PICU Doc On Call

Welcome to PICU Doc On Call, A Podcast Dedicated to Current and Aspiring Intensivists.

I'm Pradip Kamat. I’m Dr. Ali Towne, a rising 3rd-year pediatrics resident interested in a neonatology fellowship, and I'm Rahul Damania and we are coming to you from Children's Healthcare of Atlanta - Emory University School of Medicine.

Welcome to our Episode a 5-month-old, ex-28 week female with abdominal distention.

Here's the case:

A 5-month-old, ex 28 week, female with a past medical history of severe BPD, pulmonary hypertension, home oxygen requirement, and G-tube dependence presents with hypoxemia and increased work of breathing.

The patient has a history of prolonged NICU stay with 8 weeks of intubation. The patient developed worsening respiratory distress requiring increased support and eventual intubation for hypoxemic respiratory failure. Echo showed worsened pulmonary hypertension with severe systolic flattening of the ventricular septum and a markedly elevated TR jet. The patient had poor peripheral perfusion, and upon intubation was started on milrinone and epinephrine. The patient improved, but the patient then developed abdominal distention and increasing FiO2 requirements prompting an abdominal x-ray. X-ray showed diffuse pneumatosis with portal venous gas. The patient was made NPO and antibiotic therapy was initiated.

To summarize key elements from this case, this patient has NEC.

• NEC is not a homogenous disease, but rather a collection of diseases with similar phenotypes.
• Some people split NEC into two categories: Cardiac NEC and Inflammatory NEC.
• Babies who develop cardiac NEC tend to be significantly older than babies who develop inflammatory NEC (about 1 month vs 2 weeks).
• There are three main contributory factors to the development of NEC: gut prematurity, abnormal bacterial colonization, and ischemia-reperfusion injury.
• Many cases result from an ischemic insult to the bowel, resulting in translocation of intra-luminal bacteria into the wall of the bowel, but the etiology and course of NEC can be very variable.
• This translocation can cause sepsis and death; the ischemia of the bowel can result in intestinal perforation and/or necrosis.

Necrotizing enterocolitis (NEC) is one of the most common gastrointestinal emergencies in the newborn infant. It is estimated to occur in 1 to 3 per 1000 live births. More than 90 percent of cases occur in very low birth weight (VLBW) infants (BW <1500 g) born at <32 weeks gestation, and the incidence of NEC decreases with increasing gestational age (GA) and BW.

What are key risk factors for the development of NEC?

• Prematurity and Birth Weight
• NEC incidence is inversely proportional to gestational age.
• Congenital Heart Disease
• Puts children at risk for NEC due to (1) decreased stroke volume, and (2) improperly oxygenated blood which reduced oxygen supply to the SMA and decreases intestinal wall perfusion.
• On the repair of the cardiac lesion, patients develop reperfusion injury due to their now improved perfusion to their gut. This reperfusion causes hyper inflammation via neutrophil activation resulting in NEC.
•  NEC primarily occurs in healthy, growing, and feeding VLBW preterm infants. It presents with sudden changes in feeding tolerance (increase in gastric residuals) with both nonspecific systemic signs (eg, apnea, respiratory failure, poor feeding, lethargy, or temperature instability) and abdominal signs (eg, abdominal distension, bilious gastric retention and/or vomiting, tenderness, rectal bleeding, and diarrhea). Physical findings may include abdominal wall erythema, crepitus, and induration.

Other than the immediate risk of death, what are some consequences of NEC long-term?

• Higher risk of malnutrition and short gut.
• BPD
• Developmental delay.

What are some areas of current research and development on the topic of NEC?

• Improved biomarkers for early recognition of NEC prior to the development of radiographic findings.
• Preventative measures.
• Immune modulators of NEC development.
• Underdeveloped adaptive immunity of the premature infant may be contributory.
• The normal passive sharing of immune compounds between mother and babies (IgG via the placenta and secretory IgA from breastmilk) is disrupted in premature infants, particularly those that are formula-fed.
• The majority of IgG transfer occurs in the last 4 weeks of pregnancy.
• Several additional cellular and cytokine-based changes may increase the risk of NEC.

A clinical diagnosis of NEC is based on the presence of the characteristic clinical features of abdominal distension, bilious vomiting or gastric aspirate, rectal bleeding (hematochezia), and the abdominal radiographic finding of pneumatosis intestinalis, pneumoperitoneum, or sentinel loops. The definite diagnosis of NEC is made from either surgical or postmortem intestinal specimens that demonstrate the histological findings of inflammation, infarction, and necrosis. However, a pathologic diagnosis is not always possible.

What are some of the currently favored preventative measures used to decrease the risk of NEC?

• Probiotics – research has found that babies with NEC have a different underlying gut microbiome than infants without NEC.
• The underlying suggestion is that “good bacteria” prevent the overgrowth of gram-negative enteric pathogens that may lead to NEC.
• Associated with increased risk in the development of NEC between 30-32 weeks where there is a concomitant change in microbiome colonization.
• Also, some suggestions that “good bacteria” downregulate the inflammatory response in the gut.
• Dosing, type of probiotic, and other details of usage are still yet to be decided on.
• Still not the standard of care in the US.
• Human Milk over Formula – a 1990 study demonstrated that the risk of NEC is 6-10 times greater in formula-fed infants.
• Secretory IgA from breastmilk may be protected as the adaptive immune system develops.

How is NEC managed?

• NEC is typically managed with gut rest (NPO with mIVF), gut decompression (Anderson tube to LIS), and broad-spectrum antibiotic coverage (we use Vanc and Zosyn at CHOA).
• Typically is managed in conjunction with pediatric surgery to evaluate the need for surgical resection.
• Otherwise, management includes supportive care including increased respiratory support as needed and typically TPN given the length of NPO time required.
• Pradip, we talked a great deal about NEC however can you provide some key differentials to consider?
• The differential diagnosis of NEC includes other conditions that cause rectal bleeding, abdominal distension, or intestinal perforation. These include spontaneous intestinal perforation of the newborn, infectious enterocolitis, and other causes of the surgical abdomen. NEC is usually differentiated from these conditions by its characteristic clinical features (healthy, growing, and feeding VLBW preterm infants who present with feeding intolerance and evidence of rectal bleeding) and abdominal radiographic findings (eg, pneumatosis intestinalis).

To Summarize:

• Medical management should be initiated promptly when NEC is suspected and in all infants with proven NEC. It includes the following:
• Supportive care – Supportive care includes bowel rest with discontinuation of enteral intake, gastric decompression with intermittent nasogastric suction, initiation of parenteral nutrition, correction of metabolic, fluid/electrolyte, and hematologic abnormalities, and stabilization of the cardiac and respiratory function.
• Antibiotic therapy – After obtaining appropriate specimens for culture, a course of parenteral antibiotics that cover a broad range of aerobic and anaerobic intestinal bacteria should be started:
• Ampicillin, gentamicin, and metronidazole could be options.
• Vancomycin can be used in areas of high MRSA and can be coupled with Zosyn.
• The clinical status is monitored to see if the patient responds to medical management, or if NEC continues to progress, and to determine if (and when) surgical intervention is required. Monitoring entails serial physical examinations and abdominal radiographs, and ongoing laboratory testing (eg, white cell and platelet count, and serum bicarbonate and glucose measurements).
• Surgical intervention is required either when intestinal perforation occurs or when there is unremitting clinical deterioration despite medical management, which suggests extensive and irreversible necrosis.

This concludes our episode on NEC.Special thanks to Dr. Ali Towne for her deep dive into this topic.

We hope you found value in our short, case-based podcast. We welcome you to share your feedback, subscribe & place a review on our podcast! Please visit our website picudoconcall.org which showcases our episodes as well as our Doc on Call management cards. PICU Doc on Call is co-hosted by myself Dr. Pradip Kamat and Dr. Rahul Damania. . Stay tuned for our next episode! Thank you!

References:

1. Klinke M, Wiskemann H, Bay B, et al. Cardiac and Inflammatory Necrotizing Enterocolitis in Newborns Are Not the Same Entity. Front Pediatr. 2020;8:593926.
2. Alison Chu M. Necrotizing Enterocolitis: Predictive Markers and Preventive Strategies. NeoReviews. 2013;14.
3. Denning TL, Bhatia AM, Kane AF, Patel RM, Denning PW. Pathogenesis of NEC: Role of the innate and adaptive immune response. Semin Perinatol. 2017;41(1):15-28.

Welcome to PICU Doc On Call, A Podcast Dedicated to Current and Aspiring Intensivists.

I'm Pradip Kamat and I’m Kate Phelps, a second-year pediatric critical care fellow joining Pradip and Rahul today!

I'm Rahul Damania and we are coming to you from Children's Healthcare of Atlanta - Emory University School of Medicine.

Today we are honored to have Dr. John Berkenbosch- senior author of the Prevention and Management of Pain, Agitation, Neuromuscular Blockade, and Delirium in Critically Ill Pediatric Patients with consideration of the ICU Environment and Early Mobility (PANDEM) guidelines recently published in February 2022 issue of the Pediatric Critical Care journal.

Dr. Berkenbosch is a Professor of Pediatrics and Pediatric Critical Care at the University of Louisville School of Medicine, and continues to be nationally recognized as an expert in pediatric procedural sedation with multiple publications relating to sedation practices, particularly novel uses of procedural sedation medications and regimens. He currently also serves as co-chair for the American College of Critical Care Medicine’s Task Force guidelines for sedation and analgesia in critically ill children which we will be discussing in today’s episode. Dr. Berkenbosch’s research interests have primarily focused on pediatric procedural sedation and implementation of technology advances in Pediatric Critical Care and have resulted in 57 publications as well as several book chapters

Rahul: Dr. Berkenbosch welcome to the PICU Doc ON call podcast. I would also like to point out that the free full access to the PANDEM guidelines is available online at pccmjournal.org

Dr. Berkenbosch: Thanks Rahul and Pradip. I am excited to be on the PICU Doc on Call Podcast to discuss the PANDEM guidelines. I want to first start by giving a huge shout-out to all the team members who contributed to these guidelines’ development. This is a topic about which I am quite passionate but also one that provides much-needed guidance regarding pain/agitation/delirium to our entire pediatric critical care community!

KATE: Dr. Berkenbosch, the rationale for the development of the PANDEM guidelines was the high variability in pediatric sedation and analgesia. Can you speak to this variability and why it was important to address that variability?

That is a great question, the variability has been one of the key motivators in the creation of these guidelines. We also wanted to develop a guideline that was broader in scope than what was currently available. The ICU Liberation bundle provided a paradigm for liberating critically ill patients from mechanical ventilation and the ICU environment and as we delved into developing these guidelines, we realized that many elements of the ICU liberation bundle aligned very closely with PICU sedation and analgesia so it made imminent sense to incorporate all of these topics into the guidelines, an acknowledgment if you will, that PICU liberation & sedation go hand in hand!

Absolutely, as we have stated in our prior episodes, the paradigm is: intubate → ventilate → liberate, and sedation/analgesia is intertwined in each of these processes.

Dr. Berkenbosch, as we get into the guidelines, can you please highlight how the search strategy for these guidelines were derived?

Of course, this was a remarkable group effort solicited by the Society of Critical Care Medicine. We were initially modeled after the adult PAD (pain, agitation, and delirium) guidelines task force but, as described already, extended beyond that to include Pediatric Pain, Agitation, Neuromuscular Blockade, and Delirium in addition to the PICU Environment and Early Mobility. It was comprised of 29 national experts who collaborated over a ten-year period. The full task force gathered annually in person during the Society of Critical Care Medicine Congress for progress reports and further strategizing with the final face-to-face meeting occurring in February 2020, in addition to periodic teleconferences to keep us on track between congresses. Throughout this process, the Society of Critical Care Medicine standard operating procedures Manual for Guidelines development was adhered to.

KATE: Dr. Berkenbosch, what a robust process, what were some research principles you can highlight in the development of this content?

We created a created descriptive and actionable Population, Intervention, Comparison, and Outcome set of questions. An experienced medical information specialist developed search strategies to identify relevant literature between January 1990 and January 2020. Controlled vocabulary was incorporated (such as, “ICUs, Pediatric,” “Critical Illness,” “Ventilators,” “Mechanical”) along with keywords (e.g., “PICU,” “critically ill,” “intubation”) in addition to a sensitive pediatric filter to identify records specific to this population.

Dr. Berkenbosch, as we look into the guidelines, we see the term conditional cited frequently. Do you mind highlighting how this term relates to the strength of recommendation as well as the quality of evidence?

This relates heavily to the available literature addressing each question we asked. Based on the quality of available evidence, recommendations were considered strong where the available evidence made additional data unlikely to alter our recommendations, conditional where we felt that new data might alter recommendations. Where evidence was inadequate to make a formal recommendation but we felt a practice was very low risk and likely beneficial, we made what we referred to as Good Practice statements.

How should a resident or a fellow in training approach these guidelines? There are almost 37 pages worth of content as well as a large very informative supplement.

Add an initial glance, this document can look daunting. We placed a table with all of the recommendations alone at the beginning of the guidelines for quick reference. We also created an infographic, also found near the beginning of the article which graphically shows how all the domains we discuss are related and highlights specific recommendations. We really felt that this diagram put the recommendations themselves into a picture that makes clinical and intuitive sense. Additional discussing guidelines at a Divisional level -especially fellow conferences, examining your institutional practices, etc. may additionally be valuable to aid trainees in unpacking everything.

If you have not checked out our most recent episode, role & reach of the Librarian in Pediatric Critical Care Medicine, please definitely check this out!

Let's transition and talk about the PANDEM Guidelines: We will divide up the recommendations into broad categories, namely: Analgesia, Sedation, Neuromuscular blockade, ICU delirium, Withdrawal, and Environment Optimization. Let’s start with Analgesia. This Portion of the guidelines addresses The utility of developmentally appropriate pain scores as well as certain analgesics.

What pain assessment tools do the PANDEM guidelines recommend? why not vitals signs as a way to assess postoperative pain in the critically-ill pediatric patient?

Let me start with what we don’t recommend here, that being reliance on vital signs alone. As we all know, vital sign abnormalities are common in PICU patients and these abnormalities can have multiple causes including the underlying medical or surgical reason for PICU admission, medications we use to treat the diseases kids admitted to our PICUs, or pain and/or agitation. Hence, while helpful, vital sign changes are just not very sensitive to pain or agitation. Now to tools. First off, we wanted to recommend the use of tools validated within PICU patients as we discovered literature describing multiple tools, many of which had not been formally validated. As kids' developmental capacities also change over time, we wanted to make sure that the tools we recommend cover the spectrum of age and developmental capabilities. Ultimately, we came to recommend the use of 4 self-report scales for children over 6 years of age who can communicate their pain and 2 observational scales which cover kids unable to communicate their pain for whatever reason (being intubated, underlying diseases with mental status changes, developmental inability for example). These 2 categories of tools also do not have to be mutually exclusive and can be used concurrently.

