PICU Doc On Call

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 an 8-year-old admitted for PRESS syndrome with altered mental status secondary to seizures.

Here's the case presented by Rahul:

Our patient today is an eight-year-old who was admitted to the floor with a diagnosis of MIS-C. On his initial echo, his EF had mildly depressed systolic function, dilatation of coronaries, and worsening of inflammatory markers. As a result, the care team increased the dosing of the methylprednisolone administered to this patient. Since the initiation of methylprednisone, The patient's SBP had been steadily increasing with the latest systolic values approaching 140s-150s.

On hospital day 3 patient had a generalized tonic-clonic seizure and became unresponsive for which a rapid response on the floor was called. The patient was emergently bagged and brought to the PICU for airway protection and intubation

Initial vitals on PICU admission: He was afebrile, mildly tachycardic, and hypertensive to 160s even after sedation.

In the PICU an initial head CT scan done after intubation and stabilization of the patient showed no bleeding or mass. cEEG monitoring was initiated, neurology consulted and an MRI was ordered for the following day. As his AMS was thought to be related to his BP, the team pursued BP control with Nicardipine.

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

• Seizure
• Altered mental status
• Hypertension
• Acute respiratory failure
• All of which brings up a concern for an acute CNS pathology.

Absolutely, the differential is broad, however, right now I am thinking of an acute stroke categorized as hemorrhagic, ischemic, or venous thrombotic; a meningoencephalitis, CNS vasculitis, acute demyelinating encephalomyelitis, metabolic encephalopathy, tumor, or AMS related to hypertension.

Pradip, let's transition into some history and physical exam components of this case?

What are key history features in this child?

• MIS-C with cardiac dysfunction and coronary anomalies
• Increase in steroid dosage
• Progressive increase in BP as a result of this increase

Rahul, are there some red-flag symptoms or physical exam components which you could highlight?

• The patient's physical exam was relatively normal. Of note, the fundoscopic exam did not reveal papilledema and no renal bruit was auscultated.
• His Pupils were equal, round, and reactive to light. The face was symmetric. Normal bulk and tone. The patient was sedated and did not withdraw extremities to noxious stimuli. Tendon reflexes were equal throughout. and no clonus is noted. Fundoscopic exam revealed no papilledema which may rule out increased ICP as a cause for our AMS.

To continue with our case, Rahul ,what were the patient’s labs were consistent with:

• Down trending CRP, ESR, BNP, and troponin
• ECHO is consistent with improved cardiac function as well as improvement of coronary dilatation.
• CT scan with no bleed
• MRI suggestive of changes in the posterior brain with distinct edema pattern

OK to summarize, we have:

An eight-year-old, with acute severe hypertension, seizure altered mental status, and MRI changes suggestive of vasogenic edema in the posterior part of the brain -all this brings up the concern for posterior reversible encephalopathy syndrome (PRES) the topic of our discussion today.

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

A 19-year-old with h/o of renal transplant on tacrolimus and recent initiation of steroids for rejection presents with acute severe hypertension and a GTC seizure. The patient is afebrile with no rash. CT scan at OSH reveals no mass or hemorrhage. After stabilization and initiation of antihypertensive therapy, the next study of choice for diagnosis is

• A) Continuous EEG
• B) MRI
• C) Lumbar puncture
• D) Positron emission test (PET scan) of the brain

Rahul, the correct answer is B) MRI. Patients such as the one described in the above question are at high risk to develop PRES. MRI will show classic changes associated with PRES- Involvement of the parieto-occipital region of the brain. Vasogenic edema (typically affecting the brain white matter) is characterized by hyperintensity on FLAIR and T2-weighted MRI sequences. As seizure is a presentation of PRES as in our case above, cEEG monitoring especially if intubated is indicated but may not be helpful in diagnosis. An LP also will not help with the diagnosis of PRES and the patient in this question is afebrile. PET scan may have a role in unusual or atypical cases of PRES mainly to distinguish it from the tumor. There is decreased fluorodeoxyglucose (FDG) and Methionine(MET) uptake in most PRES cases compared to tumors such as gliomas or lymphomas.

To summarize:

The diagnosis of PRES relies on a combination of clinical presentation and neuroimaging. Acute or subacute presentation with encephalopathy, generalized tonic-clonic seizures (60-75% patients), headaches, visual field deficits, cortical blindness, hallucinations, or rarely focal findings such as aphasia or hemiparesis should raise suspicion for PRES. Headache+visual disturbances+generalized tonic-clonic seizures =PRES unless proven otherwise.

Rahul, as you think about our case, what would be your differential?

• Infectious encephalitis (CSF is abnormal, CSF gram stain, CX or PCR)
• CNS vasculitis (CSF pleocytosis, cytotoxic edema in a non-PRES like pattern)
• Acute demyelinating encephalomyelitis (ADEM): H/o URI/bacterial infection, fever, usually asymmetric involvement of supratentorial regions on imaging
• malignancy or tumor (glioma or lymphoma)-Typically subacute-chronic presentation, h/o malignancy, absence of quick resolution, abnormal CSF or blood work
• Another important grouping I would consider is a toxidrome — some of these we mention in our prior podcast episodes so listeners please check them out!

Rahul, can you comment on the pathogenesis of PRES**

It is hypothesized that when the patient’s mean arterial BP exceeds the upper limits of cerebral autoregulation it leads to hyper-perfusion and the breakdown of the blood-brain barrier allowing interstitial extravasation of plasma and macromolecules and subsequently vasogenic edema. 

• PRES can also develop in patients (15-20%) with normal BP or hypotension, which does not exceed the auto-regulatory capacity of the cerebral blood flow.
• In these patients, the endothelial dysfunction and breakdown of the blood-brain barrier could be from the cytokines and inflammatory mediators from systemic toxic effects of medications, etc. resulting in vasogenic edema. The posterior regions of the brain are more susceptible to vasogenic edema because little sympathetic innervation exists in the posterior fossa.

Pradip, which patients are at risk for PRES?

Apart from acute severe hypertension, a number of other conditions are associated with PRES. PRES is seen in patients receiving immune suppression, especially calcineurin inhibitors (tacrolimus or cyclosporine) after a stem cell or solid organ transplantation. Higher incidence is seen in BM or stem cell transplant as the dose of immunosuppression is higher in these patients compared to solid organ transplant patients. Autoimmune disorders, pregnancy with pre-eclampsia, eclampsia as well as those with renal disease have been linked to PRES.

Here's a summary point when you see progressive hypertension in a patient post-transplant, after doing due diligence to pain control and diagnostic workup, pay close attention to mental status as these patients (especially if they are immunosuppression) are at high risk for developing press.

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

• Acute-subacute symptoms such as confusion, seizures, visual, headache, and visual symptoms in the presence of hypertension, immune suppression, auto-immune disorders, transplant, or pre-eclampsia are highly suggestive of PRES.
• Brain imaging is the most important diagnostic test typically used to exclude other diagnoses. The presence of vasogenic edema affecting the white matter in the parieto-occipital regions of both hemispheres (rarely asymmetric) on MRI FLAIR is highly sensitive. Although vasogenic edema can be seen in other areas of the brain there is always concomitant involvement of the parieto-occipital regions. Some patients with PRES may have restricted diffusion (15-30%) seen in larger areas of vasogenic edema, some patients (10-25%) may have intracranial or subarachnoid hemorrhage, especially in allogeneic BMT patients.
• Other investigations which need to be decided on a case-by-case basis include obtaining LP, looking for CSF pleocytosis, gram-stain/Cx, PCR for viruses as well as cytology for malignancy.
• Baseline blood gas, CBC, CMP, DIC may be required depending on the severity of the presentation
• EEG: As 60-75% of patients with PRES can present with generalized tonic-clonic seizures and PRES can be suspected as the underlying cause of status epilepticus (especially when bilateral occipital sharp waves are present) continuous EEG monitoring especially in an intubated patient must be initiated.

The presence of vasogenic edema affecting white matter in the parieto-occipital regions of both hemispheres (rarely asymmetric) on MRI FLAIR in the appropriate clinical context is highly sensitive for PRES. Neuroimaging helps to exclude alternative diagnoses such as brain tumor or acute demyelinating syndromes as well as detection of intracranial hemorrhage.

