in the bolus dose and continuous infusion groups were evaluated.  On univariable analysis of the hypertonic saline bolus group, administration of the medication which resulted in infiltration had a higher mean volume of administration, 301 mL compared to 221 mL.  They had a lower mean infusion rate, 7.8 mL per kilogram per hour compared to 10.6 mL per kilogram per hour, and a lower mean number of hypertonic saline doses administered, 2.3 compared to 2.8, when compared to the group without infiltration.  However, on univariable analysis, these risk factors were not statistically significant.  When evaluating the basic demographics for the continuous infusion group, administrations with infiltration compared to those without infiltration had a lower mean volume of administration, 791 mL compared to 855 mL.  They had a higher mean infusion rate, 1.6 mL per kilogram per hour compared to 1.4 mL per kilogram per hour.  On univariable analysis, none of these factors resulted as statistically significant.  Additionally, serum sodium levels were recorded prior to and following the bolus administrations of hypertonic saline.  Serum sodium levels were found to increase from a pre-infusion mean of 138 mEqs per liter to a post-infusion mean of 143 mEqs per liter, giving us a p-value of less than 0.001.  To date, this is the largest study evaluating the rates of complication of PIV administration of hypertonic saline in pediatrics.  We found that bolus doses of the medication are associated with a low rate of complication.  Given these results, we believe that it is reasonable to consider bolus administrations of hypertonic saline in pediatric patients, a practice with minimal risk of significant harm.  We did identify a significantly higher rate of infiltration in the setting of a continuous infusion.  Continuous hypertonic saline infusions may be considered under appropriate circumstances with the recognition of a higher rate of infiltration when compared to a bolus dose.  All of the PIV failures resulted in infiltrations, and there was no evidence of extravasation injury.  No patients experienced lasting morbidity nor required a medical or surgical intervention as a result of an infiltrated infusion.  Morbidity included short duration of pain and swelling of the affected area and was treated with ice and elevation. Study limitations include the retrospective study design.  This resulted in incomplete data for some of our secondary endpoints.  Additionally, with the small number of infiltrates, we were unable to achieve statistical significance for identification of possible risk factors.  Due to the highly skewed outcome, we were unable to perform multivariable analysis with this data set.  A future study with a larger sample of administrations and complications is necessary to achieve statistical significance for determination of potential risk factors.  In conclusion, through our query of the electronic medical record, we found 526 patients with a total of 1,020 administrations of hypertonic saline through a PIV.  Of those 1,020 administrations, there were 21 or 2.1% infiltrations.  8 or 0.9% of infiltrations occurred during a bolus administration, while 13 or 7.6% occurred during a continuous infusion.  From our study, we can conclude that the frequency of complication following hypertonic saline through a peripheral intravenous catheter is low.  When administered as a bolus dose, hypertonic saline has an infiltration rate less than 1%. No extravagation injuries were observed.  No infusions were complicated by lasting morbidity.  Additional studies encompassing a cohort with a higher frequency of complication would be beneficial in achieving statistical significance for identification of risk factors contributing to infiltrations.  Thank you for your time. I hope you all remain safe and have a wonderful conference.  And thank you very much for the kind invitation to talk to you at this plenary session of the SECM Congress. I'll be talking to you today about the FIRST-ABC trial in children.  My name is Dr. Ram Narayan. I work as a pediatric intensivist in London, and I'm the chief investigator for the FIRST-ABC trial.  The trial compared high-flow nasal cannula with continuous positive airway pressure for post-extubation respiratory support in children.  A couple of disclosures unrelated to this talk.  Invasive mechanical ventilation is one of the most commonly provided interventions in paediatric intensive care. In UK paediatric ICUs, nearly 65% of admissions received invasive  mechanical ventilation between 2017 and 2019. It is also common practice to provide non-invasive  respiratory support in the post-extubation phase, commonly using CPAP, continuous positive airway pressure or high-flow nasal cannula or HFNC. Both CPAP and high-flow are used  commonly. This is indicated by international surveys as well as observational data. Cohort studies indicate that between 10% and 43% of extubated children receive non-invasive  respiratory support and there is a preference amongst clinicians for the use of high-flow cannula. However, despite the fact that these two interventions are so commonly used,  there are no randomized control trials comparing the two in children following extubation.  A very recent network meta-analysis from critically ill adults, which included 36 RCTs and 6,800 patients, did not show any difference in re-intubation rates  between non-invasive ventilation, which included CPAP and high-flow nasal cannula.  