RAHUL: As a follow-up, what about non-opioid analgesia - I see a huge push from surgeons to focus more on nonopioid adjuncts, rather than opioid infusions—whereas the PANDEM guidelines say that for moderate to severe pain opioid infusions are recommended (strong):

Thanks for the question - and we agreed with the importance of this question as opioids are not benign drugs for multiple reasons. We extensively evaluated the literature discussing adjunct use of acetaminophen or non-steroidal agents and, in the end, made strong or conditional recommendations supporting the use of both of these agents/classes of analgesics to aid in postoperative analgesia and to decrease opioid exposure. Due to inadequate literature, we were not able to extend these recommendations to patients admitted with medical diseases. Similarly, due to a lack of adequate evidence, we did not differentiate between the use of IV versus enteral formulations of these adjunct medications. Related to this, I think it is important to also mention that the guidelines also address non-pharmacologic adjuncts or interventions that can further aid in pain control. 2 such areas where we were able to make recommendations were the addition of music therapy which is applicable to the entire age range we admit to the PICU and non-nutritive sucking with or without sucrose to aid in analgesia for infants undergoing painful procedures. And I want to make it clear, these non-pharmacologic interventions are adjuncts, and should not be viewed as replacements for analgesic medications – they’re complimentary.

RAHUL: Lets now discuss Sedation:

We noticed that use of a scale to assess the depth of sedation such as comfort-B or state behavioral scale or Richmond agitation sedation Scale received a strong recommendation. What is the rationale for this? How does this help decrease the use of sedatives especially benzodiazepines in the PICU?

So, just as with analgesia assessment tools, we wanted to only recommend sedation scales that have been formally validated, hence the 3 you just listed. While we only made a conditional recommendation for use of the RASS scale, we felt it important to include it as it is the scale used to determine the appropriateness of a patient for delirium screening. These tools allow us as bedside providers to have a more objective means with which to assess patient comfort which should, then, guide when and if patients require additional sedation. This is important as a follow-up to the need for doing periodic sedation screening is our recommendation that each patient has a target level of sedation defined at least once a day. This represents a recognition that the sedation needs of a patient in the PICU change over the course of their disease evolution, perhaps requiring deeper sedation early on when they are at their highest acuity but with needs reducing as they improve and move towards a transition to extubation for example. Deeper sedation may also be required early on to protect lines and devices, especially endotracheal tubes, which may not be as critical or may be removed as the child improves and, again, sedation can be lightened. Without this reassessment, patients run the risk of oversedation or prolonged exposure to sedative medications. As we have also emphasized the value of early mobility, it also stands to reason that sedation targets should lighten as it becomes appropriate to mobilize patients more and more – it’s hard for a deeply sedated patient to do much of this on their own. That said, it is really important for providers to find a proper balance between over-and under-sedation. Over sedation increases the risk of delirium, lengthens time on the ventilator, and limits things like mobility whereas undersedation can, in addition to what we just discussed, contribute to adverse psychological effects which may not manifest until after the child has left the PICU and even the hospital, such as post-intensive care syndrome.

We see that guidelines suggest the use of protocolized sedation although the RESTORE study found no difference between the institutions, which used protocolized vs non protocolized sedation for MV patients?

This is true although data in addition to the Restore trial informed our suggestion to use protocolized sedation. The main advantages of protocolization are that medications can be given or infusions adjusted based on the desired sedation target automatically without calling a physician for every change. In most reports available, including the RESTORE trial, this person was the bedside nurse and this makes the most intuitive sense to me as that is the provider who is most frequently at the bedside and, therefore, has the best idea of what the patient is doing from a comfort perspective throughout their shift. When tied to a target sedation level, protocols also should aid in ensuring that patients are less likely to be exposed to excessive amounts of medications although, as a task force, we certainly recognize that this is a topic for which further study is definitely needed. Related to this, while I think most of us think about sedation protocols being useful during the acute phase of illness while the patient is intubated, we were also able to find a reasonable amount of literature describing the use of protocolized weaning of sedatives and that this practice resulted in more rapid discontinuation of sedative and analgesic infusions without increasing the risk of development of withdrawal syndromes. This allowed us to also make a conditional recommendation for the use of sedation wean protocols.

KATE: Dr. Berkenbosch so no more daily sedation holidays or daily sedation interruptions?

This is a great question. With the increasing desire to limit sedative exposure, for good reasons, there was a lot of early interest in the use of daily sedation interruptions and some of this initial evidence appeared to show promising advantages. However, A more recent and larger multicenter RCT found that adverse outcomes were actually increased in the arm of patients randomized to daily sedation interruptions. Additionally, since so few patients in the protocolized arm of the RESTORE trial required DSI due to oversedation, the use of protocolized sedation seems to be unnecessary as appropriately used protocols can be the mechanism whereby sedative exposure is already minimized.

KATE The guidelines advocate for the use of alpha2 agonists as the primary sedative class in critically ill pediatric patients requiring MV. What are the advantages of using Dexmedetomidine for sedation?

I suspect a lot of your listeners are already aware of the attractive properties of alpha agonists including minimal respiratory depression, mild analgesic effects which can aid in reducing opioid exposure, and they are a class of sedative that, based on EEG studies, facilitate a sedated state that closely mimics that seen in natural sleep. In head-to-head comparisons with benzodiazepines, they are equally efficacious from a sedation perspective. Given increasing data regarding the risk of delirium development with benzodiazepine exposure, these properties all tipped the scales to favor alpha-agonist-based sedation regimens. While some have expressed concerns that bradycardia and hypotension are more common with alpha-agonists, the data available suggested no difference in the occurrence of either event in the need for intervention for drug-related cardiovascular adverse events although the qualifier about the concern with alpha-agonist addition to patients already on heart rate reducing medications remains relevant.

Dexmedetomidine is also recommended as the primary agent for sedation in critically ill pediatric postoperative cardiac surgical patients with expected early extubation. They also recommend the use of dexmedetomidine for sedation in critically ill pediatric postoperative cardiac surgical patients to decrease the risk of tachyarrhythmias.

An important transition period for the critically-ill patient is the peri-extubation period. We see that PANDEM has a bundle approach along with the use of propofol. Dr. Berkenbosch can you give us more information on the approach to sedation/analgesia during the periextubation period.

This is true. To quote the guidelines, “During the peri-extubation period when sedation is typically lightened, we suggest the following bundle strategies to decrease the risk of inadvertent device removal:

a) Assign a target depth of sedation at an increasing frequency to adapt to changes in patient clinical status and communicate strategies to reach the titration goal.

b) Consider a sedation weaning protocol.

c) Consider unit standards for securement of endotracheal tubes and safety plan.

d) Restrict nursing workload to facilitate frequent patient monitoring, decrease sedation requirements, and risk of self-harm.”

I want to be sure that with this recommendation, it is also recognized that restricted nursing workloads may not always be feasible as many areas are experiencing nursing shortages. However,...

Welcome to PICU Doc On Call, A Podcast Dedicated to Current and Aspiring Intensivists.

I'm Pradip Kamat and I'm Rahul Damania. We are coming to you from Children's Healthcare of Atlanta - Emory University School of Medicine.

I will turn it over to Rahul to start with our patient case...

A 2 yo Asian M presents with difficulty feeding. He has a history of epilepsy and recently was switched to Valproic Acid for seizure control as well as OTC deficiency diagnosed at birth. He has had a 3-day history of URI, cough, which now progressed to this difficulty feeding. His parents state he was initially very fussy however in the past few hours he has been more sleepy. He has not had any fevers. They have noticed that while he is sleeping he has been breathing "fast." Prior to arrival at the emergency room, he was noted to have a large non-bloody, non-bilious emesis. Upon transfer to the trauma bay, the patient suddenly has a seizure. A quick POC glucose is normal. His care is escalated & diagnostic workup is initiated.

Pradip, our case had two key elements in his history, namely the h/o OTC deficiency & VPA use, which place him, particularly at high risk to have hyperammonemia. As this is our topic of discussion today, would you mind starting with a general background & definition of hyperammonemia?

Sure, this is a classic case of not only hyperammonemia but also a metabolic crisis in this case related to a urea cycle defect.

As background, the urea cycle is the metabolic pathway that transforms nitrogen to urea for excretion from the body. We get nitrogen sources from a few areas in the body:

• from peripheral (muscle)
• enteral sources (protein ingestion)

The urea cycle occurs in the liver and once the ammonia is converted to urea in the hepatocyte, it is excreted into the kidney as urea. We will dive into this deeper soon, however, pathologies that impair adequate hepatocyte function, can impair the urea cycle and thus lead to hyperammonemia.

This is a great basic science summary, would you mind commenting about this patient's enzyme defect — the OTC deficiency?

• Yes, Ornithine transcarbamylase, or OTC for short, is one of the first few enzymes in the urea cycle.
• As a background, the inheritance pattern of majority, all of the urea-cycle-defects (UCD) is autosomal recessive, however, OTC deficiency is different — it is X linked.
• In a 21-year, multi-center retrospective study, it was noted that only 34 % of patients with UCD presented during the neonatal period (<30 days of age) — and around 25% of cases present in the 2-12-year-old range. This is why I would like to drive home this clinical point to have a urea cycle defect or any inborn error of metabolism in your differential, especially in a child who presents in a critically ill, undifferentiated state.

Why do you think there are subsets of populations who present later?

• This is a great question and the cause may be multi-factorial — it is worth noting that patients may have partial enzyme deficiencies and this may be a major reason why patients may have atypical presentations after the newborn period. This delayed presentation is most commonly seen in patients with partial ornithine transcarbamylase (OTC) deficiency.

As we have highlighted key pathophysiologic components, do you mind highlighting the typical clinical presentation of a child with a UCD & hyperammonemia?

The presentation may be variable, however, let’s break down some key features which were in our case:

• Patients typically have a preceding illness such as a URI or gastroenteritis, which triggers a more catabolic state.
• As a result, patients end up having increased ammonia levels — this ends up creating a picture of somnolence, inability to maintain normal body temperature, poor feeding, vomiting, and in severe cases lethargy, and This is a similar presentation to sepsis and thus keeping your differential broad, having fine attention to trends in vitals or clinical exam, and early aggressive management with contingency planning is crucial to the care of these patients.

As we wrap up the clinical presentation, what would be some other physical exam abnormalities we will see upon initial presentation?

I would like to highlight some important points here:

• Subtle signs of elevated ammonia include behavioral modifications such as delirium, as well as neuro-developmental delay — thus it is important to recognize our aforementioned presentations of seizures & alteration of consciousness

Let’s finish this episode with management pearls, Rahul, what is your general approach to hyperammonemia?

Excellent, the nitrogen scavengers typically used are: sodium phenylacetate and sodium benzoate; in a study published in NEJM in 2007, these therapies along with adequate calorie intake, were reported to lower plasma ammonia levels especially in children with urea cycle disorders. A combined preparation of sodium phenylacetate-sodium benzoate (Ammonul) was approved by the US Food and Drug Administration (FDA) in February 2005 for parenteral delivery

Any recommendations on dosing?

• For patients who weigh ≤20 kg, we typically use a loading dose of 500 mg/kg (250 mg/kg of each drug) in a volume of 25 to 35 mL/kg of 10 percent dextrose solution infused over 90 minutes. For patients who weigh >20 kg, dosing is based upon body surface area; the loading dose is 11 g/m2 (ie, 5.5 g/m2 of each drug).
• A maintenance infusion of sodium phenylacetate-sodium benzoate (500 mg/kg per 24 hours for patients <20 kg, 11 g/m2 per 24 hours as a continuous infusion for patients >20 kg) is started when the loading dose is completed and is administered in the same volume as the loading dose (25 to 35 mL/kg).
• Are there some adverse events that we need to watch for in our patients?
• Most of the side effects for Ammonul are metabolic (eg, hypokalemia, hyperchloremia, acidosis), neurologic (eg, seizures), or respiratory (eg, respiratory distress or failure).
• Electrolytes should be monitored daily during loading and maintenance infusions of sodium phenylacetate-sodium benzoate because these medications contain high concentrations of sodium and chloride. Sodium phenylacetate administration may cause potassium depletion.

Going back to the NEJM trial, for children who were treated with Ammonul with recurrent admissions for hyperammonemia, the overall survival which was reported was 84 percent. It is important to note however, the neurologic outcome was not evaluated.

As I review the urea cycle, I see that arginine and citrulline are precursors which can help form urea, can you comment on their role in hyperammonemia?

• IV arginine hydrochloride is used as part of the initial management of metabolic decompensation in all forms of UCD except known arginase deficiency.
• Arginine is created via the urea cycle and in our case, this patient has an OTC deficiency so Arginine now becomes an essential amino acid.
• Blood pressure should be monitored since high doses of IV arginine can decrease blood

What about citrulline?

• In OTC or CPSI deficiency, small oral doses of citrulline also are provided because incorporating aspartate nitrogen may improve clearance as urea.
• In one retrospective study, patients treated with L-citrulline reduced ammonia levels and improved weight gain which was most likely due to increased protein intake.

When you look longitudinally, and before we go into hemodialysis and its role, are there certain medications that we want to avoid?

• Glucocorticoids increase protein catabolism and should not be used routinely.
• As patients may have seizures, remembering that valproic acid inhibits urea synthesis, leading to increased serum ammonia levels. Thus, VPA should not be routinely used.

Seizures may be treated with other antiepileptic drugs, although correcting the underlying metabolic abnormality is more likely to affect seizure control.

• Yes, finally, Mannitol is ineffective in treating cerebral edema caused by hyperammonemia due to UCDs.
• Let's conclude this episode with hemodialysis; whats the appropriate timing?
• Hemodialysis should be started as soon as possible after hospital admission of a patient with severe hyperammonemia. Indications include an ammonia level that is rapidly increasing, acute hyperammonemia that is resistant to initial drug therapy, and/or ammonia that is persistently above the range of 350 to 400 micromol/L.

As many of our centers have CVVH readily available, it is important to consult with your nephrology team to optimize flow rates to be >40 to 60 mL/min. This method is less desirable as an initial treatment, although it can be used effectively between hemodialysis treatments to continue removing ammonia.

What is our endpoint usually if we are to go down the HD or CVVH route?

• Ammonia concentration is measured hourly during dialysis.
• Hemodialysis is stopped when the ammonia concentration has dropped below 200 micromol/L because it appears to have little effect below this level.
• What is important to recognize though is that plasma ammonia may increase again (rebound) because of the delay in the effect of nitrogen scavenging medications and the ongoing catabolism.
• Thus, hourly monitoring of ammonia levels is continued until ammonia levels have stabilized below 200 micromol/L for at least 24 hours → after a while to decrease iatrogenic blood draws, the frequency of measurements can be reduced to every four hours.