Rahul, if our history, physical, and diagnostic investigation led us to PRES as our diagnosis what would be your general management of framework?

• There is no specific management for PRES.
• Treatment is supportive and basic principles of good ICU care are paramount for optimal outcomes.
• Any treatable underlying cause such as severe hypertension must be managed appropriately. The anti-epileptic agent should be initiated and may be required for 3-12months (Morris EB et al. Pediatr Blood Cancer 2007). In our case, the patient's high BP was triggered by high-dose steroids used for MIS-C. The steroid dose was reduced as the patient's BP was controlled using IV nicardipine. A collaborative approach with rheumatology, infectious diseases, and ICU helped make decisions that allowed lowering of the steroid dose and titrating the BP. Magnesium has been used in PRES due to pre-eclampsia and eclampsia for seizure prophylaxis/treatment. The management of PRES from induction chemotherapy is difficult as deciding which meds to halt in a patient receiving multiple agents may not be easy. If PRES is caused by anti-rejection meds in a transplant patient, that medication may need to be discontinued at least temporarily. Listeners are encouraged to listen to our podcast on acute severe hypertension on how to safely lower BP in patients with acute severe hypertension.
• Can you also comment on the prognosis of PRES?
• Overall the prognosis of PRES is excellent although some severe forms may not be fully reversible and can have a mortality rate of 3-6%. Mortality is due to intracranial bleeding, cerebral edema in posterior fossa, hydrocephalous or diffuse cerebral edema, or raised ICP. In 10-20% of patients with PRES there can be neurological sequelae in the form of seizures, neuro-deficits such as hemiparesis, decreased visual activity, and dizziness. In 5-10% of patients PRES can be recurrent especially in patients with difficult to treat hypertension or who are on medications for their organ transplant.
• Key objective take-aways from today's episodes:

1. Acute or subacute presentation in a patient with the constellation of headache+seizures+visual disturbances should give rise to the suspicion of PRES especially in the clinical context of induction chemotherapy, immunotherapy, preeclampsia or eclampsia or acute severe hypertension
2. MRI showing vasogenic edema in the parieto-occipital white matter regions on FLAIR (seen as hyperintensity) is typical for patients with PRES

This concludes our episode on posterior reversible encephalopathy (PRES) 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 hosted by me Pradip Kamat and my co-host Dr. Rahul Damania. Stay tuned for our next episode! Thank you!

References

• Fugate JE, Rabinstein AA. Posterior reversible encephalopathy syndrome: clinical and radiological manifestations, pathophysiology, and outstanding questions. Lancet Neurol. 2015 Sep;14(9):914-925. doi: 10.1016/S1474-4422(15)00111-8. Epub 2015 Jul 13. Erratum in: Lancet Neurol. 2015 Sep;14(9):874. PMID: 26184985.
• Ghali MGZ, Davanzo J, Leo M, Rizk E. Posterior reversible encephalopathy syndrome in pediatric patients: pathophysiology, diagnosis, and management. Leuk Lymphoma. 2019 Oct;60(10):2365-2372. doi: 10.1080/10428194.2019.1594210. Epub 2019 Sep 26. PMID: 31556774.
• Fischer M, Schmutzhard E. Posterior reversible encephalopathy syndrome. J Neurol. 2017 Aug;264(8):1608-1616. doi: 10.1007/s00415-016-8377-8. Epub 2017 Jan 4. PMID: 28054130; PMCID: PMC5533845.

More information can be found

• Fuhrman & Zimmerman - Textbook of Pediatric Critical Care Chapter 61 (page 749-750); Chapter 64 (page 781); Chapter 78 (page 951); Chapter 92 (page 1111)
• Key objective takeaways:

1. Acute or subacute presentation in a patient with the constellation of headache+seizures+visual disturbances should give rise to the suspicion of PRES especially in the clinical context of induction chemotherapy, immunotherapy, preeclampsia or eclampsia or acute severe hypertension
2. MRI showing vasogenic edema in the parieto-occipital white matter regions on FLAIR (seen as hyper-intensity) is typical for patients with PRES

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

I'm Pradip Kamat 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 24-month-old girl with increased seizure frequency.

Here's the case:

A 24-month old girl presents to the ED with h/o shaking/jerking episodes in her sleep. The patient was in the care of her aunt when this acute episode occurred. When the father arrived from work, he saw his daughter having episodes of her body shaking alternating with heavy breathing. The patient would not wake up in between episodes. There was pertinently no history of trauma. 911 was called and when EMS arrived, she was starting to arouse and respond to stimuli. The patient was transported to the ED. In the ambulance, the patient continued to have similar shaking and jerking episodes and was given rectal diazepam. On arrival to ED, the patient had a fever of 38.5 Centigrade. Due to ongoing seizures, the patient was loaded with Fosphenytoin, after having been given a total of two doses of IV Lorazepam. The patient was subsequently intubated for airway protection and respiratory failure. A respiratory viral panel was negative for SARS-COV-2 but positive for Rhino-enterovirus. The patient was admitted to the PICU with cEEG monitoring and placed on mechanical ventilation with fentanyl + dexmedetomidine infusions with as needed Midazolam administrations

Her physical examination on arrival to the PICU was unremarkable. She wasn't interactive as she had just received sedation after intubation. On her neuro-examination, Pupils are equal and punctiform. The face is symmetric. The tongue is midline. Normal bulk and tone. No spontaneous movements were noted. No withdrawal to painful stimuli. Tendon reflexes were equal throughout. No clonus is noted.

Rahul, to summarize key elements from this case, this patient has:

• Fever
• Viral infection with Rhinoentero virus
• Generalized Tonic clonic seizure lasting > 5minutes
• Acute respiratory failure
• All of which brings up a concern for status epilepticus

Absolutely, we will get to this later on in the episode; however, remember that Status epilepticus is historically defined as single epileptic seizure of >30 minutes duration or a series of epileptic seizures during which function is not regained between ictal events in a 30-minute period

• 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 status epilepticus?

• Prolonged Seizures
• Fever with viral symptomatology which may act as a trigger
• A pertinent negative is that this patient had no history of trauma or co-morbid conditions such as a genetic syndrome.
• The patient also had no presumed ingestions as well.

1. Are there some red-flag symptoms or physical exam components which you could highlight?

• Important to look for rash (darkening of the skin = adrenoleukodystrophy), genetic facies, evidence of trauma —-all of which are absent in this girl
• To continue with our case, the patients labs were consistent with:
• Initial Labs: WBC 27K, with neutrophilic predominance, Hgb and platelets were normal. Initial CMP was normal except for a glucose of 233. Gas prior to intubation in the ED was 6.9/102/85/-9. (repeat after intubation 7.19/49/40/-9). Ionized ca 4.9mg/dl. A urine analysis was unremarkable.
• Head CT negative

OK to summarize, we have: 24-month-old girl who presented with prolonged seizures and acute respiratory failure

• All of which brings up the concern for status epilepticus the topic of our discussion today.
• Let's start with a short multiple-choice question:

A 14-year-old girl is brought to the PICU from the floor with new-onset status epilepticus. She was admitted to the floor on her second day after a posterior spinal fusion surgery and is still receiving intravenous fluids. Her seizure is described as generalized tonic-clonic. After initial stabilization and maintenance of her airway and hemodynamics, which of the following is most likely to reveal the cause of her seizures?

• A) Serum electrolytes
• B) Stat MRI brain
• C) Lumbar puncture
• D) cEEG

Rahul, the correct answer here is A) serum electrolytes. Patients especially after posterior spinal fusion surgery are at risk for hyponatremia secondary to SIADH or even hypotonic fluids used for maintenance. Correction of hyponatremia in a child with seizures requires 3% hypertonic saline. The seizure threshold is typically a serum Na of 125meQ/L. Serum electrolytes will also reveal the serum glucose which is especially important to check in infants who have seizures. A stat MRI is not warranted in this patient especially if she is alert and awake prior to the seizure. Additionally, it would be dangerous to send an unstable patient for an MRI. As the patient is afebrile, LP is less likely to be illuminating about the cause of her seizures. LP could be needed especially if there is a strong suspicion of infection such as meningitis but can be delayed if the patient is unstable and antibiotics initiated. While a CEEG may be needed especially if the patient is intubated or comatose and there is a risk of non-clinical seizures, it is not the first-line diagnostic tool.