The first ABC trial was designed as a master protocol to compare high-flow nasal cannula with CPAP in the post-extubation as well as in the acute settings. Today I'll be  reporting the results of the first ABC step-down RCT. The master protocol allowed a shared  infrastructure and integrated health economic evaluation. The research question for the step-down  RCT is as follows. In critically ill children assessed by the treating clinician to require  non-invasive respiratory support within 72 hours of extubation, is the first line use of high-flow  nasal cannula at 2 litres per kilogram per minute flow rate non-inferior to continuous positive  airway pressure or CPAP at 7 to 8 centimetre water pressure in terms of the time to liberation  from all forms of respiratory support, invasive as well as non-invasive. The trial was designed  as a pragmatic open label multi-centre parallel group non-inferiority trial. Randomization was  on a one-to-one basis to high-flow nasal cannula or to CPAP and was stratified by site and age  under 12 months versus over 12 months. An independent data monitoring committee as well  as a trial steering committee were constituted and a planned interim analysis when 300 patients had reached 60-day follow-up was cancelled because of rapid recruitment to the study.  The consent model adopted was a research without prior consent model in line with previous  critical care trials. The inclusion criteria for the trial were a child who was either admitted  or accepted for admission to the paediatric intensive care unit, who was not a preterm baby and was not an adult and was assessed by the treating clinician to require non-invasive  respiratory support within 72 hours after extubation. This could be either planned initiation  or rescue initiation of non-invasive respiratory support but all it required was a clinical decision to initiate support. There were several exclusion criteria. The key amongst them  were receipt of high-flow or CPAP for a period of over two hours in the 24 hours prior to  randomization and a clinical decision to start a form of non-invasive respiratory support that  was not high-flow or CPAP such as non-invasive ventilation or negative pressure ventilation.  Other exclusion criteria included untreated air leak or agreed not for intubation or limitation  of critical care treatment and plan in place. The primary outcome for the trial was time to  liberation from respiratory support which was defined as the beginning of a 48-hour period  during which the child was free of all forms of respiratory support invasive or non-invasive.  This did not include the use of supplemental oxygen. This primary outcome was chosen because  it considered the effect of re-intubation on time to liberation as well as the fact that it took  into account long duration of non-invasive support if the patient was not re-intubated.  This primary outcome was supported by parents during pre-trial consultation over re-intubation.  Several secondary outcomes were studied such as mortality at PICU discharge at day 60 and day 180, rate of re-intubation at 48 hours, duration of PICU and acute hospital stay,  patient comfort assessed using a validated comfort B score, proportion of patients in whom sedation  was used during non-invasive respiratory support, parental stress measured using the parental  stressor scale PICU which is a validated measure. The non-inferiority margin was set at a hazard  ratio of 0.75. 508 events provided 90% power with a type 1 error rate of 2.5% one-sided to exclude  the non-inferiority margin and in context the hazard ratio of 0.75 in the pilot randomized  controlled trial that was performed before the main trial corresponded to a approximate 16 hours  of time to liberation from support. To take into account 5% for censoring for death or transfer  and 10% refusal or withdrawal of retrospective consent and non-adherence in the per-protocol population, the sample size was set at 600 patients.  The primary analysis consisted of all patients who started any form of respiratory support.  A Cox regression model was used and adjusted for age, comorbidities, length of prior invasive ventilation, reason for invasive ventilation, baseline ratio of saturation to fraction  inspired oxygen, severity of respiratory distress at randomization and the effect of sight using a shared frailty model. The per-protocol analysis consisted of all eligible patients  who started the allocated respiratory support. A number of subgroups were analyzed including age,  comorbidities, length of prior invasive ventilation, reason for invasive ventilation, the ratio of saturations to FiO2 and the severity of respiratory distress.  This slide shows the screening, randomization and follow-up of patients recruited to the first  ABC step-down trial. Over a nine-month recruitment period at 22 paediatric intensive care units in  England, Scotland and Wales, just over 3,000 children were extubated and screened, of whom just over 3,000 children were extubated and screened, of whom 1,051 fulfilled inclusion  criteria and exclusion criteria. Of the 1,051, 600 children were randomized into the trial. 451 were eligible but did not undergo randomization for several reasons.  mainly because of being missed or identified too late or a clinical decision not to include the patient in the trial.  Of the 600 patients who were randomized, 299 were randomized to high flow and 301 were randomized to CPAP.  Following randomization, consent was obtained in 291 high flow patients and 296 CPAP patients.  Of those patients, 10 did not start any respiratory support in the high flow group and 24 did not start any respiratory support in the CPAP group.  So the primary analysis set for the trial consisted of 281 patients who started any form of respiratory support on the high flow group  and 272 patients who started any form of respiratory support in the CPAP group.  As you can see, the majority of patients who started respiratory support started the allocated treatment, 272 out of 281 in the high flow group and 252 out of 272 in the CPAP group.  