To summarize today's episode...

1. In newborns, UCDs typically present after 24 to 48 hours of age. Clinical features include somnolence and poor feeding followed by lethargy, vomiting, and coma. Other features include central hyperventilation leading to initial respiratory alkalosis, hyperammonemia, and seizures.
2. The initial laboratory evaluation for suspected UCD should include arterial pH and carbon dioxide; serum ammonia, lactate, glucose, electrolytes, and amino acids; and urine organic acids and orotic acid. Elevated plasma ammonia concentration combined with normal blood glucose and normal anion gap strongly suggests a UCD.
3. The initial approach to the treatment of UCDs consists of volume repletion, ammonia removal, protein restriction, and stimulation of anabolism. Respiratory status must be closely monitored. Pharmacologic therapy for hyperammonemia consists of initial IV administration of a combination preparation of sodium phenylacetate-sodium benzoate (Ammonul) followed by maintenance with oral glycerol phenylbutyrate (Ravicti).

This concludes our episode today on Hyperammonemia. We hope you found value in this short podcast. We welcome you to share your feedback & place a review on our podcast. PICU Doc on Call is co-hosted by me and my cohost Dr. Rahul Damania. Stay tuned for our next episode!

Welcome to PICU Doc On Call, a podcast dedicated to current and aspiring intensivists. My name is Pradip Kamat. My name is Rahul Damania and we come to you from Children’s Healthcare of Atlanta-Emory University School of Medicine.

Today's episode Is part two of our pediatric post-cardiac arrest care syndrome

If you have not yet listened to part one, I would highly encourage you to visit that episode prior to delving into this one.

Part 1 addressed the epidemiology, causes, and pathophysiology of POST CARDIAC ARREST SYNDROME.

Part 2 Today will discuss management and complications related to post-cardiac arrest syndrome in the ICU.

To revisit our index case we had a:

• 11 yo previously healthy M who was admitted to the PICU after cardiac arrest. After stabilization: The patient was taken to head CT which showed diffuse cerebral edema and diffusely diminished grey-white differentiation most pronounced in the basal ganglia. He is now 18-24 hours post-cardiac arrest and the team is dealing with hemodynamic changes, arrhythmias, and difficulty with ventilation. The patient’s neurological exam still remains poor with fixed 5 mm pupils and upper motor neuron signs in the lower extremities.

Let’s get right into it:

• What are some of the principles in management of patients with post cardiac arrest syndrome (PCAS)? Where do we keep the patients blood pressure?
• Hypotension after ROSC is commonly encountered in children with PCAS. Early hypotension occurred in 27% of children after cardiac arrest is associated with lower survival to hospital discharge and unfavorable neurological outcome. When post-cardiac arrest hypotension is present, it is not clear whether increasing the blood pressure through administration of fluids and inotropes/vasopressors can mitigate harm, despite this 41% of patients under 18 receive vasopressor therapy within the first 6 hours after ROSC. Currently, there is no high-quality evidence to support any single specific strategy for post-cardiac arrest hemodynamic optimization in children. Treatment of post-cardiac arrest hypotension and myocardial dysfunction may be assisted by monitoring and evaluating arterial lactate and central venous oxygen saturation. Parenteral fluids, inotropes, and vasoactive drugs are to be used as needed to maintain a systolic blood pressure greater than the fifth percentile for age. Appropriate vasoactive drug therapies should be tailored to each patient and adjusted as needed.
• What about cardiac arrhythmia's such as Vtach seen in our patient?
• The rhythm disturbances observed during the post-cardiac arrest period include premature atrial and ventricular contractions, supraventricular tachycardias, and ventricular tachycardias. Heart block is unusual but can be observed as a manifestation of myocarditis. There is inadequate evidence in adults and no published studies in children to support the routine administration of prophylactic antiarrhythmics after ROSC, but rhythm disturbances during this period may warrant therapy. Treatment depends on the cause and hemodynamic consequences of the arrhythmias. Premature depolarizations, both atrial and ventricular, usually do not require therapy other than maintenance of adequate perfusion and normal fluid and electrolyte balance. Ventricular arrhythmias may signify more serious myocardial dysfunction. QT prolonging agents must be avoided. Many of the vasoactive agents used to support myocardial function can increase myocardial irritability and risk of arrhythmias. Premature atrial or ventricular depolarizations are frequently observed and can be controlled by optimizing the dose of the vasoactive drugs. Bradycardia is frequently seen in TTM and typically requires no therapy. During PCAC, mechanical circulatory support (ECMO) may be considered if significant cardiorespiratory instability persists despite appropriate volume expansion and administration of inotropes, vasopressors, and, if indicated, antiarrhythmics.In a study de Mos N et al (CCM 2006) in a PICU population, the use of ECMO within 24 hours after ROSC was associated with reduced mortality. Case series have documented the role of ECMO88 and ventricular assist device support89,90 in children with refractory cardiogenic shock or acute fulminant myocarditis (Blume Ed et al., J Heart Lung Transplant 2016).
• What about oxygenation and ventilation strategies in our patient with PCAS
• Optimal oxygenation and ventilation of children after ROSC may be hampered by the pathology that precipitated the cardiac arrest (such as drowning with resultant post-pulmonary edema) and by the ensuing post-cardiac arrest pathophysiology. Further management challenges may be caused by aspiration and lung injury occurring during resuscitation efforts as well as ventilator-induced lung injury. Additionally, use of TTM alters the relationship between arterial oxygen saturation and arterial oxygen tension such that, for a given arterial oxygen saturation, the arterial oxygen tension (Pao2) is lower than that observed when the temperature is normal. Hypothermia also decreases the metabolic rate; thus, carbon dioxide production will be lower at any given minute ventilation.
• Post–cardiac arrest blood gas abnormalities are common in children, particularly in the first hours after ROSC as seen in our patient case. Published evidence has failed to demonstrate a consistent effect of post-cardiac arrest hyperoxia or hypoxemia on outcome. After ROSC, it is reasonable to aim for normal PaO2 (or the value appropriate for the child’s condition if the child has, for example, cyanotic heart disease) and to use the lowest possible fraction of inspired oxygen, weaning to maintain an oxygen saturation of 94% to 99% as a guideline. Throughout PCAC, hypoxemia must be avoided whenever possible, particularly during oxygen titration. The 2010 AHA PALS guidelines recommended prompt arterial blood gas analysis as soon as possible after ROSC and within 10 to 15 minutes of establishing initial mechanical ventilation to guide oxygen administration and titration and to support mechanical ventilation.
• Post–cardiac arrest derangements in PaCO2 are common. On the basis of available evidence, after ROSC, it is reasonable to target normocapnia (ie, normal for the child, or PaCO2 35–45 mm Hg) or a PaCO2 specific for the patient’s condition, limiting exposure to severe hypercapnia and hypocapnia. Lung protective strategies such as low TV, high PEEP should be used to minimize VILI.
• Can you comment on targeted temperature management?
• Post–cardiac arrest pyrexia (elevated core body temperature) is common, and persistent hyperthermia is associated with unfavorable neurological outcomes in children (Bambea MM PCCM 2010).During PCAC, fever (≥38°C) should be aggressively treated. To treat the child who remains comatose after OHCA, the 2015 AHA PALS guidelines update recommended that it is reasonable either to maintain continuous normothermia (TTM to 36°C–37.5°C) for 5 days or to maintain 2 days of continuous hypothermia (TTM to 32C°–34°C) followed by 3 days of continuous normothermia (TTM to 36°C–37.5°C).2 Because increased mortality was associated with temperatures <32°C, if TTM to 32°C to 34°C is used, meticulous care must be provided to prevent temperatures <32°C.

Post–cardiac arrest derangements in PaCO2 are common. On the basis of available evidence, after ROSC, it is reasonable to target normocapnia (ie, normal for the child, or Paco2 35–45 mm Hg) or a Paco2 specific for the patient’s condition, limiting exposure to severe hypercapnia and hypocapnia. Lung protective strategies such as low TV, high PEEP should be used to minimize VILI.

• What about treatment of seizures in PCAS and can you also comment on sedation , analgesia and the use of NMB in these patients ?
• Seizures occur in 10% to 50% of children who remain encephalopathic after achieving ROSC. (Abend NS et al Neurology 2009). Furthermore, about half of children with post-ROSC seizures experience exclusively non-convulsive (subclinical, EEG only) seizures, which cannot be identified by clinical observation alone. Seizures could not be predicted from any clinical or resuscitation variables. Seizures were associated with unfavorable gross neurological outcomes at discharge but not with higher mortality. Because seizures increase metabolic demand, can worsen metabolic dysfunction, and can increase intracranial pressure, they can contribute to secondary brain injury.
• For these reasons, many clinicians aim to treat seizures, although the approach is generally guided by the child’s overall medical condition and other prognostic indicators. Typical acute clinical or electrographic seizures are often initially treated with benzodiazepines, levetiracetam, or phenytoin. Myoclonic seizures such as those reported in our patient case may be refractory to treatment. (Ostendorf AP et al PCCM 2016) Providers must be alert for potential adverse effects of anticonvulsants such as cardiac arrhythmias, hypotension, and respiratory depression. In addition, sedation induced by anti-seizure drugs may complicate the neurological examination. Pain and discomfort needs to be controlled using opioids (morphine or fentanyl) and sedatives (dexmedetomidine or benzodiazepines). Neuromuscular blocking agents (eg, vecuronium or pancuronium) with analgesia or sedation (or both) may improve oxygenation and ventilation in case of patient-ventilator dyssynchrony or severely compromised pulmonary function. Providers are cautioned, however, that NMB agents can mask seizures and impede neurological examinations.If TTM is used, practitioners must be aware that the pharmacokinetics and pharmacodynamics of sedatives/hypnotics and neuromuscular blocking agents will be altered, resulting in prolonged time to both hepatic and renal clearance.
• What about endocrine dysfunction in PCAS patients ? Can you comment on glucose control and treatment of adrenal dysfunction?
• Both hypoglycemia and hyperglycemia have been associated with unfavorable outcomes in critically ill children and adults. During PCAC, clinicians should avoid and promptly treat hypoglycemia.Severe hyperglycemia can also be problematic because it can lead to uncontrolled osmotic diuresis, which can exacerbate post–cardiac arrest volume depletion and hemodynamic instability. Therefore, it is important to monitor serum glucose concentration, to treat significant hyperglycemia, and to monitor urine volume. There is currently insufficient published evidence to determine the optimal blood glucose concentration during PCAC that will maximize neurological outcome. Approximately 30% of critically ill children have relative adrenal insufficiency, but this has not been evaluated in children resuscitated from cardiac arrest. There is insufficient evidence to support the routine use of corticosteroids after cardiac arrest. Patients should be treated per recommendations for critically ill children.
• How do we manage Renal failure in these patients?
• In a recent retrospective study of 296 children during PCAC, 37% had AKI, 11.5% had severe AKI by Acute Kidney Injury Network criteria, and 6.4% required RRT within 48 hours of ROSC.(Neumayr TM et al. PCCM 2017). Risk factors for severe AKI after cardiac arrest included abnormal baseline creatinine, lack of a chronic lung condition, in-hospital arrest location, higher number of doses of epinephrine during arrest, and worse post–cardiac arrest acidosis.Throughout PCAC, it is important to monitor kidney function, including urine output and creatinine, because patients are at risk for developing AKI, and RRT may be indicated. Nephrotoxic medications and medications excreted by the kidneys should be used with caution, and dose adjustment may be needed. Serum concentrations of nephrotoxic medications should be closely monitored.
• Do we need antibiotics during post cardiac arrest care (PCAC) ? Can you also comment on management of inflammation and coagulation abnormalities?
• Infection is common after pediatric cardiac arrest. Most studies reporting the incidence of infection during PCAC enrolled children treated with THAPCA trial. The incidence varied from < 5 infections per 100 days in IHCA to 11.1 infections per 100 days for OHCA patients. The incidence of culture-proven infection did not differ between patients treated with TTM 32-34 and those treated with TTM to 36-37.5. During ECMO therapy for PCAS, the infection rate was ~ 10%. Monitoring for signs of infection is important during PCAC. The decision to obtain cultures and to initiate empirical antimicrobial coverage should follow local PICU protocols.
• Inflammatory pathways are activated as part of PCAS, including disturbances of the coagulation cascade. The effects of blocking or modulation of these pathways have been studied in adults and in animal models; we identified no studies to date involving infants or children. Extensive animal research into blocking or modifying inflammatory pathways has yielded promising results. However, to date, most attempts to translate this work to humans have been unsuccessful. Because inflammation can alter the coagulation cascade, providers should monitor for signs of bleeding or coagulopathies; this is particularly important for patients receiving ECMO support. At this time, there is insufficient evidence to support specific treatments to modulate inflammatory pathways during PCAC.

To summarize, Infection is common after pediatric cardiac arrest. Inflammatory pathways are activated as part of PCAS, including disturbances of the coagulation cascade. The effects of blocking or modulation of these pathways have been studied in adults and in animal models; we identified no studies to date involving infants or children.

• Can you comment on rehabilitation and recovery after cardiac arrest ?
• Children surviving cardiac arrest are at high risk for physical, cognitive, and emotional disabilities that can affect quality of life, family function, activities of daily living, school performance, and employment. There is little evidence on specific interventions during PCAC that will improve functional outcomes of children after cardiac arrest. Small observational studies of children after critical illness or injury suggest that children with anoxic injury have more severe disability and demonstrate less improvement compared with children with traumatic brain injury. There is insufficient evidence to support specific rehabilitation interventions or the optimal timing of initiation of such interventions. However, on the basis of the benefits of rehabilitation for patients with traumatic brain injury and stroke, it is reasonable for providers to consult rehabilitation experts within the first 72 hours after cardiac arrest to tailor a plan of rehabilitation interventions for survivors of cardiac arrest.
• As we look into the future, What about biomarkers for post arrest prognostication?
• Currently, there is insufficient evidence to support the use of serum biomarker concentrations alone to predict outcome after pediatric cardiac arrest. Although specific biomarkers have shown promise, they have yet to be validated in prospective pediatric studies after cardiac arrest. After cardiac arrest, elevations in lactate concentration may reflect not only severe post–cardiac arrest systemic hypoperfusion but also severe cerebral hypoperfusion. In several pediatric cardiac arrest studies, higher serum lactate concentrations in the first 12 hours after cardiac arrest were associated with increased mortality, and higher concentrations within 12 hours of ROSC were modestly predictive of unfavorable outcome (area under the curve: for IHCA, 0.76; for OHCA, 0.75). (Meert K et al. PCCM 2009; Topjian A PCCM 2013). Numerous other promising biomarkers of neurological injury, systemic inflammation, and genetic polymorphisms are currently under evaluation. An ongoing trial is investigating concentrations of NSE, S100B, glial fibrillary acid protein, and ubiquitin carboxy-terminal hydrolase L1 in the first 72 hours after pediatric OHCA and their association with 1-year neurological outcomes. (Prout AJ et al. Curr Opin Pediatr 2017).