Excellent explanation Pradip, it is of utmost importance to make sure you assess for electrolyte disturbances or glucose abnormalities in your rapid diagnostics when patients are seizing. Remember hyponatremia, hypoglycemia, and hypocalcemia. If you have a child with Seizures 

• As you think about our case, what would be your differential for rhythmic jerking movements that mimic or are associated with seizures?
• Movement disorders: Any abnormal involuntary movements such as Tics, tremor, chorea, athetosis, dystonia, myoclonus, ballismus, asterixis. Dyskinesia is a generalized term used for abnormal involuntary movements
• Migraine (its paroxysmal nature + association with neuro-deficits or altered consciousness) may lead to confusion with seizures.
• In infants paroxysmal non-epileptic disorders such as jitteriness, benign neonatal myoclonus may be confused with seizure
• Myoclonus from drugs such as etomidate or post drowning due to hypoxia reperfusion injury may be mistaken for seizures

Let’s transition and highlight key definitions of status epilepticus:

Previously defined as a seizure lasting > than 30minutes or recurrent seizures lasting > 30minutes without patient regaining consciousness between seizures. The new definition refers to SE as 5minutes or more of either continuous seizure or 2 or more discrete seizures between which there is incomplete recovery of consciousness.

Refractory SE = SE that persists despite the administration of first and second-line anti-seizure medications with different mechanisms of action.

Super refractory SE refers to SE that continues 24 hours or more after the onset of anesthetic therapy for SE and includes recurrence during reduction or withdrawal of anesthetic therapy.

Pradip what is the most common cause of seizures in the pediatric population?

The majority of pediatric SE (30-50%) involved febrile seizures. About 9-17% involved either acute metabolic derangement or a CNS infection. 12% of first seizures in children present with status epilepticus (Shinnar, Pediatrics 1996)

What is the pathophysiology of seizures and its progression to status epilepticus?

There is an imbalance between excitation and inhibition. Ineffective recruitment of GABA neurons coupled with excessive excitatory NMDA neuronal stimulation leads to initiation and propagation of the electrical disturbance in SE. Prolonged seizures lead to selective neuronal loss in the hippocampus, cortex, and thalamus.

There is neurotoxicity due to excitotoxicity (via excess stimulation from glutamate on NMDA and AMPA receptors) as well as hypoxic-ischemic injury (imbalance between increased metabolic demand and cerebral blood flow/oxygenation). Hypoxia, acidosis, hypotension, and hypercarbia add to the ongoing damage.

There are early (< 30minutes) and late (> 30minutes) time-related complications of status epilepticus which are nicely elucidated in the LearnPICU status epilepticus-pathophysiology. (http://www.learnpicu.com/neurology/status-epilepticus)

The risk of subsequent epilepsy after status epilepticus is 26-36% (Barnard, J child Neurol 1999 and Eriksson, Develop Med Child Neurol 1997).

Would you also mind highlighting the way seizures are classified?

Seizures are classified as Partial or generalized based on clinical presentation or EEG FINDINGS. Partial Seizures arise in specific areas of the brain and are further classified as simple, local, or focal. Generalized seizures arise from diffuse cortical areas at one time. They involve both cerebral hemispheres and consciousness is typically impaired. Generalized can present as motor movements or absence seizures during which no convulsions are seen.

• If you had to work up this patient with status epilepticus what would be your diagnostic approach?
• I would start with some basic labs such as glucose, serum electrolytes including magnesium and calcium. I also typically add a DIC panel and CPK for especially for prolonged seizures.
• If there is concern for infection then CBC with differential, Lumbar puncture, CRP, procal, appropriate cultures (urine, blood, and CSF) should be sent. Virals studies such as HSV PCR from blood/CSF as well as a respiratory viral panel.
• Another thing to look at is the drug levels of any previous anti-epileptic agents (as agent withdrawal or change can precipitate seizures).
• In selected cases where inflammation is suspected- ESR, CRP, vWF antigen may be required. additionally, oligoclonal bands, testing for antibodies including neuronal and ion channel antibodies may be required from blood as well as the CSF.
• Rarely evaluation for toxins, metabolic disease, ophthalmologic evaluation may be needed in selected cases.
• In patients with established epilepsy- imaging is typically not necessary. Otherwise, brain imaging (either a CT or MRI) is required especially for a new status epilepsy
• cEEG in the PICU is required especially if the patient is intubated or comatose as the patient could continue to have non-clinical status. The overall incidence of electrographic seizures in critically-ill patients was ~ 26%.
• Yes, Rahul - I would also like to highlight a “new-age technology” with regards to EEG.
• One study (Fung F. et al. Epilepsia 2020) devised a predictive model for capturing electrographic seizures in critically ill pediatric patients. The model had a sensitivity of 92% with a negative predictive value of 93%. Variables associated with increased capturing of seizures on this monitor included:
• age (<1 or >1 year of age)
• acute encephalopathy category
• clinical seizures prior to CEEG initiation
• EEG background (slow disorganized, discontinuous, or burst suppression background)
• epileptiform discharges during the initial 30minutes of the recording. We should be cognizant that equipment for cEEG, as well as staffing, may not be available at all centers.

To summarize, these are the common causes of seizures in the PICU — AED withdrawal or change, drug toxicity or withdrawal, electrolyte problems, hypertensive encephalopathy, tumor, TBI, vasculitis, renal/hepatic dysfunction, fever, hypoxia/ischemia, and postoperative conditions. Pre-existing epilepsy, genetic and central nervous system disorders can also present with seizures. Intensivists should be vigilant about non-convulsive status especially in children who have hypoxic injury s/p cardiac arrest, submersion injury, TBI, and stroke.

• If our history, physical, and diagnostic investigation led us to status epilepticus as our diagnosis what would be your approach to general management?
• In the initial phase (0-5minutes): I would focus on stabilization of the patient’s airway/breathing and hemodynamics. Establish IV/IO access and supplement patients’ oxygenation and focus on correcting any abnormal glucose or electrolytes.
• Medications: Benzodiazepines (BZDs) are the first-line agents for status epilepticus.
• The BZDs work by potentiating the neuro-inhibitory effects of Gamma-aminobutyric acid (GABA).
• Lorazepam, diazepam and midazolam are frequently used.
• Zhao ZY et al. (J Child Neurol. 2016) in a network meta-analysis of 16 RCTs including 1821 patients which compared the efficacy of midazolam, lorazepam, and diazepam in treating pediatric status epilepticus concluded that non-IV midazolam and IV lorazepam were superior to IV or non-IV diazepam, and IV lorazepam was at least as effective as non-IV midazolam.

Summary: IV Ativan and IV Midazolam if your patient has good access are equally effective

• Yes, All the aforementioned benzodiazepines are lipid-soluble entering the brain within 2 minutes of IV administration.
• Diazepam has the highest lipid solubility and is also highly protein-bound and thus has a large volume of distribution of the unbound drug. Thus the effective duration of action for diazepam in SE is 20-30minutes resulting in rapid redistribution compared to lorazepam which has a much smaller volume of distribution of unbound drug and thus has a longer duration of action in SE. Hence lorazepam is the preferred agent in the initial management of SE.
• Midazolam can be given intranasally or intramuscularly inpatient without IV access. In fact, one study (Silbergleit R et al. NEJM 2012) showed that IM midazolam was as effective and safe as IV lorazepam for prehospital seizure termination. Rectal Diazepam is an option if unable to get IV access.
• How many doses of benzodiazepines would you give Rahul, and what is the pharmacokinetics to keep in mind?
• More than two doses of benzodiazepines are associated with side effects without a substantial increase in efficacy. The potency of BZDs decreases 20 fold over 30 minutes of SE. Receptor trafficking of GABAa receptors resulting in movement of the receptors from the synaptic membrane into the cytoplasm where they become functionally inactive. This reduces the number of GABAa receptors available on the synaptic surface to bind BZD, and in turn, leads to a single seizure becoming self-sustaining a time-dependent resistance to BZD develops. Additionally > 2 doses increases risk of respiratory depression (43% risk compared to 13% with < 2 doses). Furthermore, only 13% of patients achieved seizure termination

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 Three-Year-Old with recent cough and leg weakness.