The follow-up was nearly complete and time to liberation was evaluable in the vast majority of patients.  So 258 patients in the high flow group and 260 patients in the CPAP group contributed primary outcome data. The rest was censored.  The baseline characteristics between the two groups were quite similar.  The age was three months. Male patients represented nearly 60% of the population.  At least one comorbidity was present in nearly 60% of the groups. There were some differences in the main reason for invasive ventilation.  More children with bronchiolitis were represented within the CPAP group and more children were ventilated for cardiac reasons within the high flow group.  In both groups, the duration of prior invasive ventilation was around 89 hours.  The nature of post-extubation non-invasive respiratory support was planned in nearly two-thirds of the patients in both groups.  And rescue in about 20% of both the groups.  This slide shows that the physiology and clinical characteristics at randomization were quite similar between the two groups.  This includes the comfort B score, which indicates a measure of discomfort in the patient.  Clinical management of the patients was as expected as per trial recommended algorithms in both the high flow and the CPAP groups.  And as can be seen on the left, the high flow group, the median flow rate that was provided was 100% of the recommended starting rate based on weight.  And on the CPAP group, pressure was a median of 7 centimetres of water with range between 6 and 8 centimetres of water as recommended by the trial protocol.  These graphs show the primary outcome for the primary analysis set and for the per protocol analysis.  On the left is the primary analysis set, which shows that the median time to liberation for high flow nasal cannula was 50.5 hours, whereas for CPAP it was 42.9 hours.  And following adjustment, the adjusted hazard ratio was 0.83 and the lower limit of the 95% confidence interval was 0.7, which fell below the non-inferiority margin of 0.75.  Similar findings were seen in the per protocol analysis, where the median time to liberation was 50.5 hours for high flow and 42.9 hours for CPAP, with an adjusted hazard ratio of 0.82 and a 95% confidence interval lower limit of 0.68, falling below the non-inferiority margin of 0.75.  A number of secondary outcomes were examined and as you can see, there were no significant differences in key outcomes such as re-intubation at 48 hours, 13% in high flow and 11% in CPAP.  The mean comfort score whilst on randomized treatment, sedation used during non-invasive respiratory support, mean parental stress score, mean duration of stay in the PICU, mean duration of acute hospital stay and PICU mortality.  There were however significant differences in mortality at day 60 and day 180, which as you can see there represent proportions of 4% in the high flow and 1.2% in the CPAP at 60 days and 5.6% versus 2.4% at 180 days, the significance of which is unclear and clearly these findings are not powered to show a difference.  The subgroup analysis looking at age, comorbidities, duration of prior invasive ventilation, main reason for invasive mechanical ventilation, nature of respiratory support in terms of planned or rescue and baseline ratio of saturations to FiO2 did not indicate any subgroups where there was an interaction between the treatment allocation and the subgroup.  So in conclusion, high flow compared to CPAP did not meet the preset non-inferiority criterion for time to liberation from respiratory support in extubated children.  These findings were seen in the main analysis and they were consistent in the protocol analysis and in subgroup analysis.  The high proportion of patients who were extubated and received planned non-invasive respiratory support, nearly 40% of extubated patients, indicates the need for more protocolized approaches to post-extubation support in children, which in the absence of evidence is variable practice.  I'd like to thank the entire First ABC trial team, the oversight committees, the clinical trials unit at ICNHRC and all the staff there, the staff at all participating sites and the patients and families who consented to being part of the trial because without them this trial would not have been possible.  Thank you very much for the opportunity to talk to you today about the First ABC trial.  Hello everyone and welcome to the late break for session of the Society for Critical Care Medicine Congress.  I am really excited to be here and be able to moderate the question and answer session from these fabulous speakers on what is truly an international panel.  I was really excited to see we have one from the US, one from the UK and one from Italy.  We have some really great work being presented here as well.  Please do enter your questions into the chat and we can get started answering some of them.  We're going to start with Dr. Mowry who comes to us from Milan, Italy, our first speaker.  We have a question from Dr. Meason in the audience who asks, she has two questions actually so I'm going to give you the first one and then ask the second.  She asked what severity of patient was included in the study and specifically what were the FIO2 and PEEP requirements?  Thank you for the question.  These were ARDS, acute respiratory distress syndrome patients with COVID-19 positive tests.  The severity was a clinical indication to prone position.  You can say PF ratio below 150 with PEEP above 10.  We included patients after the clinical team decided to prone them.  After we included them, we modified the PEEP to a standardized 10 centimeters of water level.  