To summarize, In several pediatric cardiac arrest studies, higher serum lactate concentrations in the first 12 hours after cardiac arrest were associated with increased mortality, and higher concentrations within 12 hours of ROSC were modestly predictive of unfavorable outcome

How do we prognosticate PCAS

• Providers must consider multiple variables when attempting to prognosticate outcomes during and after cardiac arrest. Providers must consider multiple variables when attempting to prognosticate outcomes during and after cardiac arrest. Although there are factors associated with better or worse outcomes, no single factor studied predicts outcome with sufficient accuracy to recommend termination or continuation of CPR or to enable prognostication after ROSC (de Caen AR et al. Circulation 2015).
• Several prearrest conditions and therapies have been independently associated with worse survival to discharge and unfavorable neurological outcomes after pediatric cardiac arrest: Worse outcomes from OHCA are associated with decreased age and some causes of arrest, including sudden infant death syndrome and blunt trauma. (Meert KL et al. PCCM 2016. Matos RI et al. Circulation 2013). Factors associated with lower survival after IHCA include older age; presence of preexisting conditions; interventions such as tracheal intubation, mechanical ventilation, and use of vasopressors at the time of arrest; and arrests occurring...

Welcome to PICU Doc On Call, a podcast dedicated to current and aspiring intensivists. My name is Pradip Kamat.

My name is Rahul Damania, a current 2nd-year pediatric critical care fellow. We come to you from Children’s Healthcare of Atlanta-Emory University School of Medicine.

Today's episode is dedicated to pediatric post-cardiac arrest care.

We are going to split this topic into two episodes, part one of pediatric post-cardiac arrest syndrome will address the epidemiology, causes, and pathophysiology.

I will turn it over to Rahul to start with our patient case...

• 11 yo previously healthy M who is admitted to the PICU after cardiac arrest.
• The patient was noted to be found unresponsive and submerged in a neighborhood pool.
• He was pulled out by bystanders and CPR was started for 5 minutes with two rounds of epinephrine prior to achieving ROSC.
• During transport to the OSH, the patient developed hypotension requiring a continuous epinephrine infusion.
• His initial blood gas was notable for a mixed respiratory and metabolic acidosis:
• 7.0/60/-20
• His initial serum lactate was 6.8 mmol/L.
• He presents to the PICU with a temperature of 36.6, HR 130s, MAPs 50s on Epinephrine infusion at 0.03mcg/kg/min
• He is mechanically ventilated with notable settings PEEP of 10, FiO2 65%.
• The patient is taken to head CT which shows diffuse cerebral edema and diffusely diminished grey-white differentiation most pronounced in the basal ganglia.

Great Rahul, can you please comment on his physical exam & PMH?

• Important physical exam findings include an unresponsive intubated patient with a cervical collar and bilateral non-reactive pupils at 4mm. The patient received mechanical ventilation with coarse breath sounds. A heart exam revealed tachycardia with no murmur or gallop. The patient does not respond to stimuli, intermittent jerking movements of arms and legs were observed. There was no evidence of rash or trauma. No past medical history of seizures or any heart disease. No home medications or toxic ingestions are suspected.

So now he is transferred to the ICU, what did we do?

• An arterial line, central venous line, urinary catheter, esophageal temperature probe was placed. The patient was ventilated using a TV of 6cc/kg and a PEEP of 10 (FIO2 ~65%) to keep SPO2 >94%. The patient initially had runs of ventricular tachycardia for which lidocaine was used. Although the initial EKG showed mild QTc prolongation, it subsequently normalized and was considered to be due to his cardiac arrest and resuscitation. An echocardiogram revealed normal biventricular systolic function (on epinephrine) and also showed normal origins of the coronary arteries. Comprehensive Arrhythmia Panel did not identify a specific genetic cause for the patient's sudden cardiac arrest. The patient was placed on continuous EEG, which demonstrated severe diffuse encephalopathy with myoclonic status likely from anoxic brain injury Patient was also started on Levetiracetam and valproic acid. Initial portable CT scan done on day # of admission showed diffuse cerebral edema and diffusely diminished gray-white differentiation (most pronounced in the basal ganglia). MRI was deferred due to patient instability.

The case we talked about highlights a patient who had a trigger that then resulted in cardiac arrest is common is one of the common reasons for admission to the PICU at Children's hospitals whether from submersion injury, trauma, ingestion, cardiac arrhythmia, sepsis, etc. Can we start by defining post-cardiac arrest syndrome?

• Successful resuscitation from cardiac arrest results in a post-cardiac arrest syndrome, which can evolve in the days to weeks after the return of spontaneous circulation. The components of post-cardiac arrest syndrome are brain injury, myocardial dysfunction, systemic ischemia/reperfusion response, and persistent precipitating pathophysiology. Prior to 2008, the AHA pediatric advanced life support (PALS) guidelines focused chiefly on the prevention of cardiac arrest, immediate recognition of cardiac arrest, and provision of early CPR because outcomes of pediatric cardiac arrest were poor. The past decade has led to focused efforts by resuscitation experts to address specific pediatric post-cardiac arrest knowledge gaps. In the 2019 Aug issue of Circulation (Vol 140, issue 6) published a scientific statement from the American Heart Association, which summarizes the epidemiology, pathophysiology, management, and prognostication after the return of sustained circulation after cardiac arrest, and it provides consensus on the current evidence supporting elements of pediatric post-cardiac arrest care.
• In order to provide post-cardiac arrest care (PCAC), caregivers need to understand the phases of cardiac arrest. Can you give us more information on the phases of cardiac arrest care?
• Let me start by defining ROSC or return of spontaneous circulation: ROSC refers to a return of sustained circulation, which can include circulation that results either from a perfusing spontaneous heart rhythm or from the establishment of extracorporeal circulation with extracorporeal membrane oxygenation (ECMO).
• The immediate phase: the first 0 to 20 minutes after ROSC
• The early phase: the period after ROSC from 20 minutes up to 6 to 12 hours
• The intermediate phase: 12 to 72 hours
• The recovery phase: approximately 72 hours to day 7. Starts at different times for different patients; the timing may be influenced by factors such as cardiovascular function or use of targeted temperature management (TTM)
• The rehabilitation phase: traditionally began with the application of care after discharge from the acute care hospital, but rehabilitation services are now often initiated during the intermediate phase or the recovery phase.
• What is the epidemiology of post-cardiac arrest syndrome (PCAS)?
• The timing and severity of the phases of post-cardiac arrest syndrome (PCAS) may differ between patients with out-of-hospital cardiac arrest (OHCA) and those with in-hospital cardiac arrest (IHCA) because witnessed status, preexisting conditions, cause of arrest, and timing and quality of bystander actions, such as immediate administration of high-quality CPR, may differ between OHCA and IHCA.
• It is estimated that >5000 children experience OHCA annually in the United States with an estimated incidence of non-traumatic OHCA of 8.04 per 100 000 person-years.11 With current ROSC rates of ≈36%. The reported survival to discharge in OHCA remains poor- 6.7-10.2% although favorable neurological outcome has been reported in 77% of pediatric OHCA survivors. One study using PECARN data (Moler FW et al. CCM 2011) of TTM in comatose children who survived OHCA to be admitted to a pediatric intensive care unit (ICU), reported that 38% survived to hospital discharge.

An estimated 6000 infants and children develop IHCA annually. Non–risk-adjusted ICU ROSC occurred in 78%, with 45% surviving to discharge; 89% of survivors had a favorable neurological outcome (Berg RA et al. CCM 2016)

Approximately 6500 children per year in the US have PCAS. The goal of PCAC is to increase not only survival to hospital discharge but also survival with favorable neurological outcomes.

• Can we take a deeper dive into the pathophysiology of PCAS? Let's start with brain injury
• Post–cardiac arrest brain injury remains a leading cause of morbidity and mortality in adults and children because the brain has limited tolerance of ischemia, hyperemia, or edema. The first 3 phases of PCAS involve hypoxemic-hypotensive perfusion with energy deprivation. With ROSC, there is a burst of reactive oxygen species, and oxidative stress may ensue in tissue that is depleted of antioxidants. As a result, reperfusion is associated with excitotoxicity, calcium accumulation, and free radical-mediated cell injury or death. The myoclonic status seen in your case is probably due to this excitotoxicity. Both neuronal cellular necrosis and apoptosis result from this cascading injury and can continue in the days to weeks after ROSC. 
• A variety of post-cardiac arrest clinical conditions, including hyperoxia, hypoxemia, and hypotension, can exacerbate the neuronal injury.
• What about cardiac injury in PCAS?
• Global myocardial dysfunction occurs even in the absence of a cardiac cause of the arrest, and the severity of the myocardial dysfunction may be related to the duration of no-flow time during cardiac arrest. Myocardial dysfunction has been associated with early mortality despite successful initial resuscitation in children and adults. The onset of post-cardiac arrest myocardial dysfunction begins within hours of the arrest, peaks at ≈8 hours, begins to improve at 24 hours, and typically resolves within 48 to 72 hours. The pathophysiology contributing to this frequently reversible deterioration of cardiac function after cardiac arrest is not fully understood but is associated with cardiovascular ischemia/reperfusion injury, cytokine-mediated cardiovascular dysfunction, and induced myocardial injury secondary to catecholamines or electric shocks. (Adrie C et al. Circulation 2002).Children may initially demonstrate a hyperdynamic state and then develop cardiac dysfunction over time. Because myocardial dysfunction is likely to develop in approximately two-thirds of patients after ROSC and subsequently improve, it is thought to be a modifiable risk factor.

Clinical manifestations of myocardial dysfunction include hypotension, left ventricular and RV systolic or diastolic dysfunction resulting in reduced cardiac output, arrhythmias, and pulmonary edema, which can result in recurrent cardiac arrest. Cardiac arrhythmias such as Vtach noted in the patient in your case are common during PCAC and may be exacerbated by catecholamine administration, which is required to maintain adequate cardiac output.

• Rahul**: What about systemic ischemia/reperfusion ?**
• The combination of systemic ischemia/reperfusion produces a state similar to the sepsis syndrome, with elevated cytokines, the presence of endotoxin in plasma, activation of coagulation pathways, and inhibition of anticoagulant pathways. Transient critical illness hyperglycemia occurs after cardiac arrest from a relative insulin-resistant state that is associated with high levels of endogenous catecholamines and cortisol secretion, with resulting gluconeogenesis and glycogenolysis. In children, the serum glucose is typically elevated in the first 12 to 18 hours after the insult and then falls to normal. Clinical manifestations of systemic ischemia/reperfusion include capillary leak with intravascular hypovolemia, vasoplegia, coagulopathy, hyperglycemia, adrenal insufficiency, and impaired oxygen utilization and delivery, contributing to multisystem organ dysfunction. I would like to advise our listeners that management of the child after cardiac arrest includes diagnosis and treatment of the precipitating cause of cardiac arrest. Failure to identify and correct the original cause of cardiac arrest leaves the patient at risk for secondary injury and even recurrence of cardiac arrest. A team approach using experts from cardiology, genetics, infectious disease, radiologists and toxicologists, etc., may be required to investigate the cause of cardiac arrest.

To summarize, the combination of systemic ischemia/reperfusion produces a state similar to the sepsis syndrome, with elevated cytokines, the presence of endotoxin in plasma, activation of coagulation pathways, and inhibition of anticoagulant pathways. Transient critical illness hyperglycemia occurs after cardiac arrest from a relative insulin-resistant state that is associated with high levels of endogenous catecholamines and cortisol secretion, with resulting gluconeogenesis and glycogenolysis. In children, the serum glucose is typically elevated in the first 12 to 18 hours after the insult and then falls to normal.

• Let's discuss monitoring typically used in patients with PCAS?
• In the post-cardiac arrest period, it is important for the healthcare team to anticipate and assess for evolving systemic and organ dysfunction and to proactively support organ function. This requires ongoing monitoring to guide intensive care therapies. Monitoring in the field continues through transport and includes ECG, pulse oximetry, capnography, noninvasive blood pressure measurement, and point-of-care glucose testing.
• General monitoring: General intensive care monitoring includes continuous cardiac telemetry, pulse oximetry, continuous capnography, continuous temperature monitoring, and measurement of blood pressure and urine output. Monitoring includes laboratory analysis of venous or arterial blood gases, serum electrolytes, and glucose and calcium concentration. Arterial lactate and central venous oxygen saturation assist in evaluation of the adequacy of tissue oxygen delivery. A chest x-ray aids evaluation of endotracheal tube position, heart size, and pulmonary status.52 Additional monitoring includes evaluation of renal function, measurement of hemoglobin concentration, monitoring of coagulation function, and assessment for signs of inflammation and infection.
• Hemodynamic monitoring includes: arterial line placement for intra-arterial blood pressure monitoring to facilitate the identification and treatment of hypotension. In addition, central venous catheters may be useful to monitor central venous oxygen saturation and to provide a route for the administration of fluids and medications. Pulmonary artery catheters are now rarely used in pediatrics. An echo and ECG should be performed. The optimal timing or frequency of echo acquisition remains unknown.
• Neuro-monitoring: Serial neurological examinations may help identify evolving hypoxic-ischemic brain injury. Given the high incidence of electrographic seizures after ROSC(Abend NS et al. Neurology 2011) monitoring with an electroencephalogram (EEG) is increasing in pediatric PCAC. Neuroimaging can be helpful to identify a cerebral cause of cardiac arrest and the presence of severe brain injury. One small pediatric study (36 patients) by Lee JK et al (Resuscitation 2014) evaluated the role of cerebral autoregulation in guiding hemodynamic management and oxygen delivery and assisting in neuroprognostication in comatose children after cardiac arrest, but more studies are needed.

This concludes our episode today on PCAS. We hope you found value in this short podcast. We welcome you to share your feedback & place a review on our podcast. PICU Doc on Call is co-hosted by Dr. Pradip Kamat, and my cohost Dr. Rahul Damania.

Stay tuned for our next episode which covers Part 2 of PCAS focused on Management! Thank you

Welcome to PICU Doc On Call, A Podcast Dedicated to Current and Aspiring Intensivists.

I'm Pradip Kamat and I'm Rahul Damania. We are coming to you from Children's Healthcare of Atlanta - Emory University School of Medicine.

Welcome to our Episode a 2-year-old with severe pallor and O2 desaturation.