Here's the case presented by Rahul.

A 3-year-old previously healthy female presented to the hospital with a 2-week history of productive cough and congestion and the new 1-day onset of bilateral weakness. Today, the mother noticed weakness and inability to stand/walk following after shower as well as her voice becoming hoarse. She also noticed her lying more limp sitting on her lap, unable to sit up fully without her mother supporting her. She had no trouble holding up her head. The mother endorses increased fussiness but is able to be consoled. Decreased p/o intake, last meal was yesterday. About 1-2 weeks prior to this patient also had non-bloody diarrhea that resolved spontaneously after a few days.

UOP normal with 2-3 wet diapers. No difficulty breathing. No history of head trauma or trauma to lower extremities, no erythema/swelling to joints. No pain associated with leg movement. No previous difficulty with walking - developing normally otherwise. No fever, recent travel, H/O sick contact at home (sibling with URI). No allergies, immunization UTD. CMP largely unremarkable. CBC with leukocytosis to 19.72 with L shift and platelets of 647. CRP 0.3, ESR 12.

Afebrile, RR 24/min, HR 130, BP 140/86.

On PE: Patient was coughing, had a hoarse voice heart and lung exam was normal. Normal abdominal exam. No rash

Neurological exam: PERRL, (A+O) X3, 3-4/5 strength at ankles and knees and 5/5 in arms, +UE DTR's but none at patella or ankles. Has a wide-based ataxic gait and needs to hold on to the wall/furniture to ambulate.

Rahul, to summarize key elements from this case, this patient has:

• A cough with a hoarse voice
• No fever
• Inability to stand/walk (i.e. lower extremity weakness) with no DTRs in patellae or ankle
• Normal mental status
• Diarrhea (non-bloody) preceding neurological weakness
• All of these bring up a concern for Guillain-Barré syndrome-An immune-mediated disease possibly triggered by a recent infection and targeting the peripheral nervous system.

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

1. What are key history features in this 3-year-old child

• Acute (B) leg weakness
• Cough with hoarse
• Diarrheal illness
• No fever, no /o rash or trauma

1. Pradip, Are there some red-flag symptoms or physical exam components which you could highlight?

• Bilateral lower leg weakness with absent patellar and AJ DTRs
• Normal mental status
• No rash, trauma
• Rahul continues with our case, the patient's initial labs and imaging were consistent with:
• The CMP, CBC with differential, and blood gas were unremarkable
• ESR = 12, CRP 0.29, pro-cal 0.09(all normal)
• Normal CPK
• Normal Urine analysis
• A lumbar puncture revealed colorless CSF with 4 white cells, 0 reds, Glucose 73 (serum Glucose 90) and protein 94, Gram stain and culture-negative
• MRI of the brain and lumbar spine with and without contrast was completely normal
• Chest radiograph with no infiltrate or atelectasis
• Nerve conduction studies were not performed

Any patient with acute ascending lower extremity flaccid paralysis with CSF showing acellular protein predominance should be considered to have Guillain-Barré syndrome unless proven otherwise. MRI brain spine is necessary to rule out any other etiologies such as brain tumor or spinal pathologies. Features strongly supporting the diagnosis of Guillain-Barré syndrome include a progression of onset over several days to less than 4 weeks, symmetrical involvement, painful onset, mild/absent sensory symptoms, cranial nerve involvement, autonomic dysfunction, absence of fever, and recovery 2 to 4 weeks after the onset of peak or plateauing of symptoms.

• Rahul Let's start with a short multiple-choice question:
• A five-year-old girl with acute ascending bilateral lower limb weakness, normal MRI, CSF with acellular protein predominance would require immediate airway management in case the girl has
• A) A chest radiograph with large atelectasis
• B) A Maximum inspiratory force of -40cm H20
• C) A vital capacity of > 25cc/kg
• D) A strong cough
• Rahul, the correct answer is A. 
• Chest radiograph with large atelectasis, which suggests upper airway compromise and weakness of pharyngeal and laryngeal muscles leading to difficulty in the clearing of secretions and airway maintenance and resulting in aspiration. A maximum inspiratory force of less negative than -30cm H20 is a risk for respiratory arrest (i.e. more sub-atmospheric the better), a maximum inspiratory force of -40 is actually good (> 60% predicted). The answer C is wrong because its a vital capacity of < 20mL/kg that puts a patient at risk for respiratory failure. D) A strong cough is not an indication for intubation or suggestive of impending respiratory failure but hoarseness or a weak cough is. Remember trends are more important than a single value. In infants: inability to lift their head when supine, bulbar symptoms, tachypnea, increasing O2 requirement, and use of accessory muscles of respiration implies impending respiratory failure. Remember hypercarbia is a late finding of impending respiratory arrest.

PFT measurement in GB syndrome is remembered as the 20/30/40 rule: A vital capacity < 20ml/kg, a maximum inspiratory pressure less negative than -30cm H2O, or maximum expiratory pressure of ≤ 40cm H2O. Serial measurements are required.

Rahul, what is the pathogenesis of Guillain-Barré Syndrome?

The exact pathogenesis is unknown. An immune trigger such as infection, vaccine, etc affects peripheral nerve components due to molecular mimicry. A gastrointestinal or upper respiratory tract illness within 4 weeks of presentation triggers the onset of Guillain-Barré Syndrome. Possible viral agents include cytomegalovirus (detected in 26%), Epstein-Barr virus, influenza, and human immunodeficiency virus, and bacterial triggers include *Mycoplasma*, *Haemophilus*, and, most commonly, *Campylobacter jejuni*, which accounts for 20% to 30% of US and European cases. Although rare, vaccination (influenza), surgery, trauma, transplant, lymphoma, and systemic lupus erythematosus have also been associated with GBS. Recently GBS after exposure to Zika virus has been described with most patients having a complete recovery.

• As you think about our case, what would be your differential for Guillain-Barré syndrome and neuromuscular weakness in general?
• Encephalopathy. Location cerebral cortex/brainstem. The patient will have altered sensorium, seizures, autonomic dysfunction, upper motor neuron findings, seizures, and movement disorder.
• Cord compression or Transverse myelitis: The location of the lesion is in the spinal cord. unclear etiology, MRI reveals inflammation within the spinal cord. A sensory level is present on the back. There is bilateral, sensory, motor or autonomic spinal cord dysfunction. Bowel bladder dysfunction at presentation or that which persists should lead to questioning of the diagnosis of Guillain-Barré syndrome. Typically rectal tone is maintained in Guillain-Barré syndrome.
• Acute flaccid myelitis: Lesion in anterior horn cell. Sudden onset of arm or leg weakness and loss of muscle tone and reflexes. Preceded by a viral infection such as enterovirus D68. Listeners should be vigilant for vaccine-preventable diseases that are making a come back such as poliomyelitis.
• Botulism: Lesion at NMJ. Presynaptic binding of toxin prevents the release of Acetylcholine. Infants can present with constipation. Descending paralysis with early bulbar findings (weak cry, poor suck, and bilateral ptosis). Can progress to respiratory failure.
• Myasthenia Gravis: Location NMJ. Autoantibodies are directed against postsynaptic AcH receptors leading to destruction. Typically ocular and bulbar muscle weakness is common. Fatigable weakness is a hallmark.
• Organophosphate poisoning: Location NMJ, Inhibits Acetylcholinesterase leading to increased AcH and its action at NMJ. Muscle weakness with miosis, diarrhea, urination, lacrimation, salivation, and bronchorrhea
• Tick paralysis: Location NMJ. Neurotoxin prevents the release of AcH into the NMJ. Symmetric ascending paralysis with areflexia.
• Periodic paralysis. Location: muscle. Episodic muscle weakness triggered by exercise, carbohydrate-rich meal (release of insulin) a genetic mutation affecting Na, K, and Ca ion channels
• Rahul: If you had to work up this patient with Guillain-Barré syndrome, what would be your diagnostic approach?
• MRI brain/spine with and without contrast
• LP with CSF: Typically shows elevated protein and normal cell counts (called albumino-cytological dissociation)is present in only 64% of cases with Guillain-Barré syndrome. Initially may be seen in 50% in the first three days but in 80% of patients after the first week. An elevated CSF cell count > 50 should really cast doubt on the diagnosis of Guillain-Barré syndrome.
• CBC, CMP, CRP, ESR. GI PCR for campylobacter Jejuni (most common infection in the US giving rise to Guillain-Barré syndrome).
• Never conduction studies (NCS): Can help diagnose in difficult cases and help differentiate between axonal and demyelinating subtypes. Nerve conduction studies peak > 2 weeks after onset of weakness. NCS in AIDP reveals features of demyelination such as reduced nerve conduction velocity, prolonged F-wave latency, and prolonged distal motor latency and conduction block. Axonal Guillain-Barré syndrome reveals decreased motor or sensory amplitudes especially with the absence of demyelination features.
• Antibodies: Anti GQ1b antibodies may be detected in 90% of patients with the Miller Fisher variant of Guillain-Barré syndrome. Anti ganglioside GM1 antibodies may be seen in 50% of patients with Guillain-Barré syndrome secondary to Campylobacter jejuni infection. (relatively specific but not sensitive)