The FIO2 was 60 to 80 percent. They were not all moderate severe COVID-19 ARDS, but the study was performed with standardized PEEP in order to decrease confounding effects.  How are you guys doing with COVID over in Italy and are you still using a lot of prone positioning?  Well, we had, I don't remember, maybe five waves and we started more than two years ago.  It changed a lot over time, but we have very few patients now and we try mostly to treat them outside of the ICU or I would say without intubation you can say.  So either inside or outside depends on the size of the ICU, but for sure we learned to push more with the non-invasive ventilation, especially CPAP.  And I flown as a cannula, which were presented by our colleague from London and a lot of awake prone position.  So spontaneous breathing prone position, which was not the case for this patient, but the mechanism also for a spontaneous breathing prone position should be very similar.  The physiological effectiveness in this patient population.  And just to make sure I address Heather's follow-up question, she also asked at what point did you prone these patients or start the proning protocol?  Was it upon admission to the ICU?  Well, I think there are two points here.  One is maybe as early as possible, but sometimes COVID patients get worse over the days.  So I would say not as soon as possible, as soon as they meet the criteria.  So even if you have a minor patient that enters the ICU, but there's some evolution over time, you have to be careful and carefully monitor them.  So as soon as they get the criteria, I will not prone all the COVID patients that you have in your unit.  I would say as soon as they reach the criteria and this may not be the first day.  The second point is quite evident now, both for intubated and non-intubated patients, that the amount of hours over one day that they spend prone impacts the outcome.  So the more, the better, and the least should be eight hours.  So we use a lot of proning overnight.  Sleeping prone, especially for a non-intubated patient, seems quite effective to obtain both the eight-hour period and the comfort of the patient.  Thank you, and thank you for presenting this wonderful work.  Dr. Pohl, so I have a question that I, because I was looking through some of your tables and you did show much of your data.  I don't want to suggest you didn't, but I was really curious.  It's such a small number of subjects who had peripheral catheters in some unique, rarely used sites like the scalp and the foot.  But I did notice that it seemed like just eyeballing the data, you know, you had two patients with scalp catheters and one of the two had an infiltrate.  Like, do you think that, what do you think about that if you had a larger sample?  Do you think it would play out that some of these other sites might show with more infiltrates?  Yeah, so that's a great question.  I think in pediatrics, we actually, it's not as uncommon to use scalp sites as peripheral access.  I think that if I had to hypothesize the reason why certain sites might be more prone to infiltration than others,  it's been shown in other parts or in other parts of the literature that particularly joints or places where there's higher articulation  or any sort of situation in which the catheter might move slightly or become slightly dislodged.  And I would include the scalp on that where just you're moving your head all the time.  I wouldn't be surprised that in those types of situations, the catheter might slide out of the endovascular space and thus result in an infiltration.  So you focused your study on hypertonic same administration.  Do you think that, did your subjects receive any other vesicant medications that may have exacerbated or complicated your results in your interpretation?  Yes, so we did look at other vesicant medications as a potential risk factor.  Our pharmacy staff at Rady's Children's Hospital does have a policy which lists everything that they consider a vesicant medication.  So we use that as kind of our framework for identifying what medications would qualify as a vesicant.  So in the process of collecting the data, I looked at the entire medication administration record,  and I looked for those medications that would be considered a vesicant.  For our patients, none of them received any vesicant medications other than hypertonic saline through that particular PIV.  So it was possible for a patient to receive hypertonic saline once through a PIV and then a second time through a PIV.  And we did account for that as part of our model for looking at risk factors. Unfortunately, because of the low incidence or the low rate of complications,  it was not sufficiently powered to be statistically significant as a risk factor.  Thank you.  And you were very smart because you did not include patients throughout COVID, so you've avoided that line of questions that I always like to ask.  So Ram, we did have a question from Brenda Schultz in the audience.  She asked, one of your conclusions was to protocolize post-extubation care.  Based on your research, what would you suggest for such a protocol?  I think that's a really good question.  Thank you.  I think the main conclusion from our trial was that possibly the rate of use of non-invasive respiratory support post-extubation that we saw in the trial was high at around 45%, which was one of the inclusion criteria.  So there may be some patients who may have not needed non-invasive respiratory support, but clinically decided that they should start something.  So in the future, one of the lines of research would be to try and protocolize the decision around which patients should start non-invasive respiratory support post-extubation.  