Here's the case presented by Rahul:

A two-year-old presents to the PICU with severe pallor + O2 requirement. The patient went for a routine check with her primary care who noted the patient appeared severely pale. He sent the patient to the ED. An initial Hgb check revealed a Hgb of 1.5gm/dL. Per mother, she is otherwise healthy but a very picky eater. She also reports the patient drinks milk as a soothing adjunct at night, consuming between 12 - 36oz a day. No family h/o of anemia or any other blood disorders.

No h/o recent illness. Mother had a normal spontaneous full-term delivery. The patient is up to date on her immunizations. Per mother, developmental milestones are normal. The mother also denies any history of decreased activity in the child. Given the low Hgb, the patient was admitted to the PICU.

Let's transition into some history and physical exam components of this case?

What are key history features in this child?

• Severe pallor in a 2-year-old
• H/o being a picky eater
• H/o excessive milk consumption
• Pertinent negatives include: No obvious blood loss, No petechia, bruising, or jaundice

What did the physical exam show?

• The patient was hypertensive, tachycardic to the 140s, and 10th% weight for growth percentiles
• On physical exam, the patient was in no acute distress. Her lips, gums, and conjunctiva were pale. She had a systolic ejection murmur. As a pertinent negative, she had no hepatosplenomegaly. She also has no rash, bruising, or petechiae.

The lack of hepatosplenomegaly may indicate that the patient has no signs of extramedullary hematopoiesis. Patients with hemolytic processes resulting in anemia may present with signs of scleral icterus, jaundice, and hepatosplenomegaly resulting from increased red cell destruction. In fact, in an emergency department setting, the clinical detection of jaundice was found to have sensitivity and specificity of only approximately 70 percent.

To continue with our case, then what were the patient's labs consistent with:

• Initial CBC showed: WBC 8.5K, RBC 1.14 (L), Hgb 1.5gm/dL; Hct 6.1, MCV 53.5, and an elevated RDW 37.7. Initial platelet count was 50K, reticulocyte count 1.1%
• Peripheral smear revealed no blasts, thrombocytopenia - with occasional medium-sized platelets - ghost cells and anisocytosis/poikilocytosis- which appears most consistent with iron deficiency.
• It was interesting that the patient had thrombocytopenia

Absolutely, typically with Iron deficiency, there is thrombocytosis (erythropoietin is increased which closely mimics thrombopoietin stimulates platelets). In fact, both act via the non-TK, JAK-STAT pathway.

OK, to summarize, we have:

• Two year old with severe anemia most likely secondary to iron deficiency.
• As you think about our case, what would be your differential?
• For any patient with acute severe anemia presenting to the PICU- One has to think in terms of blood loss, decreased or impaired production (i.e bone marrow failure), or peripheral blood destruction (i.e hemolysis).
• Here would be the organizations:
• Blood loss
• Decreased or impaired production
• Increased destruction

Let’s go into detail for each:

• Blood loss can be internal or external (due to trauma, excessive blood draws, due to surgery)-typically gives rise to normochromic normocytic anemia.
• Decreased or impaired production: Deficiency of substances needed for Hgb & RBC production such as iron Vit B12 etc. Depression of BM due to infection (parvo B), chemicals, pharmacologic agents or immune mechanisms. Bone marrow aplasia can be idiopathic with or without congenital anomalies. Infiltration of BM due to malignancies such as leukemia, Hodgkin disease, neuroblastoma, etc.

Increased blood destruction:

• Can be due to intrinsic defects of the RBC such as hereditary spherocytosis, defects of Hgb such as sickle cell disease, thalassemia syndromes, enzyme defects.
• Extrinsic factors include immune mechanisms which can be related to drugs, infections, and non-immune mechanisms such as drugs, toxins, sepsis, HUS, TTP.
• Also a combination of intrinsic and extrinsic defects such as PNH, Favism, G-6PD. Patients with peripheral destruction in addition to pallor, typically have evidence of hemolysis such as jaundice, red cell breakdown (erythrocyte fragmentation) on the peripheral smear is seen typically in microangiopathic hemolytic anemias.
• There is typically an increase in the reticulocyte count, which keeps the MCV in the macrocytic range. Bone marrow will typically reveal erythroid hyperplasia. The sine qua non of immune hemolysis is the demonstration of the presence of antibodies or complement components bound to the erythrocyte membrane using the Direct Coombs test.

A prospective study by Bateman ST et al (Am J Respir Crit Care Med. 178:26-33 2008) reported 73% of blood loss in the PICU is attributable to blood draws. We need to limit both the number as well as the frequency of blood tests in our patients especially if these are not helping make a change in patient management. Conservative blood draws will help reduce blood transfusions in patients in the PICU. The SCCM’s “Choose Wisely” campaign recommendations from 2015 advises us not to order diagnostic tests at regular intervals (such as every day) but rather in response to specific clinical questions.

Rahul, can you give us a brief synopsis on the physiology of iron metabolism in the human body?

• Iron metabolism is unique in that iron balance is achieved by control of absorption rather than by excretion.
• About 1.5mg/day of iron is lost due to cell exfoliation from the skin, gut, and urinary tract.
• About twice this amount is lost by menstruating women and about three one-half times lost during pregnancy.
• Dietary iron is either in form of heme iron (from hemoglobin and myoglobin of animal sources) or non-heme iron from salts of non-animal sources. The mucosal cell of the small intestine (mostly duodenum and ileum) ultimately controls the absorption of iron in the body. Once taken up by the mucosal cell the iron is either incorporated into the ferritin of the mucosal cell (sloughed off in 3-4 days) or transferred to the portal circulation of the liver with help of mucosal cell transferrin.

The cellular metabolism of iron is mediated by three proteins:

• Transferrin, transferrin receptor, and ferritin.
• Transferrin production is increased in iron deficiency states. Iron storage exists in the soluble easily available form ferritin or insoluble more stable fraction hemosiderin. Ferritin is widely distributed in all cells whereas hemosiderin is deposited primarily in the liver, spleen, and bone marrow. Serum ferritin < 10 or 12 microgm/ml indicated depletion of iron reserves.

To summarize, iron metabolism uptake occurs primarily in the duodenum. Thus, always watch out for patients with duodenal disease, for example, short gut, celiac, IBD, etc. Also, transferrin transports iron, and ferritin represents your stores

Rahul, a frequently asked question on the Peds CCM boards is about oxygen content and oxygen delivery. Can you shed some light on this with the respect to this case?

We have discussed this in detail in episode 33: Oxygen Content and Oxygen Delivery. Definitely worth a listen.

• As a review, the formula for O2 content is 1.34 X Hgb X O2 saturation +0.003X PaO2.
• If we assume PaO2 is 100 and O2 saturation is 100%, our O2 content for this patient = (1.34 X 1.5 X 1) +0.003 X 100 = 2.01+ 0.3 = 2.31 ml O2/dL
• If patient is transfused to a Hgb of 6, O2 content = 8.04+0.3 = 8.34
• Conversely, If patient is given 100% O2, the PaO2 = 713, The O2 content of above patient is 2.10+ 0.003 X 713 =4.239,
• So we either have to increase the Hgb or if unable to transfuse, increase PaO2 as shown in the calculations above.
• What gives us more bang for our buck is increasing Hgb concentration — this will in turn increase our O2 content.

I think it is great to practice calculations of the O2 content, anytime they are faced with a patient with low Hgb or a patient for whom blood transfusion on is indicated. I would also recommend folks read the TAXI guidelines for pRBC transfusion in the Peds ICU. (PCCM)

If you had to work up this patient with severe anemia, what would be your diagnostic approach?

• CBC with differential, reticulocyte count, peripheral smear
• CMP, urine analysis, stool guaiac
• Infectious workup should include RVP, Parvovirus
• Hgb electrophoresis
• Serum lead level
• If the patient has pancytopenia despite PRBC replacement, she would need workup for bone marrow arrest/failure process - such as peripheral flow, BMA/Bx
• No single test or combination of tests reliably documents iron deficiency in all clinical situations. I would also add that review of the peripheral smear is an essential part of any anemia evaluation. Even if the patient's RBC indices are normal, a review of the blood smear may reveal abnormal cells that can help identify the cause of anemia.
• If our history, physical, and diagnostic investigation led us to severe most likely due to iron deficiency anemia as our diagnosis what would be your general management of framework?
• When a patient is admitted to the PICU with severe anemia the usual principles of good PICU care in terms of monitoring, management of airway, and hemodynamics should precede the workup and therapy. I also make sure the patient has at least two good peripheral IVs of which one can be used to send the required labs. We work very closely with our hematology colleagues and the nutritionist.
• When Hgb is < 5gm%, the patient should be administered a sequential small aliquot 2.5mL/kg very slowly (typically over 3-4 hours). Frequent rechecking of hgb/hct is required as well as close monitoring for any signs of heart failure. Once Hgb is > =5gm%, we can give 5ml/kg over 2-3 hours and wait at least 2 hours in between aliquots.
• Absolutely, Rahul, Iron supplementation should also be started at around 3mg/kg/dose BID.
• Nutritionists recommended limiting milk intake and encouraging iron-containing foods and eating a healthy toddler diet. iron should not be taken with Calcium but Vitamin C, which promotes its absorption.
• Social work referral to get family the necessary support may be needed. Especially if there is a concern for lead in the home.

It is also essential to involve the Pediatric Hematology team for appropriate workup, management and follow-up!

This concludes our episode on acute anemia in the PICU. We hope you found value in our short, case-based podcast. We welcome you to share your feedback, subscribe & place a review on our podcast! Please visit our website picudoconcall.org which showcases our episodes as well as our Doc on Call management cards. If you are interested in learning more regarding acute severe anemia please refer to Fuhrman & Zimmerman - Textbook of Pediatric Critical Care Chapter 91. Transfusion Medicine. PICU Doc on Call is co-hosted by myself Dr. Pradip Kamat and Dr. Rahul Damania. Stay tuned for our next episode! Thank you!

• Cummings BM, Shailam R, Rosales AM, Huang MS, Nardi V. Case 37-2019: A 20-Month-Old Boy with Severe Anemia. N Engl J Med. 2019 Nov 28;381(22):2158-2167. doi: 10.1056/NEJMcpc1904048. PMID: 31774963
• Mattiello V, Schmugge M, Hengartner H, von der Weid N, Renella R; SPOG Pediatric Hematology Working Group. Diagnosis and management of iron deficiency in children with or without anemia: consensus recommendations of the SPOG Pediatric Hematology Working Group. Eur J Pediatr. 2020 Apr;179(4):527-545. doi: 10.1007/s00431-020-03597-5. Epub 2020 Feb 4. PMID: 32020331.
• Powers JM, McCavit TL, Buchanan GR. Management of iron deficiency anemia: a survey of pediatric hematology/oncology specialists. Pediatr Blood Cancer. 2015 May;62(5):842-6. doi: 10.1002/pbc.25433. Epub 2015 Feb 7. PMID: 25663613; PMCID: PMC4376588.
• Fuhrman & Zimmerman - Textbook of Pediatric Critical Care Chapter 91. Transfusion Medicine.

Welcome to PICU Doc On Call, A Podcast Dedicated to Current and Aspiring Intensivists.

I'm Pradip Kamat and I'm Rahul Damania. We are coming to you from Children's Healthcare of Atlanta - Emory University School of Medicine.

Welcome to our episode, which is Part 2 of our acute severe asthma management. Today we discuss invasive mechanical ventilation of the acute asthmatic.

A patient with a history of asthma presents to the PICU with decreased air entry. Somnolence. Hypercarbia and drooling. The patient is hypoxemic and has see-saw breathing.

Rahul: Let’s dive right into this. What are the indications for intubating a child with acute severe asthma?

Absolute indications include:

• Altered mental status which may be preceded by obtundation, agitation
• Cardiac and respiratory arrest

Relative indications decided on a case by case basis:

Progressive exhaustion-despite, despite maximal therapy. Profound hypoxemia refractory to supplemental oxygen administration, and respiratory failure.

The decision to intubate should not be solely determined based on blood gas results.

Pradip, can you shed light on how we prepare for the intubation of the patient with acute severe asthma?

Rahul, first and foremost- we take the intubation of an asthmatic very seriously. In fact we try the whole “kitchen sink” to avoid intubation. But there will be times when we have to intubate especially for the indications you mentioned above.

The intubation will worsen the patient’s bronchospasm, put the patient at risk for barotrauma as well as cardiovascular collapse.

Preparation is the key- A team huddle and mapping prior to proceeding to intubate is the key. Every person in the room should have clear roles and responsibilities. Scenarios of what to do if “X” happens should be clearly laid out to the team by the team leader (preferably the attending or a senior fellow). The senior-most experienced person should manage the airway. At least two dedicated RTs to provide bag-mask ventilation as well as manage the ventilator are required. Nursing roles to push meds, chart the vitals and other activities as well a role for the resource nurses to help in case of cardiac arrest should be clearly laid out. Additionally, facilities that have access to isoflurane should have that ready to go. We typically give a heads up to our ECMO team to be on stand-by.

Prior to Intubation: Have central access or multiple large-bore PIVs if possible. Keep crystalloids boluses ready for hypotension. We also have peri-arrest epinephrine as well as an epinephrine infusion ready for any hypotension, bradycardia, or cardiac arrest. For intubation, we typically use Ketamine, fentanyl, and rocuronium (some centers may use succinylcholine). We use cuffed endotracheal tube. We don't bag-mask at fast rates but rather wait for a full expiration prior to the next breath being delivered. These patients require slow respiratory rates with very prolonged expiratory times to allow for adequate gas exchange and lung volumes. A helpful technique is to use a stethoscope to auscultate at the lower neck for the disappearance of expiratory wheezes prior to starting the next inspiration. We sometimes place a nasogastric tube to prevent gastric distension.

If there is hypoxemia, hypotension, not improving with fluids, ventilator manipulation, - A consideration for tension pneumothorax should be given especially if there is asymmetric chest rise. Bedside POCUS can be used to make a diagnosis.

Intubation of an asthmatic is a high-risk procedure and requires a team approach, proactiveness, and anticipation. Intubation should be approached cautiously in patients with severe acute asthma exacerbations because manipulation of the airway can cause laryngospasm and worsening bronchoconstriction.

Rahul, what are some of the principles we should all follow prior to initiation of mechanical ventilation in an asthmatic after intubation?

It is important to note that most complications of intubating an asthmatic happen in the immediate post-intubation period. Hypoxemia, hypotension, tension PTX/air leaks as well as cardiac arrest can happen immediately upon initiation of positive pressure ventilation. An important cause of hypotension is hyperinflation and decreased venous return. So slowing down manual bag-mask ventilation of even disconnecting the bag and allowing for a brief period of apnea while applying manual pressure to the rib cage may help decrease hyperinflation. Hypotension should respond to fluid boluses and decrease manual bagging.