Rahul, can you comment on the Guillain-Barré syndrome variants?

Acute inflammatory demyelinating polyneuropathy (AIDP) is considered synonymous with Guillain-Barré syndrome and has the best prognosis. Most prevalent form in Europe and North America.

AMAN (acute axonal motor neuropathy): Has no to minimal sensory symptoms and predominantly presents with progressive flaccid ascending quadriparesis complicated by respiratory failure. (slow recovery and high mortality rate). More prevalent in South East Asia

ASMAN: acute motor-sensory axonal polyneuropathy. Both sensory, as well as motor fibers, are involved. It’s a form of axonal GBS and is considered a variant of AMAN.

Miller Fisher Variant: The patient presents with a triad of areflexia, ataxia, and ophthalmoplegia and can progress to AIDP in some cases.

Rahul can you comment on the autonomic dysfunction in Guillain-Barré syndrome

 1/2 patients diagnosed with **Guillain-Barré syndrome** will present with autonomic dysfunction such as diarrhea/constipation, bradycardia (15% of patients), followed by hyponatremia, SIADH. Others such as cardiomyopathy, syncope, urinary retention, BP instability syncope, reversible cardiomyopathy, and Horner syndrome are rarely seen. Cranial neuropathies (seen in 60% of patients) in form of bulbar weakness, facial palsy, ophthalmoplegia, and hypoglossal nerve palsy. Bradycardia may be difficult to treat and may require pacing. Patients can have excessive sweating and light-fixed pupils as a part of their autonomic dysfunction. A small percentage of patients can have paresthesias/numbness and pain.

• If our history, physical, and diagnostic investigation led us to Guillain-Barré syndrome as our diagnosis what would be your general management of framework?
• Requires a multidisciplinary collaborative effort between the intensivists, neurologists, apheresis, and the rehabilitation teams.
• Patients (~25%) with risk factors for respiratory failure should be intubated early. This also helps facilitate procedures such as MRI, LP, and placement of a catheter for PLEX.
• Patients with bradycardia, cardiac dysrhythmias, and hemodynamic instability can be difficult to manage. Bradycardia may require pacing. The help of the cardiologist or CICU colleagues is required.
• First-line therapies include IVIG and plasmapheresis. PLEX removes neurotoxic antibodies, complement factors, and other humoral mediators of inflammation. Treatment with PLEX should be initiated in the first 2 weeks of the onset of weakness. Typically five sessions each one administered every other day are performed. IVIG improved symptoms by unknown mechanisms (inhibits Fc mediated activation of the immune cells, binding of antiganglioside antibodies to their neural targets) but may also suppress further autoantibody formation and reduces T-cell and macrophage activation of the immune system. IVIG dose is 2gm/Kg. Steroids have no role in the management of GBS. The use of eculizumab (currently in phase 2 trial) has shown promise but requires RCT.
• Patients require thromboembolism prophylaxis in form of low molecular weight heparin, pain management with opioids, gabapentin, management of urinary retention, as well as constipation. Frequent turning of patients will prevent decubitus ulcers. Aggressive early physical, occupational, and speech therapies are required.

Rahul, what are the Key Objectives and Takeaways?

1. Guillain-Barre Syndrome is the most common cause of acute flaccid paralysis in children. Symmetric ascending paralysis, mild sensory symptoms, cranial nerve involvement, & autonomic symptoms.
2. Risk Factors for acute respiratory failure in Guillain-Barre Syndrome include: Elevated CSF protein during the first week of disease, short time interval between prodrome and onset GBS symptoms, cranial involvement, and weakness that waxes and wanes.
3. In the Miller Fisher variant of GBS: The patient presents with a triad of areflexia, ataxia, and ophthalmoplegia. In most cases, diplopia is the presenting symptom

• References:
• Malek E, Salameh J. Guillain-Barre Syndrome. Semin Neurol. 2019 Oct;39(5):589-595. doi: 10.1055/s-0039-1693005. Epub 2019 Oct 22. PMID: 31639842
• van den Berg B, Walgaard C, Drenthen J, Fokke C, Jacobs BC, van Doorn PA. Guillain-Barré syndrome: pathogenesis,...

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

And my name is Rahul Damania, we come to you from Children's Healthcare of Atlanta/Emory University School of Medicine. Today's episode is dedicated to Noninvasive and Invasive ventilation in children post-hematopoietic cell transplantation.

We are delighted to be joined by Dr. Courtney Rowan, MD, MSCR, Associate Professor of Pediatrics, and the Director of the Pediatric Critical care Fellowship at Indiana University School of Medicine/Riley Children’s Health.

Dr. Rowan's research interest is in improving the outcomes of immunocompromised children with respiratory failure. She is active in this field of research and has led and participated in multi-centered studies. She is the co-chair of the committee of the hematopoietic cell transplantation subgroup of the Pediatric acute lung injury and sepsis investigators network. In our podcast today we will be asking Dr. Rowan about the findings of her recent study published in the journal-Frontiers in Oncology reporting on the risk factors for noninvasive ventilation failure in children post hematopoietic cell transplant.

She is on twitter @CmRowan.

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

• A 15-year-old female with a history of AML s/p Allogeneic hematopoietic stem cell transplantation T+15 days presents with tachypnea and a new O2 requirement. She has been on the BMT floor for 48 hrs after being admitted for respiratory distress and fevers. Her blood cultures are negative but she is febrile intermittently. Her CXR shows nonspecific haziness, no focal opacity, and underinflation. Her weight is up 2KG in the last 48 hours. She is found to have increased work of breathing and mild desaturations to 88%. She is placed on HFNC and continued on broad-spectrum antibiotics. A respiratory viral panel and Sars-CoV-2 PCR is sent. Transfer to the Pediatric ICU is initiated.

Dr. Rowan, welcome to our PICU Doc on-call podcast.

Dr. Rowan: Thanks Rahul & Pradip for having me. I am delighted to be here to discuss one of my favorite topics. I have no conflicts of interest but I have funding from the NHLBI.

Today we will be discussing the up-to-date evidence for NIV (HFNC and NIPPV) use in children who have had BMT. Additionally, we will also be discussing the use of invasive MV strategies including HFOV in the pediatric BMT population. To start us off, Dr. Rowan, why is the BMT cohort different from other patients admitted to the PICU?