In order to do that, we would have to have a very clear idea of who high-risk patients are.  And at this point in time, there is some observational data, but no very large recent contemporary data sets that tell us which patients are at highest risk of extubation failure.  And so we could use that data then to decide which patients should automatically start non-invasive support and which patients could be allowed to see if they would progress and need rescue respiratory support.  So potentially having some data that would tell us high risk, moderate risk, or low risk for extubation failure prior to extubation would allow us to stratify the risk.  And I think that's one clear area of research that we need to work on in the next few years.  Thank you.  So I am strictly a researcher, and I have to ask you, I noticed that you apparently had faster-than-anticipated recruitment, and it sort of mucked up the need for an interim analysis.  How did you accomplish that?  What tips do you have for the rest of us?  I think all credit goes to the sites rather than to any of us.  But we were fortunate in two things.  One was COVID had not struck, and we finished recruitment in May 2020, so just after COVID started.  So we were lucky to not be affected by that.  We would have been very affected by that.  So that was one lucky feature.  The second was that the pragmatic inclusion criteria and the fact that the algorithms for the trial allowed clinicians flexibility around rescue treatments when clinically indicated, I think, got a lot of buy-in from the clinicians.  We had nearly 11 rounds of discussions and versions to agree on the algorithms, and then a final collaborators meeting to try and finalize them.  So it took a long time to get buy-in before we went live.  And I think that helped with patient recruitment.  A lot of the patients that we may have thought would have been difficult to recruit were recruited, and actually clinician willingness to randomize was quite strong.  But it did mess up the interim analysis a little bit, although there was no signal for harm at that point.  So we continued the trial, even though we were proceeding at faster than anticipated rates.  Thank you.  If we can go back to Dr. Mowry.  Can and do you use EIT to help predict response to prone positioning?  Well, EIT is becoming more and more popular, but still is a little, I will not say for expert, but a little difficult to arrive to useful information at the bedside.  But for sure, for example, as I said, I don't think proning is something to do to all patients, but should be in a sense personalized as well.  And what we are seeing, and we published a couple of people on this, is that if you have a lower amount of tidal volume reaching the dorsal region of the lungs, the back of the lung, that's more likely to benefit when you turn the patient to reopen and reiterate those.  So I think that given the clinical criteria, like a PF ratio and the diagnosis of moderate severe RDS, that could be an adjunction.  Maybe if you have doubts whether proning is worth, like an obese patient or ECMO patient, if you have the support of EIT in this kind of patient and you confirm that you have missing ventilation in the dorsal region,  that makes it more personalized and more likely to respond for the patient.  Thank you.  Dr. Pohl, I think there were a number of additional variables that you might have collected, but did not include in your statistical model.  Things like time of cath replacement to infusion.  How did you evaluate those risk factors and leave them out?  Why did you leave them out?  Yes, so when we were collecting all the data, or all of the things we wanted to do with the study, at the beginning, we had included a couple other things that weren't able to make it into our model,  simply because the rate or the frequency of complications was so low, even across the 1,020 incidences of administrations.  So we did collect data on how long the catheter had been in place before the administration of hypertonic sealing, as well as some other variables.  But ultimately, after speaking with our statistician and speaking with the group, the other co-authors, we decided that we kind of had to select which ones we would be able to fit into our model for the generalized estimating equation.  So that was kind of our consensus, what we were able to publish with regards to which ones we hypothesized would be resulting as a more likely potential risk factor for a complication.  Well, thank you very much. I actually would love to sit here all day and just chit-chat with you guys and talk more about this work.  But we are just closing in time. And in closing, I just would like to say thank you to all of our wonderful speakers.  Congratulations on this fabulous work that you're doing and the recognition.  And to all of you and to our entire audience, I hope you enjoy the Congress. Thank you.  Thank you. Thank you.  Thank you.

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Professional Development and Education, 2022

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Learning Objectives: -Articulate your core purpose and values as a first step toward leadership -Identify characteristics and core competencies for leadership success -Assess strategies to advance your leadership development and build your leadership portfolio

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Knowledge Area Professional Development and Education

Knowledge Level Foundational

Knowledge Level Intermediate

Knowledge Level Advanced

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Tag Team Leadership

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Tag Early Career

Year 2022

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