Dynamic Hyperinflation: Severe airflow obstruction results in incomplete exhalation resulting in dynamic hyperinflation (DHI). Progressive DHI leads to an end-expiratory lung volume reaching a new equilibrium that exceeds the functional residual capacity. In the early stages of asthma, the increased lung volume increases pulmonary elastic recoil pressure thus increasing pulmonary expiratory flow and expanding small airways thus decreasing expiratory resistance. Thus lung volume will reach a point where the entire tidal volume can be expired during the available exhalation time. However, this process becomes maladaptive in severe asthmatic such that hyperinflation required to maintain normocapnia cannot be maintained as it would expand total lung capacity

Positive pressure ventilation worsens DHI especially if ventilator settings are aimed at normocapnia. This will also increase the risk of hypotension and pneumothorax. The initial rule of thumb would be to use low Tidal volumes and low respiratory rates to allow for controlled hypoventilation and permissive hypercapnia.

Pradip, with the above is mind what are your initial ventilator settings?

We typically use pressure regulated volume control (PRVC) to set a TV of 8-12m//kg (reduce to generate a plateau pressure of ~30 cm H2O), respiratory rate of 6-10/minute time of 1-1.5 seconds, which allows for an expiratory time of 4-9seconds. in the patient with NMB, we set PEEP initially at zero. Peak pressures in the 50s are expected initially due to airflow obstruction but plateau pressures of 30 or below should be reassuring.

An inspiratory hold will determine the plateau pressure whereas an expiratory hold will give us information about the auto-PEEP. The applied PEEP should be set below the auto peep in a spontaneously breathing patient in order to decrease the trigger work.

Another ventilation strategy, which is comfortable for the patient is the use of pressure support ventilation with PEEP. PEEP narrows the gap between proximal and distal airway pressures during the hyperinflated obstructed state. Pressure support facilitates inspiration while decreasing the work of breathing. The patient determines the time, respiratory rate, and depth. of each breath.

In summary: RR 10-12/min; Tidal volume: 6 to 8 mL/kg; set the sensitivity for triggering a ventilator-assisted breath at -2. Allow increased expiratory time by decreasing the I:E ratio (1:3 or 1:4 up to 1:5).

Rahul, What are the variables you closely monitor during the ventilation of a child with acute severe asthma?

Frequent auscultation of the patients’s chest at the bedside, observing vital signs including hemodynamics is helpful. Watching flow volume, PV loops gives useful information about patient’s condition. Monitoring peak-to-plateau pressure differences tell us about improvement in airway resistance. in response to therapy.

Following the capnography waveform can give us information about lung emptying.

Rahul, what are the sedation-analgesia-neuromuscular blockade therapies used in the child intubated for Near-fatal asthma.

We prefer to use ketamine with low-dose benzodiazepines such as midazolam. We initially chemically paralyze the patient using rocuronium to abolish spontaneous respirations which can add to the DHI and hypercapnia. If we use isoflurane gas we D/C all other sedatives a, analgesics and NMBs. The use of steroids along with NMB can add to the neuromuscular weakness in such critically ill patients. Consideration for early stooping of NMB should be given.

Pradip, can you talk about the use of isoflurane in a child with NEAR fatal asthma?

Inhalational anesthetics such as isoflurane can be delivered by means of an anesthesia machine that feeds into the low-pressure gas port of a conventional mechanical ventilator or via a dedicated anesthesia ventilator with its own vaporizer. Isoflurane is preferred over others has it has no negative inotropic effects although it can cause hypotension due to peripheral vasodilatation. Typical concentration used is 0.5-2%. Appropriate scavenging of the waste gas is important so as to not expose the staff. The exact mechanism of action remains unclear. although studies indicate that inhaled anesthetics reduce vagal tone and reflexes as well as alter circulating catecholamines and ß receptor sensitivity. Inhaled anesthetics may also have a direct relaxation effect on the airway smooth muscle. Potential neurotoxicity especially in the very young is a concern and withdrawal with prolonged use has been seen. Improvement is seen as early as within 30 minutes of initiation of isoflurane and typically by 12 hours. Some refractory cases may need isoflurane for 2-3 days. Inhaled anesthetics should not be used in patients at risk for malignant hyperthermia.

To summarize, isoflurane is an inhaled anesthetic that can be employed in near-fatal asthma by creating smooth muscle relaxation in the respiratory tree. As isoflurane is a potent anesthetic that has a smooth muscle relaxation effect, we must be mindful of the 

Rahul, what is the role of ECMO in NEAR Fatal asthma?

Some refractory cases of NFA that do not respond to isoflurane or have severe air leaks, cardiac arrest may be candidates for ECMO. Mechanical ventilation of patients with NFA is challenging, and high ventilator settings may cause lung injury and hemodynamic instability secondary to barotrauma and dynamic hyperinflation.

A more recent ELSO registry query (Crit Care. 2017;21(1):297.) for ECMO support for adults with asthma found successful decannulation in 86.7% and survival to discharge of 83.5%, with nonsurvivors being older in age, with lower pH and higher PEEP, higher post-ECMO oxygen requirement, and post ECMO driving pressures significantly associated with in-hospital mortality. The use of full-flow VV ECMO for refractory asthma in children is not uncommon and has been described previously as case reports and small studies. An ELSO registry report (published in CCM 2009) on ECMO use in children with SA reported a median time of ECMO support of 94 hours and was associated with 94% survival. Nine percent of the children placed on ECMO had a cardiorespiratory arrest before ECMO initiation. The presence of cardiorespiratory arrest or neurological injury was not associated with higher mortality.

A more recent study of children with rhinovirus (Pediatric pulmonology 2020) reported a survival rate of 100%.

Pradip, as these patients have hypoventilation due to obstruction, what are some of the cutting-edge therapies recently highlighted in the literature?

ECCO2R (or AVCCO2R-requires double lumen cannula) is a more recent strategy and is designed to remove CO2, but, unlike ECMO, does not provide significant oxygenation. Essentially, ECCO2R consists of a drainage cannula placed in a large central vein, a pump, a membrane lung, and a return cannula, or a double lumen VV cannula. Blood is pumped through the membrane and CO2 is removed by diffusion. In contrast to ECMO, where the need for oxygenation requires high blood flow rates, ECCO2R allows much lower blood flow rates. ECCO2R does not provide for oxygenation which ultimately most NFA patients require due to viral or bacterial infection, as well as doesn't provide hemodynamic support as ECMO would. There are no randomized controlled trials or large studies to compare the outcomes of ECMO versus ECCO2R in children with asthma to assess the superiority or benefit of one over the other.

In Chapter 50 in Furhman, Zimmerman’s textbook of Pediatric Critical Care, Dr. Steve Shein, and colleagues highlight that the use of extracorporeal life support (ECLS) has been reported in the management of the very few patients with near-fatal asthma who continue to exhibit a profound degree of clinical instability despite maximal therapy. Moreover, only 4% of patients in the Extracorporeal Life Support Organization registry have had runs for near-fatal Asthma. The survival rate for persons with near-fatal asthma necessitating ECLS is approximately 81%, which is remarkable considering that the vast majority of these patients were extraordinarily sick and had failed to respond to very aggressive treatment.

To Summarize:

1. Intubation of an asthmatic is a high-risk procedure and requires a team approach, proactiveness, and anticipation.
2. Ventilator strategies include allowing time for expiration by modulating the I:E ratio and decreasing the RR and TV.
3. Isoflurane & ECMO are last-ditch efforts in near-fatal asthma and should be performed in quaternary care facilities.

• References:
• Medar SS, Peek GJ, Rastogi D. Extracorporeal and advanced therapies for progressive refractory near-fatal acute severe asthma in children. Pediatr Pulmonol. 2020 Jun;55(6):1311-1319. doi: 10.1002/ppul.24751. Epub 2020 Mar 30. PMID: 32227683.
• Werner HA. Status asthmaticus in children: a review. Chest. 2001 Jun;119(6):1913-29. doi: 10.1378/chest.119.6.1913. PMID: 11399724.
• Demoule A, Brochard L, Dres M, Heunks L, Jubran A, Laghi F, Mekontso-Dessap A, Nava S, Ouanes-Besbes L, Peñuelas O, Piquilloud L, Vassilakopoulos T, Mancebo J. How to ventilate obstructive and asthmatic patients. Intensive Care Med. 2020 Dec;46(12):2436-2449. doi: 10.1007/s00134-020-06291-0. Epub 2020 Nov 9. PMID: 33169215; PMCID: PMC7652057.

More information can be found

• Fuhrman & Zimmerman - Textbook of Pediatric Critical Care Chapter 50 entitled Asthma

This concludes our episode on Near-Fatal Asthma. We hope you found value in our short, case-based podcast. We welcome you to share your feedback, subscribe & place a review on our podcast! Please visit our website picudoconcall.org which showcases our episodes as well as our Doc on Call management cards. PICU Doc on Call is co-hosted by myself Dr. Pradip Kamat and Dr. Rahul Damania. Stay tuned for our next episode! Thank you!

Welcome to PICU Doc On Call, A Podcast Dedicated to Current and Aspiring Intensivists.

I'm Pradip Kamat and I'm Rahul Damania. We are coming to you from Children's Healthcare of Atlanta - Emory University School of Medicine.

Welcome to our Episode a 15 mo F with respiratory distress and runny nose.

Here's the case:

A 15 mo F presents to the ED with cough, runny nose, and increased work of breathing. Her mother states that the patient has had these symptoms for the past three days, however, the work of breathing progressed. The patient has had 2 fevers during this course, with the highest 101F. She says that her 3 yo cousin who she visited for the holidays had similar symptoms. Mother notes decreased PO and wet diapers. The patient presented to the ED with the following vital signs: T 38.5C, HR 155, BP 70/48 (MAP 50), RR 48, 92% on RA. The patient on the exam was noted to be tachypneic with abdominal retractions, grunting, and nasal flaring. The patient was nasally suctioned and initiated on 12 L 40% of HFNC. The patient was then transferred to the PICU for further management.

To summarize key elements from this case, this patient has:

• Increased work of breathing indicates respiratory distress.
• She has a prodrome of symptoms that worsened prior to presentation
• And a sick contact.
• All of which brings up a concern for acute respiratory failure requiring non-invasive positive pressure ventilation in the form of HFNC.
• Let's transition into some history and physical exam components of this case?

1. What are key history features in this child who presents with respiratory distress & URI sx?

• Usually, children under the age of two with bronchiolitis will present with cough, respiratory distress, and crackles on lung exam.
• The crackles indicate atelectatic alveoli that are filled with fluid which occurs due to inflammatory processes in the lung triggered by respiratory viruses.
• Respiratory distress, increased work of breathing, respiratory rate, and oxygenation all can change rapidly with crying, coughing, and agitation.

1. Are there some red-flag symptoms or physical exam components in a child with acute respiratory distress which you could highlight?

• That is a great question. We really want to highlight the distinction between respiratory distress and respiratory failure.
• Children with respiratory failure in our case may have issues with oxygenation or ventilation as well as increased work of breathing that necessitates higher levels of respiratory support like HFNC.
• In a 2003 Journal of Pediatrics study, infants who were most severely affected with bronchiolitis were born prematurely, <12 weeks of age, or who have underlying cardiopulmonary disease or immunodeficiency. These children are at risk for apnea and respiratory failure which may require escalation to mechanical ventilation.
• Finally, Infants with bronchiolitis may have difficulty maintaining adequate hydration because of increased fluid needs and metabolic demand. Remember these children will have increased insensible losses due to fever and tachypnea, as well as decreased oral intake related to their systemic illness.

To continue with our case, the patient's labs were consistent with:

• Mild hyper NA 149
• All other electrolytes were within normal limits.
• The patient had a respiratory viral panel which was positive for Rhino/Entero and RSV. Her COVID PCR was negative.
• A CXR was performed and showed alveolar airspace disease consistent with I would like to highlight an important point, with the exception of otitis media, a secondary bacterial infection is uncommon among infants and young children with bronchiolitis. In a nine-year prospective study of 565 children (<3 yo) hospitalized with documented RSV infection published in the Journal of Pediatrics, subsequent bacterial pneumonia was present in only 0.9 percent of these. 

Yes, Rahul, that is a great point. The risk of secondary bacterial pneumonia is increased among children who require admission to the intensive care unit, particularly those who require intubation.

Ok to summarize, we have:

• A 15 mo F who presented with URI symptoms and respiratory distress was admitted to the PICU with Rhino/Entero, & RSV+ bronchiolitis with concurrent community-acquired PNA. We would like to focus the rest of this podcast on discussing the use of HFNC, its principles of action, and the data surrounding its use in the PICU.
• Before we get into this topic, let’s start with a short multiple-choice question:
• A 13 mo ex-34 week infant presents to the ED with increased work of breathing, tachypnea, and hyperthermia. The patient is on a home 1/8 L nasal cannula and has no echocardiographic evidence of pulmonary hypertension on prior follow-up. HFNC is initiated at 1.5 L per kg. Which of the following responses best describes the MOA of HFNC?
• A. Increased nasopharyngeal dead space
• B. Decreased humidification of gas
• C. Negative distending pressure
• D. Reduction in upper airway resistance.

The correct answer here is D. Reduction in upper airway resistance. By providing gas flows that match or exceed spontaneous inspiratory flow rates, HFNC minimizes inspiratory resistance across the nasopharynx. The resultant reduction in work of breathing has been demonstrated in studies in neonates and infants by measuring diaphragmatic electrical activity and respiratory plethysmography.

Rahul, what does the literature say regarding positive distending pressure with the use of HFNC?

The data is definitely mixed but leans towards not HFNC not providing clinically significant PEEP. In a study of infants with bronchiolitis published in 2013 in Intensive Care Medicine, a flow rate of 2 L/kg per minute resulted in mean pharyngeal pressures >4 cm H2O as measured by transesophageal probes and improved breathing.

Subsequent studies have documented a difference in increased pharyngeal pressure during HFNC when the mouth is closed compared with when it is open. So if you are going to use HFNC to promote distending pressure concurrent use of a pacifier may be helpful in achieving the full benefit of HFNC.