There is an increase in the # of patients undergoing BMT as indications for BMT are being expanded to different disease processes. The Etiologies for lung disease in BMT patients can be infectious (common organisms as well as opportunistic organisms). They can have lung disease from non-infectious causes and even fluid overload from renal dysfunction/medications given and there is a constant threat of alloreactivity which can manifest as GVHD or engraftment syndrome. 75% of PICU admits of immunocompromised children come from the heme-onc inpatient services. BMT patients have a higher risk to progress to ARDS. Recent reports show the incidence of ARDS in the intubated BMT population reaching upwards of 92%. These patients are also at high risk for MODS and can have a mortality rate close to 60%.

💡 To summarize, the BMT population is a unique ever-growing population that represents a relatively large cohort of immunocompromised children in the PICU with a risk of high mortality. As we have set this basis, we will be focusing the rest of our episode on the need for early recognition and intervention in this special population.

• Dr. Rowan: A common conundrum faced by the PICU team given limited resources and bed availability is when to transfer a patient with BMT to the PICU especially when they start requiring respiratory support on the floor. Are there any risk factors we as PICU physicians need to know which can help us transfer a child from the BMT floor to the PICU in a time-appropriate manner?

Dr. Rowan: This is a great question. We have had a few studies examining this very question. In a paper we published in Pediatr Blood Cancer in 2017, we evaluated 87 allogeneic HCT recipients to investigate the association of clinical risk factors with the development of respiratory failure.

Of the 87 allogeneic HCT recipients, 22 (25%) developed respiratory failure. The group with respiratory failure had a significantly higher percent weight gain increase at multiple time points.

The odds ratio, (OR) for respiratory, failure increased with increasing percentage peak weight gain. We also found that the OR for respiratory failure in patients requiring more than 1 liter supplemental O2 is 25.3 (6.5, 98.7).

We concluded that the percent weight gain and need for supplemental oxygen is highly associated with the development of respiratory failure in pediatric HCT recipients. Additionally, Dr. Algunik et al, have reported (PCCM 2016) that Pediatric Early Warning Score is highly correlated with the need for unplanned PICU transfer in hospitalized oncology and hematopoietic stem cell transplant patients. Additionally, the authors also reported an association between higher scores and PICU mortality. In another study, Dr. Algunik et al (Cancer 2017)reported that PEWS accurately predicted the need for unplanned PICU transfer in pediatric oncology patients in this resource-limited setting, with abnormal results beginning 24 hours before PICU admission and higher scores predicting the severity of illness at the time of PICU admission, need for PICU interventions, and mortality.

Cater et al (PCCM 2018) showed that adding weight gain to PEWs (cutoff of 8) score can increase specificity as well as the AUC to predict children with BMT at risk for clinical deterioration.

💡 Key points from these studies which we can clinically apply — trending of weights and attention to respiratory support and PEWS. Contingency planning and prompt recognition of when to initiate a transfer from floor to PICU is essential in intervening early.

• Dr. Rowan: What are the advantages of early transfer of BMT patients to the PICU?

A controlled transfer with the pediatric patient not in extremis allows for opportunities and time for in-depth multidisciplinary discussion.

This also allocates time for goals of care discussions.

We need to balance this with bed availability, familial stress of transitioning their stay from the floor to the PICU and introduction of a new care team being us in the PICU.

Dr. Rowan: In the case above, our patient was started on non-invasive PPV and antibiotics prior to transfer to the PICU. Could you comment on the ideal interface to provide respiratory support in our patient in this case?

• Little data for BMT pediatric patients for NIV compared to adults. Adult studies show that there is no difference between HFNC and standard O2 (Lemiale CCM 2017) in terms of intubation rate /mortality. Similarly, a large RCT in 776 immunocompromised adults which compared HFNC to standard O2 therapy showed no difference to 28-day mortality, LOS (ICU) stay, patient comfort or dyspnea scores (Azoulay E JAMA 2018).
• As mentioned there is Limited Pediatric data on HFNC use in BMT patients however we can extrapolate that the pediatric BMT population are not merely "tiny adults" and have different respiratory mechanics as well as a physiologic reserve.
• Multiple RCT of NIV vs supplemental O2 (374 organ transplant patients) (Antonelli JAMA 2015) showed no difference in intubation rates or mortality. Frat (Lancet 2016): Compared Adults on HFNC to NIV via supplemental O2 in 82 immunocompromised adults. They concluded that those on supplemental O2 had the highest risk for intubation and worst survival. A study by Squadrone V., et al in Intensive Care Med, published in 2010 Compared early 40 adults with BMT who were placed on CPAP were less likely to go to ICU, less likely to be intubated, and had better survival.
• Pediatric data on NIV is limited however a study by Pancera and colleagues published in 2008 in the journal of Pediatric Heme Onc concluded that the use of BIPAP in the pediatric oncology population was associated with adverse outcomes especially in patients with hemodynamic compromise.

💡 Yes from both the adult and pediatric literature It seems like there is a trend towards worsened outcomes with non-invasive ventilation in a BMT patient with acute respiratory failure.

• Dr. Rowan, we would love to hear more about your research interests specifically related to the pediatric BMT population. How have you addressed the challenge of limited pediatric critical care studies on the Pediatric BMT population?
• As this is a growing population of interest We have created the SIRCH (Study of Intensive Care and Respiratory Support in Children Post HSCT) database to offer collaboration across institutions in efforts to optimize patient care and understand key patient trends. The search database is comprised of 12 centers across the nation. One of our unique students looked at pediatric BMT patients aged 1 month to 21 months with RF. In our population of 222 individuals, we found that patients on NIV had a higher mortality and risk of pARDS (especially at 48 hrs).
• As we have commented on non-invasive PPV, let’s transition to intubation and MV. What are the risk factors for intubation in BMT patients treated with NIV?
• Great question. We developed a study that looked at 153 non intubated patients who were treated with NIV: Risk factors for failure were evaluated:
• RR > 40, Vasoactive use were the biggest risk for developing RF requiring intubation. matched related donor was protective. (Rowan CM, Frontiers in Oncology 2021).

💡 This is a great summary point that answers the question when do these patients need to be considered for intubation:

1. Tachypnea
2. Vasoactive use

Dr. Rowan, If a BMT patient needs intubation, what does your study using search data inform us of?

• Of the 153 patients who received NIV, 63% progressed to intubation. A small subset of these patients, around 10% of the 97 who were intubated, had a cardiac arrest during intubation. And of those who arrested during intubation, only 18% survived to PICU discharge.
• 24% of patients who arrested peri-intubation had a NiPPV started outside of the PICU. 8% of children who arrested upon intubation had NiPPV started in the PICU.
• Our search database also -used PALICC criteria to define ARDS after these children were intubated. We found that 92% of intubated HSCT patients have ARDS in the first 3-7 days (Rowan PCCM 2017). The majority are diagnosed with PARDS on the day they are intubated.

💡 This high percentage of ARDS in intubated pediatric patients with BMT is close to the incidence in adult studies.

• If we take a step back, what were the characteristics of children who survived with NIPPV?
• Those who were successful with NIV had better PICU survival 90%, however, hospital mortality was 41% when placed on NIV regardless of whether they were successful or failed NIPPV. My personal opinion is that we are pushing NIV too much and too long. Don't delay intubation. As we see, this may increase the risk for cardiac arrest.
• If we comment on our case further, our patient on HFNC now continues to worsen and upon admission to the PICU is escalated to BIPAP and is initiated on a norepinephrine infusion for vasoplegia and shock. The PICU team decides to intubate. What would be your approach in this high-risk situation?
• Intubation should be a multi-disciplinary approach. This patient in particular is high-risk not only due to her significant past medical history but also the concurrent hemodynamic instability!
• Exactly. As we know, these patients are at high risk for ARDS.

     Our strategy, once the patient is intubated, should be surrounding lung-protective ventilation. 

These include close attention to:

• Plateau pressures
• Driving pressures
• Higher PEEP
• and lower FiO2

Our goal is to decrease ventilator-induced lung injury. (Rowan PCCM 2018).