To summarize key principles of how HFNC let’s review some respiratory physiology:

1. Rahul, what is Dead Space?
2. Dead space is the volume of air that is inhaled that does not take part in the gas exchange, because it either remains in the conducting airways or reaches alveoli that are not perfused or poorly perfused.
3. This means that not all the air in each breath is available for the exchange of oxygen and carbon dioxide.
4. HFNC creates a washout of nasopharyngeal dead space and creates a richly oxygenated reservoir of air. This reserve in the upper airway is what the patient draws from with each breath, minimizing the entrainment of room air and also decreasing the amount of CO2 in the anatomic zone of the respiratory tree.
5. What are key concepts related to Airway Resistance in Pulmonary Dynamics?
6. West Physiology defines airway resistance as the change in transpulmonary pressure needed to produce a unit flow of gas through the airways of the lung.
7. More simply put, it is the pressure difference between the mouth and alveoli of the lung, divided by airflow. Bronchiolitis creates a decrease in airflow thus increasing airway resistance. As HFNC increases flow, i.e. the denominator of our equation, It reduces resistance in the airway tree.
8. By providing gas flows that match or exceed spontaneous inspiratory flow rates, HFNC minimizes inspiratory resistance across the nasopharynx.
9. In a study published in 2009 in Respiratory Care, it was hypothesized that the resultant reduction in airway resistance which high flow provides the decrease in WOB. This was especially studied by measuring infant diaphragmatic electrical activity.

Rahul, what is the last major mechanism of a high-flow nasal cannula?

1. HFNC reduces the energy expenditure required by the body to condition air. It does this by delivering heated and humidified gas. This also promotes less bronchospasm which would occur with the delivery of cold air.

Pradip, in your experience, what are disease states we see in the PICU that are most amenable to HFNC?

1. Many causes of respiratory distress can respond to the use of HFNC. In this state, I would recommend that providers start HFNC, and then ensure close monitoring and frequent reassessment of these patients to ensure response as well as the need to escalate respiratory support.
2. Conditions for which HFNC can be used to include conditions such as Asthma, Tracheomalacia, Apneic Oxygenation, and Bronchiolitis.

HFNC should not delay advanced airway management in a patient deemed to require immediate endotracheal intubation. This may include patients with acutely impaired mental status, risk of aspiration, or other needs for airway protection

Yes, thank you for highlighting this, HFNC should be avoided in patients who have facial anomalies that preclude appropriate nasal cannula fit (like choanal atresia). Children who have active vomiting, bowel obstruction, or even sensory issues which may create Agitation may be some relative contraindications for HFNC. Lastly, I would also not delay escalation in invasive respiratory support especially if the patient does not have a significant change in hemodynamic (such as a decrease in HR) or oxygenation parameters after about 4 hrs on HFNC therapy.

Finally, HFNC oxygen therapy is considered an aerosol-generating procedure. Thus, appropriate infection control precautions are required when it is being administered to patients with unknown or positive coronavirus disease 2019.

This concludes our episode on bronchiolitis and HFNC. We hope you found value in our short, case-based podcast. We welcome you to share your feedback, subscribe & place a review on our podcast! Please visit our website picudoconcall.org which showcases our episodes as well as our Doc on Call management cards. PICU Doc on Call is co-hosted by myself Dr. Pradip Kamat and Dr. Rahul Damania. Stay tuned for our next episode! Thank you!

Welcome to PICU Doc On Call, A Podcast Dedicated to Current and Aspiring Intensivists.

I'm Pradip Kamat and I'm Rahul Damania. We are coming to you from Children's Healthcare of Atlanta - Emory University School of Medicine.

Welcome to our discussion today on airway clearance in the critically-ill patient in the PICU. We will focus on the use of pharmacological as well as non-pharmacological techniques in critically ill children admitted to the ICU. This episode will be a general overview as specific clinical scenarios such as NM disease may warrant specific therapeutics.

Let’s get started with the case:

We have an 8-month old ex-34 week premie intubated for acute respiratory failure secondary to RSV bronchiolitis. The patient is on a conventional mechanical ventilator receiving a TV of 6ml/kg, rate of 20, PEEP 6, 40% FiO2 inspiratory time of 0.7

CXR shows a pattern suggestive of viral pneumonia with minimal hyperinflation and atelectasis of the right middle lobe. The patient has excessive secretions when the suction catheter is assessed. The patient is hemodynamically stable and is on feeds via a NG tube.

Rahul, Can you comment on how a child clears his/her pulmonary secretions normally when not ill?

That's an excellent question. Normally some baseline secretions are produced by all humans. Normal bronchial secretions are made up of contributions from mucus-secreting (goblet)cells as well as cells secreting serous fluid. The ciliary epithelium made of columnar cells line the entire tracheobronchial tree up to the alveolar ducts. This ciliary epithelium provides the coordinated rhythmic force that propels the overlying “mucus blanket” towards the central airways and upper respiratory tract.

Primary mechanisms of tracheobronchial clearance of these secretions consist of (1) The mucociliary (MC) escalator in the smaller airways and (2) Cough in central and larger airways. The co-ordinating activity of the beating cilia and their interaction with the overlying viscoelastic layer of mucus makes up the mucociliary escalator. The MC escalator helps remove both healthy and pathologic secretions from the airways as well as the removal of inhaled particles. This MC transport can be affected by mycoplasma, influenza and other viruses as well as exposure to toxins (cigarette smoke, vaping) as well as in CF, asthma, COPD, and ciliary dyskinesia just to name a few.

Once the secretions are in large or central airways they are coughed out or swallowed.

Let’s transition and talk a little on how one generates an effective cough:

1. For an effective cough one needs firstly to take a sufficiently deep breath in.
2. The glottis needs to close briefly to allow an increase in intrathoracic pressure
3. This is followed by expulsive glottic opening together with abdominal contraction, which results in air being forcibly expelled.

 Individuals with neuromuscular disease, bulbar insufficiency, obtunded patients, those on MV with chemical neuromuscular blockade, severe skeletal deformity may have decreased cough expiratory airflow. Reduced ability to cough results in secretion retention, mucus plugging, atelectasis and pre-disposition to infection even if the MC escalator function is normal.

Q2. Pradip can you tell us about atelectasis

This is a great question. The term atelectasis means “imperfect expansion” and indicates reversible loss of aerated lung with otherwise normal lung parenchyma.

Thats a nice concise definition, so if atelectasis reperesents imperfect expansion, what are mechanisms which keep our lungs open?

There are three major mechanisms:

1. Pulmonary Surfactant 

2. Collateral Ventilation 

3. Lung & Chest Wall Balance

Let’s go into each of these in more detail:

A pulmonary surfactant that covers the large alveolar surface is composed of phospholipids (mostly phosphatidylcholine), neutral lipids, and surfactant-specific apoproteins (termed surfactant proteins A , B , C , and D ). By reducing alveolar surface tension, pulmonary surfactant stabilizes the alveoli and prevents alveolar collapse.

There is a collateral ventilating mechanism (intra-alveolar pores & bronchiole-alveolar communications) that prevents alveolar collapse. Inter-alveolar pores by which alveoli are connected to each other via are called the Pores of Kohn. There also exist connections between distal bronchioles and neighboring alveoli called channels of Lambert. These structures can aerate hundreds of alveoli adjacent to a bronchiole preventing the collapse of one in case there is resorption of the air from that alveolus. Resorption occurs when an airway becomes occluded, the air is trapped in lung units ventilated by that airway, and the trapped gases are absorbed by the blood perfusing that part of the lung. Oxygen is absorbed faster than nitrogen from the alveolus into the blood resulting in collapsed lungs postoperatively especially if high O2 concentrations are used.

The balance between Inward recoil of lung tissue and outward expansion of the chest wall (myo-elastic element: smooth muscle fibers interwoven with elastic fibers in distal airways and alveolar sacs) is is opposed by an outward recoil of the chest wall. An exact balance of these forces is essentially FRC at end of exhalAnion. An imbalance of these forces which keep lungs open can predispose to atelectasis. An example of chest wall inability to provide outward recoil is the reason a patient with pneumothorax develops lung collapse

Awesome, let’s quickly summarize, atelectasis represents airway collapse, in order to keep alveoli open, our body’s mechanisms include pulmonary surfactant, collateral ventilation, and FRC.

Let's transition and talk about the various types of atelectasis and the diseases we encounter in the PICU which can create an imperfect expansion of the alveoli?

 Surfactant deficiency or dysfunction: Infant with surfactant deficiency or neonate with prematurity.

• Children with ARDS or Near drowning, as well as hydrocarbon ingestion, can all have surfactant dysfunction which can lead to atelectasis.

Resorption atelectasis (most common): high FIO2 concentration, intra-bronchial obstruction due to inflammation, infection, mucus plugs, and foreign body.

Another mechanism is an extrinsic compression of the small airways. c) Compression of normal lung tissue: Pleural effusion, chylothorax, cardiac enlargement or tumors, Extra bronchial compression: vascular ring, lobar emphysema or by lymph nodes

All in all, when you have atelectasis you run the risk of having decreased lung compliance, impairment of oxygenation, increased pulmonary vascular resistance, and development of lung injury.

In asthma and bronchiolitis, the right middle lobe and the lingula segment are the most common localization of the atelectasis and this is called the middle lobe syndrome. It is possible that hilar Lymph node enlargement due to viral infection and subsequent compression of middle lobe bronchus may be a cause of its preferred location.

Pradip, what are the clinical consequences of atelectasis?

This is a great question, and like many processes, clinical consequences Depend on the patient’s age, rate of formation, extent and of course the underlying cause of the atelectasis, however, let’s talk in general:

Going back to our case, a critically -ill patient such as an intubated infant with bronchiolitis on moderate ventilator settings, development of atelectasis can lead to rapid deterioration. This is contrasted, In a clinically stable child admittedly postoperatively for a non-pulmonary reason who is on RA, a significant atelectasis may go completely unnoticed and detected only on a chest radiograph.

5) Rahul how is atelectasis treated in the PICU patient admitted for acute illness (i.e without chronic neuromuscular condition)?

One of the primary approaches to tackle atelectasis involves Airway clearance or chest physiotherapy or pulmonary toilet (an outdated term) refers to a spectrum of physical and mechanical interventions aimed at interacting therapeutically with acute and chronic respiratory disorders.

Over the next few minutes we will cover some primary approaches, ranging from suctioning to manual CPT. To start,

One of the simplest modality is suctioning. In infants and toddlers with small ETT tubes transport of secretions may be hampered by the size of the ETT. Sedation/NMB use may diminish the cough reflex. So the suction acts like a cough substitute. Type of catheter, its size, depth of insertion are all standardized and moist centers gave their own policies/procedures. Pre-oxygenation prior to suctioning or mechanical hyperinflation post suctioning can also be used.

Another useful technique is postural drainage which is easily achieved in intubated patients: Gravity helps mobilize and transport secretions. If the atelectasis is in the right lung, then placing the patient in a left lateral decubitus position so that the right side is up will help open the right lung. This can be helped with chest percussion (RTs cupped hands or small cushioned mask or mechanical percussion devices), vibration, and even compression. I use this technique in small infants, and toddlers especially if they are intubated.

That’s great and I should add that it is important to have a sedation management plan or algorithm adequately balanced to the patient’s needs during these interventions.

Additionally, gentle bagging-(sometimes with saline lavage)-leading to an increase in lung volume and manual hyperinflation may help open a lung segment up. We need to be careful not to de-recruit the lung by frequent disconnection of the ventilator to do bag-lavage.

Pradip what are some of the mechanical devices you use in the PICU to help conventional chest physiotherapy?

This is a great question and to be honest, each type of chest PT has its risks and benefits, lets's review the most common. We will talk about:

1. IS
2. IPV
3. Mechanical In Ex (Cough Assist)
4. Flutter/Acapella
5. Vest therapy

Incentive spirometry (IS): The basis of incentive spirometry involves having the patient take a sustained, maximal inspiration (SMI). An SMI is a slow, deep inspiration from the FRC up to the total lung capacity (TLC) followed by ≥5 seconds breath hold. An incentive spirometer is a medical device that facilitates SMI. The device gives the individual visual feedback regarding flow and volume and also prevent and reverse atelectasis when used appropriately and regularly.

Patients who are at risk for developing atelectasis due to immobility especially post-operatively may be helped by the use of incentive spirometer. It can help improve lung volume, optimize oxygenation and maintain inspiratory muscle strength. One study by Fahd et al (Journal of Pediatric Hematology/Oncology) reported that mandatory IS for sickle cell disease patients admitted without respiratory complaints reduces transfusions and acute chest syndrome, particularly for those presenting with back pain.

IPV: Intrapulmonary percussive ventilator: The IPV device delivers high-flow jets of air to the airways by a pneumatic flow interrupter at a rate of 100 to 300 cycles/min through a mouthpiece. The patient controls variables such as inspiratory time, peak pressure, and delivery rates. IPV has been shown to be beneficial for secretion clearance (particularly for cystic fibrosis patients) and improvement in atelectasis in intubated patients.

Mechanical insufflator-exsufflator: CoughAssist is a portable, electric mechanical insufflation-exsufflation device that attempts to simulate a cough by using a blower and valve to alternately apply a positive and then a negative pressure to a patient’s airway to assist the patient in clearing retained bronchopulmonary secretions.

Flutter and Acapella devices are small, handheld devices that provide positive expiratory pressure (PEP). Exhaling through the device creates oscillations in the airway, resulting in loosening of mucus.

Percussive vests: A high-frequency chest wall vibrating/oscillating vest device has been shown to mobilize secretions in patients with cystic fibrosis and is commonly used as an adjunct airway clearance device in children with a reduced ability to clear secretions due to neuromuscular abnormalities

Rahul can you comment on some pharmacological approaches in the PICU?

Saline: 0.9% saline enables clearance of secretions, especially in an intubated patient. 0.9% saline loosens secretions, lubricates the ETT, enhances cough as well as decreases viscosity of the secretions. Studies are mixed as to the benefit of using saline instillation prior to suctioning in intubated patients.

One pediatric RCT (Riddling DA et. al. Am J Crit Care 2003) in postoperative patients with congenital heart disease showed no benefit with regard to incidence of VAP or mucus plugging. They also found (similar to adult studies) a drop in SpO2 from baseline in the group that used saline.

Hypertonic Saline: Although shown to be beneficial in children with cystic fibrosis who are > 6 years of age, One study showed no benefit in children under 6 years of age.

In bronchiolitis HS is believed to help by decreasing airway edema and thinning of mucus to alleviate plugging via the osmotic effect of HS. Literature about 3% HS has been conflicting at best with some studies showing benefit with regards to the length of stay and symptom score and others showing no benefit.

A 2017 Cochrane database review published by Zhang et al reported that nebulised hypertonic saline may modestly reduce length of stay among infants hospitalised with acute bronchiolitis and improve clinical severity score. Treatment with nebulised hypertonic saline may also reduce the risk of hospitalisation among outpatients and emergency department patients. However, we assessed the quality of the evidence as low to moderate. Quality of evidence is moderate due to substantial clinical heterogeneity between studies and large multicenter trials are still warranted.

Yes, Pradip, actually — One PICU randomized study by Shein et al (2016) reported on 18 intubated patients (9 in each group)- receiving either hypertonic saline or 0.9%NS used 4 times a day for 7 days. They found no difference in any outcomes measures between the two group after adjustment for baseline differences in respiratory parameters.

So Pradip, I have heard of N-Acetylcysteine or Mucomyst used as a pharmacological — how does it work?

N-acetylcysteine (mucomyst) : It hydrolyzes the disulfide bonds of mucins and other proteins. The sodium salts of NAC may also disrupt DNA. Animal studies suggest there may be some benefit to the airway due to its antioxidant effect, its use in ARDS has not shown any benefit although in one study in pediatric burn patients, the combination NAC and heparin resulted in lower rates of reintubation, atelectasis, and mortality. (Desai MH et al. J burn care rehabilitation).

What about Dornase Alpha?

Dornase alfa: is a recombinant human DNAase, which degrades DNA of the neutrophils, which migrate to the airway in inflammatory conditions. DNA from neutrophils increases the viscosity of the sputum and mucus plugging in the airway. Dornase decreases mucus viscosity and helps its clearance from the airway.

A Cochrane database review from 2018 (Yang et al)reported improved lung function in patients with cystic fibrosis in trials lasting from one month to two years. There was a decrease in pulmonary exacerbations in trials of six months or longer. A meta-analysis from 2012 (Enriquez et al.) reported no benefit with respect to clinical scores in patients with bronchiolitis but longer duration of...

Welcome to PICU Doc On Call, A Podcast Dedicated to Current and Aspiring Intensivists.

I'm Pradip Kamat and I'm Rahul Damania. We are coming to you from Children's Healthcare of Atlanta - Emory University School of Medicine.

Welcome to our episode of a three-year-old girl presenting with a cough and difficulty breathing

Here's the case presented by Rahul:

A previously healthy 3-year-old girl presented to the OSH for difficulty breathing. She had a two-day h/o of cough (worse at night) and congestion but no fever. She has no h/o of emesis, h/o recent travel, or exposure to some/toxins. Initially, she received steroids, albuterol, and O2 but due to continued worsening of breathing and hypoxia-She was transferred to our PICU for initiation of High Flow Nasal Cannula. She has no allergies and her immunizations are up to date. There is a strong family history of asthma and atopic dermatitis. The mother also noted that the patient has h/o of coughing episodes while playing outside with her siblings.

Initial Vitals: Temp 37.9, HR 100, BP 97/73, respiratory rate 49, SPO2 98% on 15LPM HFNC at 60% FIO2 , weight 17.5kg

On PE: The child is awake, playful. she is tachycardic with no murmur. She has subcostal, intercostal, supra-sternal retractions. There is bilateral symmetric chest expansion. The air entry is decreased with diffuse (B) wheeze. There is atopic dermatitis in the flexor areas of the elbows/knees. The rest of the physical examination was normal. No hepatosplenomegaly.

Viral panel: positive for HMP, SARS COV-2 negative

CXR: Atelectasis superimposed upon viral pneumonitis versus multifocal bronchopneumonia. No evidence of parapneumonic effusion or air leak.

CBC and BMP are normal.

To summarize key elements from this case, this 3-year-old girl has:

• Cough and congestion
• Increased WOB and difficulty breathing
• Hypoxia
• No fever or rash
• No recent ingestions or exposure to tobacco smoke
• All of which brings up a concern for a lower airway obstructive process most likely acute asthma

Let's transition into some history and physical exam components of this case?

Rahul, what are key history features in this child who presents with increased work of breathing?

• Cough and congestion
• Difficulty breathing
• No h/o suggestive of atopic dermatitis
• Increased WOB: retractions (subcostal, intercostal, suprasternal). Important to note there is no nasal flaring, head bobbing or grunting.
• Decreased AE
• Diffuse (B) wheezing. No subcutaneous emphysema on palpation of the chest or cervical region.
• Hypoxia needing oxygen
• Atopic dermatitis
• No crackles
• No hepatomegaly
• No altered mental status

Not all respiratory distress arises within the respiratory tract. Important physical examination to note in any infant or toddler with increased work of breathing is to palpate for hepatomegaly as well as carefully listen for bilateral inspiratory crackles. The presence of hepatomegaly or (B) crackles should raise concern for myocarditis or congestive heart failure. In Newborns with respiratory distress-always make a habit to feel femoral pulses. Acidosis, intracranial hemorrhage, foreign body, panic attacks can also present as respiratory distress.

To continue with our case, Pradip, the patient’s labs/diagnostic were consistent with:

• CBC, BMP were normal
• Respiratory viral panel positive for HMP virus, Negative for SARS-COV-2
• Chest radiograph: Atelectasis superimposed upon viral pneumonitis versus multifocal bronchopneumonia

OK, to summarize, we have: A 3-year-old with acute respiratory distress, wheezing, hypoxia after 2 days h/o of cough/congestion.

Rahul, let's start with a short multiple-choice question:

A 15-year-old teenager with know h/o asthma presents to the ED in severe respiratory distress, increased work of breathing, hypoxia, and diffuse wheezing. Of the following the presentation that would most likely require intubation in this teenager include-

• A) Inability to talk in complete sentences
• B) A blood gas that shows hypocapnia and mild respiratory alkalosis
• C) Presence of pulsus paradoxus
• D) Deteriorating mental status

Rahul, this is an excellent question. The correct answer here is D-Deteriorating mental status. While choice A-inability to talk in complete sentences as well as Choice C-presence of pulsus paradoxus in a patient with asthma correlate with severity of acute asthma, those choices are not indications for intubation. In early asthma -in a patient who is tachypneic and breathing hard the blood gas should have hypocapnia and a mild respiratory alkalosis. I would be more worried about a normal gas or a rising PCO2 in a patient with status asthmaticus.

So just for our listeners, indications for intubation and mechanical ventilation in a child with asthma should be based on clinical judgment and include: cardiac and respiratory arrest; severe hypoxia as well as rapid deterioration in the child’s mental status. Progressive exhaustion despite maximal therapy constitutes a relative indication for intubation on a case-by-case basis. The traditional rule that respiratory acidosis dictates intubation has become outdated.

Rahul, can you comment on the commonly used Clinical Respiratory Score (CRS) ?

The Clinical Respiratory Score (CRS) is a tool that was developed based on the National Asthma Education Program’s guidelines for the diagnosis and management of asthma. The CRS contains six equally weighted variables. It uses both objective and subjective criteria when evaluating a child with asthma to calculate a score. A CRS assessment requires a member of the care team to calculate a respiratory rate and record the room air oxygen saturation using a pulse oximeter. Auscultation of the lung fields, assessing the use of accessory muscles, mental status, and the child’s color also contribute to the CRS. Respiratory rate scores are differentiated by normal values for age. Each of the 6 categories are then categorized as mild (score = 0), moderate (score = 1), or severe distress (score = 2), and the total score is calculated from 0 to 12. The CRS is a reliable asthma severity scoring tool for pediatric patients presenting with an acute asthma exacerbation when utilized across care team members. (McLaughlin P. et al Journal of Asthma 2021).

Rahul also what are risk factors for severe acute asthma?

In a review by Werner H (Chest 2001; 119:1913-1929), risk factors for acute severe asthma were classified as medical factors include: Previous attack with severe, unexpected, rapid deterioration, respiratory failure, seizure or LOC, attacks precipitated by food.

Psychosocial factors: denial or failure to perceive the severity of illness associated depression or psychiatric disorders, non-compliance, dysfunctional family unit, inner-city residents

Ethnic factors: Nonwhite children.

A study by Grunwell et al (PCCM 2018) reports risk factors for PICU admission, with or without intubation. These include hospitalization in past 12months, a h/o pneumonia, chronic asthma severity on high dose ICS, a father with asthma, living in a region with a high burden of poverty, and being of black race.

In a more recent study, Grunwell J. et al ( J Allergy Clin Immunol Pract. 2021) reported on school Age children at risk for asthma exacerbation. The authors identified Four latent classes with differing demographic features, sensitization and Type-2 inflammatory markers, prior exacerbation severity and healthcare utilization, and lung function. They found that children with exacerbation-prone asthma were present in each latent class, but were most strongly represented in the latent classes with multiple sensitization and airflow limitation.

Rahul, can you explain the pathophysiology of acute asthma in terms of lung mechanics/gas exchange and cardiopulmonary interactions.

Acute asthma there is (1) Inflammation is triggered by a respiratory virus, cigarette smoke, air pollution, allergens, etc. IL-4, IL-5, IL-8, IL-13 primarily mediate inflammation, amplified by increased production of IgE by B cells. There is bronchospasm due to airway hyper-responsiveness, (3) Hyper-secretion of mucous plugging the airways (worsened by dehydration due to increased insensible

Airway obstruction leads to hyperinflation with resultant dead space ventilation. In fact, hyperinflation results in the conversion of lung segments from West zone 3 and two to West zone 1, thus increasing the V/Q mismatch. The Increase in respiratory rates in response to impaired ventilation results in dynamic hyperinflation and air trapping due to prolonged expiratory times.

Hyperinflation leads to the flattened diaphragm, which becomes inefficient for optimal respiratory function. Diaphragmatic fatigue is further exacerbated by acidosis, hypoxia, and dehydration.

VQ mismatching: Mucus plugging results in VQ mismatching due to atelectasis and intrapulmonary shunting

PVR is elevated due to increased lung volumes worsened by acidosis and hypoxia, adding to the VQ mismatch by decreasing blood flow(Q). The use of albuterol can further worsen VQ mismatch

In spontaneously breathing children with acute severe asthma, the pleural pressures can be as negative as -35cm H2O. The negative pleural pressure increases the (L) ventricular afterload, which favors the trans-capillary filtration of edema fluid into the airspaces resulting in a high risk for the development of pulmonary edema. Due to hypoxic pulmonary vasoconstriction, acidosis, and increased lung volume, the RV afterload is also increased.

Pulsus paradoxus is not specific for acute asthma. It can also be seen in cardiac tamponade, pulmonary embolus, and tension PTC. Fall in arterial systolic blood pressure with inspiration of > 10mm Hg (normal <10 mmHg). Hyperinflation leads to the expansion of vascular beds. During inspiration, the increased RV preload leads to the septum bowing into the LV thus decreasing LV preload and exacerbating the normal physiologic drop in BP with inspiration. LV preload may be further compromised by increased pulmonary vascular bed compliance and increased (L) ventricular afterload.

As you think about our case, what would be your differential in a patient with respiratory distress and/or wheezing?

• Foreign body (unilateral wheezing, h/o choking/coughing while eating or playing).
• Non-respiratory causes of respiratory distress include: CNS causes such as intracranial hemorrhage, airway obstruction, air leaks, acidosis, panic attacks, cardiac causes such as myocarditis, congestive heart failure. A detailed h/o and physical examination with pertinent imaging will help with the diagnosis in the above conditions.

Wheezing in asthmatics occurs due to turbulent airflow in the intrathoracic airways and bilateral. NOT all wheezing is Asthma! If wheezing is asymmetric caregivers should consider the diagnosis of a foreign body, PTX, mucous plugging, or atelectasis. The degree of wheezing correlates poorly with asthma severity. If there is no airflow, no wheezing will be heard and the patient may have a silent chest, which is an ominous sign. If a patient who previously had loud wheezing but has now worsening work of breathing, a reduction in wheezing may be a harbinger of respiratory failure.

• Pradip If you had to work up this patient with acute asthma what would be your diagnostic approach?
• Really don’t need a lot of investigations in the routine asthma admission to the PICU. Some may not even get a chest radiograph or a viral panel. CXR may be indicated if the clinical exam suggests an air leak (such as crepitus or asymmetry of chest rise).
• Frequent repeat assessments at the bedside after an intervention is the most important. Close observation of respiratory effort, pulse oximetry, and alertness serve as continuous clinical correlates of pulmonary gas exchange.
• Blood gas: Typically in early asthma we see hypocarbia with mild respiratory alkalosis. If the patient clinically worsens one may see initially a normal PCO2 followed by hypercarbia and hypoxemia. Routine blood gases are not indicated in acute severe asthma and one single abnormal blood gas should not be used as an indicator to decide the need for mechanical ventilation. As the patient worsens, one may see a mixed picture of respiratory acidosis with metabolic acidosis.
• Lactic acidosis: Serum lactates should not be routinely obtained in acute severe asthma as some degree of lactic acidosis is common in acute severe asthma due to the use of albuterol and adrenergic stimulation (Type B lactic acidosis(associated with adrenergic stimulation and occurring with normal oxygen delivery)) Meert K et al (PCCM 2012).
• Routine BMP/CBC is not required. Hypokalemia may be seen due to continuous albuterol use. If there is dehydration, BUN may be elevated. If a CBC is obtained- there may be leucocytosis from stress or use of steroids. rarely eosinophil count may be elevated in atopic patients.
• Rahul If our history, physical, and diagnostic investigation led us to acute severe asthma as our diagnosis what would be your general management of framework?
• Status asthmaticus is now replaced by the term acute severe asthma and is defined as an asthma attack unresponsive to repeated doses of beta-agonists and requiring hospital admission. Critical asthma is defined as acute severe asthma which requires intensive care admission. Near-Fatal asthma is defined as critical asthma that requires endotracheal tube intubation and mechanical ventilation. General principles of good PICU care should be followed. O2, albuterol, and steroids are the mainstays of therapy in acute severe asthma.
• O2 for hypoxia. Can be given with nebulizer treatments and continuously between the treatments.
• Fluids: Patients with acute severe asthma have dehydration (insensible losses or decreased PO intake). Fluids also help loosen the mucus in the airways.
• Corticosteroids: IV methylprednisolone 0.5-1mg/kg/dose Q6 followed by PO when the patient is able to take PO. Continue for 5-7days. It is not necessary to continue home ICS when the patient is acutely ill and on IV steroids in the PICU.
• Albuterol nebulizer therapy is used initially over 20minutes at 0.05-0.15mg/kg. less than 10% of the inhaled drug is deposited in the lungs. After initial series of 3 albuterol treatments, continuous albuterol nebulization is started at a dose range of 0.15-0.45mg/kg/hr (maximum of 20mg/hr). albuterol is a 50:50 mixture of R-albuterol and S-albuterol. The R-albuterol, also called levalbuterol, is the enantiomer that causes broncho-dilation, whereas the S-albuterol is the inert form and may contribute to adverse events. We do not recommend the use of Levalbuterol as there is no advantage of its use over albuterol. Levalbuterol doesn’t cause less tachycardia than racemic albuterol and continues to have a higher cost compared to R-albuterol. In patients who do not improve with albuterol or have poor air entry, to begin with, I start IV terbutaline. I give 5-10mcg/kg IV bolus followed by an infusion at 0.1-4mcg/kg/min. I do not use IV epinephrine due to its greater affinity for beta-1 compared to terbutaline.

So let's summarize A, B, C — in parallel, we optimize anti-inflammatory &...