• 💡 Totally agree. And for our listeners, please refer to our prior episode on high-risk intubation to review key management principles surrounding the hemodynamically unstable patient.
• This is a great overview, what specific numerical values or trends should we target in our management?
• Peak inspiratory pressure (PIP) is the first value. Our studies show that PIP > 31 had an increase in mortality.
• Particular attention to OI should also be a cornerstone of management. In fact, we showed a 13% increase in mortality for every 1 unit increase in OI (Rowan 2012). Patients who had an OI > 18 had upwards to 24% increase in mortality.
• In line with Oxygenation limiting, FiO2 is key. In patients requiring upwards of 60% FIO2 and four times greater odds of mortality, we found that there was heterogeneity amongst centers and some centers did not use a high PEEP-low FIO2 strategy or grid. Centers that were compliant with a high-peep low FIO2 strategy had better survival.
• In terms of ventilation, we need to allow for permissive hypercapnia.

💡 Summary: limit peak pressures, initiate high PEEP early, and limit FiO2.

Dr. Rowan: Our patient now is intubated and has an OI of 28. The patient is starting to have increased peak pressures to 35. She has saturations ~87% with high-mean airway pressures. How would you approach the management in this case?

• At this time it is important to consider HFOV or APRV (Yehya PCCM 2014): If O2 gets better at 24 hrs the child will have a higher likelihood of surviving.
• From our SIRCH database, 85 patients/222 received HFOV (Rowan Resp care 2018). If HFOV started after 48 hrs none of the kids survived. Lower OI at 24hrs after initiation of HFOV was correlated with increased survival. Those who didn't survive continued with higher OI past 24 hours. We showed no survival in patients who received HFOV after 1 week of conventional mechanical ventilation.

Dr. Rowan, would you mind commenting on the data related to early vs. late oscillator initiation?

• Using the SIRCH database, we identified children with severe pARDS.
• We compared early HFOV (within the first 2 days) vs late HFOV (> 2 days start) compared to CMV. Early HFOV had better survival, whereas late HFOV only 9% survived.
• Adding HFOV after a week of CMV may not offer a survival benefit.

 💡 The summary for our listeners here is to consider if HFOV is indicated within 48hrs from CMV to allow for peak survival.

Unfortunately, the patient in the above case died during her stay in the PICU. If we reflect, were there opportunities for us to improve her outcome?

This is a great question and as there are many factors that are patient-specific. Here are some general rules to consider:

1. Early transfer to the PICU upon recognition of respiratory failure
2. The trend of weights and optimizing diuresis in the setting of fluid overload
3. A consideration to intubate early and if oxygenation continues to be poor early use of HFOV

Conclusion

Dr. Rowan, we appreciate your insights on today's podcasts, as we wrap up, would you mind highlighting your

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

I'm Pradip Kamat 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 of a 14-year-old girl with sudden acute outbursts of aggression and severe agitation.

Here's the case presented by Dr. Damania:

A 14-year-old previously healthy teenager with no significant past h/o presents to the PICU with a three-day h/o of aggressive behavior, agitation, and screaming. Her mother reports that her daughter has recently developed insomnia, abnormal movements and is more irritable with temper tantrums and episodic unintelligible verbal output. Parents report no recent stressors at home or at school. She has been also complaining of headaches for the past week along with things "being too loud". She denies any vertigo symptoms or tinnitus. The patient is brought to the ER due to persistent auditory/visual hallucinations followed by agitation, aggressive behavior, and catatonia. There is no h/o of recent illnesses, head trauma, fevers, rash, abdominal pain, diarrhea, or vomiting. Social history is negative for drugs of abuse in the home. Family h/o negative for seizures, and psychiatric disorders.

The patient is sent to the ED and upon arrival has an unprovoked convulsive episode concerning a GTC seizure. The patient was initially admitted to the floor but transferred to the PICU for management of severe agitation, aggressive behavior, and fluctuations of blood pressure and heart rate.

Initial vitals in the PICU were notable for tachycardia. The patient was found to be afebrile, normotensive for age, and SpO2 96% on RA. Her physical exam though limited by her aggressive behaviors was normal. The heart, lung, and abdominal exams are normal with no rash or bruising on her body.

Initials lab work includes a negative:

• U preg
• Serum and Urine tox screen
• CBC, CMP, and UA are all within normal limits
• Inflammatory markers — including ESR CRP are unremarkable.
• A head CT which was normal and an A lumbar puncture revealed colorless CSF with 8 white and 0 red cells. Serum and CSF glucose were within normal limits and protein count in CSF was negligible.
• An extended multi-disciplinary work-up is initiated.

To summarize key elements from this case, Rahul this teenage girl has:

• Sudden outbursts of agitation, and aggression
• Recent difficulty in sleeping
• Irritability, and decreased verbal output
• Auditory and visual hallucinations
• Potential autonomic dysfunction as she has fluctuating BP and HR All of which brings up a concern for neuropsychiatric symptoms that could be organic in nature.
• Let's transition into some history and physical exam components of this case?
• Rahul, what are key history features in the patient presented this case.
• Seizures, Agitation, and aggressive behavior which could reflect CNS dysfunction are seen in this case.
• The patient additionally has concern for hallucinations which point to a primary psychiatric disturbance as well. Remember the incidence of new-onset psychosis or schizophrenia in a child <13 is increasingly rare — 1 in 40K and thus identification and thorough workup for an organic cause is increasingly important.
• Rahul, are there some red-flag symptoms or physical exam components which you could highlight?
• The physical examination (although limited by her behavior) in this patient is negative
• I would particularly stress the need for a detailed neurological and skin exam.
• For many of the differentials we will discuss, we must evaluate for rashes, changes in nails or hair, bruising or cutting marks in her arms, and even evidence of trauma to the (head and spine), and considering both an abdominal exam to r/o organomegaly as well as bi-manual pelvic exam is important to perform.
• Pradip, to continue with our case, the patient’s labs were consistent with?
• Rahul, actually her labs were normal. Besides the CBC, CMP being normal her presentation CRP & ESR were also normal. This was interesting as CRP and ESR are non-specific highly sensitive markers whose elevations may point to an infectious or inflammatory process.
• Speaking of infection or inflammation, a lumbar puncture was done and her CSF revealed zero red cells but 8 white cells with a normal protein and glucose.

1. Thyroid studies include the presence of serum thyroid (thyroid peroxidase, thyroglobulin) antibodies. All of which were negative.

• As we continued to observe this patient's behavior in the PICU we expanded our CSF and serum studies. One of the panels which we sent from the CSF and serum was the auto-immune encephalopathy panel. The panel includes various Ab including:

1. Glutamic Acid Decarboxylase (GAD) Ab
2. Aquaporin-4 Receptor Ab,
3. Gamma-Aminobutyric Acid Receptor, Type B (GABA-B-receptor) Ab, GFAP Ab,
4. Voltage-Gated Potassium Channel (VGKC) Antibody, and many more.

• One essential Ab that is tested in the panel, which is an important differential in our case and one that has increased in media popularity, is the N-methyl-D-Aspartate Receptor (NMDA receptor) Ab. The book Brain on Fire by Susannah Cahalan published in 2012 and the subsequent movie released in 2016 has brought this diagnosis to the public limelight.

OK to summarize, we have a 14-year-old girl with acute onset of neuropsychiatric symptoms and a working diagnosis of autoimmune encephalitis — the topic of our discussion today.

• Let's start with a short multiple-choice question: A patient presents with new-onset aggression, irritability, and seizures. A diagnosis of Anti-NMDA encephalitis is suspected, the subsequent test to confirm the diagnosis is:
• A) MRI chest, abdomen, and pelvis
• B) Serum antibodies against GLUN1 subunit of the NMDAR
• C) CSF antibodies against GLUN1 subunit of the NMDAR
• D) CSF antibodies against Leucine-Rich, Glioma-Inactivated Protein 1(LGI-1)
• Rahul the correct Answer is C. CSF antibodies against the GLUN1 subunit of the NMDAR. Answer A (MRI chest, abdomen, and pelvis) is not required for an initial diagnosis but make be required for the detection of teratomas (58% of young females have an ovarian teratoma). ( Answer B (Serum antibodies against GLUN1 subunit of the NMDAR) is wrong because of false-negative results in 14% of cases. False-positive serum results can also be seen in patients without anti-NMDA receptor encephalitis. Answer D (CSF antibodies against Leucine-Rich, Glioma-Inactivated Protein 1(LGI-1)) are typically seen in adults with anti-LGI1 encephalitis who have faciobrachial dystonic seizures, memory loss, hyponatremia, and paroxysmal dizzy spells. In our patient antibodies against the GLUN1 subunit of the NMDAR were detected in the CSF and the serum.
• As you think about our case, Pradip what would be your differential
• Acute Demyelinating encephalopathies would be at the top of my differential. These would specifically be seen after an infectious trigger or vaccin
• Common features on MRI would be an abnormality in gray and white matter with CSF testing suggesting Ab against myelin oligodendrocyte glycoprotein (MOG)
• Another differential I would consider is the Neuromyelitis Optica spectrum. The classic Ab associated with this condition is towards the aquaporin-4. MRI abnormalities adjacent to periventricular and ependymal regions are seen in these patients.
• Viral encephalitides are also going to be important to consider. Remember that encephalitis typically causes aberrations in mental status with or without meningeal signs.
• To transition outside of the CNS, I would also consider Hashimotos encephalopathy (serum antithyroid Ab, absence of neuronal Ab in serum and CSF).
• Autoimmune diseases like systemic lupus would be an important consideration — specifically the diagnosis of lupus cerebritis.
• Other rare causes of these neuro-psychiatric disturbances include:
• Bickerstaff’s brainstem encephalitis (characterized by subacute onset, in less than 4 weeks, of progressive impairment of consciousness along with ataxia and bilateral, mostly symmetrical, ophthalmoparesis). CSF pleocytosis (45%) and brain MRI is normal with brainstem abnormalities in T2- weighted FLAIR imaging is present in 23% of patients.
• Limbic encephalitis (Ab against GAD, CSF oligoclonal bands)
• Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) and its subset Pediatric autoimmune neuropsychiatric disorder associated with group A streptococcal infections (PANDAS)- is characterized by OCD and/or tic disorder, and a temporal relationship between symptoms and group A streptococcal (GAS) infection typically in prepubertal children. Controversy exists as to whether these conditions exist as distinct clinical entities.
• 💡 Great - so for our working diagnosis in this case Anti-NMDA receptor encephalitis let’s go through the diagnostic criteria.

4 of the following 6 are required for a diagnosis: 1. abnormal (psychiatric) behavior or cognitive dysfunction, 2. speech dysfunction (pressured speech, verbal reduction, mutism), 3. seizures, 4. movement disorder, dyskinesias, or rigidity/abnormal postures, 5. decreased level of consciousness, 6. autonomic dysfunction or central hypoventilation.

These symptoms must be with rapid onset typically less than < 3months.

Laboratory study results include abnormal electroencephalogram (EEG) showing focal or diffuse slow or disorganized activity, epileptic activity, or extreme delta brush, cerebrospinal fluid (CSF) with pleocytosis or oligoclonal bands.

Rahul, If you had to work up this patient with Anti-NMDA encephalitis, what would be your diagnostic approach in the PICU?

1. MRI brain and spine: In our patient case the MRI showed: hyperintense signal on T2-weighted (FLAIR) sequences highly restricted to both medial temporal lobes involving both the grey and white matter suggestive of demyelination/inflammation.
2. I would also do an EGG. Her EEG showed extreme delta brush pattern (rhythmic delta activity (1–3 Hz) with superimposed beta activity riding on each delta wave)
3. Serum and CSF antibodies against the GLUN1 subunit of the NMDAR as explained previously were detected in this patient.
4. If Anti-NMDA Ab is detected then an MRI of the ches,t abdomen, and pelvis to detect ovarian teratoma is necessary. The frequency of an underlying tumor varies with age and sex, ranging from 0–5% in children (male and female) younger than 12 years, to 58% in women older than 18 years (usually an ovarian teratoma). Adults older than 45 years have a lower frequency of tumors (23%), and these are usually carcinomas instead of teratomas.
5. It is also important to evaluate for infections like herpes simplex virus (CSF PCR), arboviral diseases which can cause infectious encephalitis. A respiratory viral panel that includes SARS COV-2 must be obtained.

 💡 Most patients with encephalitis undergo brain MRI at early stages of the disease. The findings could be normal or non-specific, but sometimes they might suggest an autoimmune cause. It may be necessary to repeat the MRI especially if the initial was performed early in the disease process and is normal.

Additionally, a team approach with the neurologist, infectious disease, a rheumatologist is necessary prior to sending tests or obtaining imaging for optimal outcomes. The pediatric ICU fellow/attending needs to be the linchpin who updates the family on any results that are obtained from the various tests which are sent. Weekly care conferences with the family to answer the questions the family may have will help alleviate their anxiety and keep them up-to-date on their child's progress. As treatment modalities may have various responses, it is important to also focus on neuro-behavioral rehab for these patients and consider a consultation with in-patient PM&R colleagues.

Rahul before we go to the management framework can you briefly inform us about the pathogenesis of anti-NMDA autoimmune encephalitis?

The big picture pathophysiologic framework is simple: auto-immune attack and inflammation to neurons leading to neuro-psychiatric changes.

To go into more detail:

1. Antigens released from viral destruction of neurons or from tumors elicit an auto-immune reaction.
2. The antigens released are transported by the dendritic cells to the regional lymph nodes, where the naive B cells become differentiated into memory B cells.
3. The memory B cells enter the brain where they differentiate into antibody-producing plasma cells directed against in our case the N-methyl-D-aspartate receptor (NMDAR).
4. In the case of Anti-NMDA encephalitis, there is cross-linking and internalization of the NMDAR leading to a decreased density of the NMDAR. The clinical features thus will resemble those observed with drugs like ketamine or phencyclidine, which work through non-competitive NMDAR antagonists.

• If our history, physical, and diagnostic investigation led us to Anti NMDA encephalitis as our diagnosis what would be your general management of framework?
• Good basic supportive care in the PICU, while maintaining patient and staff safety should be a top priority. A collaborative approach with neurologists, infectious disease, rheumatology, and neuroradiologists is necessary for an optimal outcome. The main job of the PICU team is to facilitate early diagnosis by the acquisition of MRI and other diagnostic studies. Intubation and CVL/arterial line may be required for procedure completion, and getting the blood for multiple labs draws and close follow-up labs. Neuroleptic agents such as haloperidol are best avoided in these patients but may be required in extreme agitation. Close monitoring of serum CPK and patient temperature may be required. An EKG to measure a baseline QTc. Sedation of an intubated patient may be challenging and ketamine should be avoided. Continuous EEG monitoring must be initiated if the patient is intubated.
• Current therapy involves the removal of immunologic triggers such as teratoma, tumors, and immunotherapy. No large randomized trials show the efficacy of any single therapy.
• In autoimmune encephalitis, most antibody production and inflammatory changes are behind the blood-brain barrier so it is not surprising that treatments that target serum immunologic triggers are rarely effective.
• Patients are treated with high-dose systemic steroids (followed by a taper), intravenous immune globulin, or plasma exchange. Rituximab may be...

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

I'm Pradip Kamatand 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 19 month old female with bloody stool, petechiae and no urine output

Here's the case presented by Rahul:

A 19 month old previously healthy female was brought to the pediatric emergency department for blood in her stool. Patient was at daycare the previous day where she developed a low grade fever, congestion and URI symptoms along with non-bloody-non-bilious vomiting and diarrhea. Patient had a rapid COVID test which was negative and was sent home with instructions for oral hydration. That evening, patient began having vomiting/diarrhea which worsened. She was unable to retain anything by mouth and her parents also noted blood in her stool.

Due to this, she was rushed to the Emergency Department. In the ED here, she was hypertensive for age BP of 124/103 mm Hg, febrile, and ill. Specks of blood were noted on the diarrheal stool in the diaper.

On her physical exam she was noted to be pale with petechiae on neck and chest. Her abdomen was soft, ND, with some hyperactive bowel sounds, and no hepatosplenomegaly. The rest of her physical examination was normal.

In the ED, initial labs were significant for WBC 19, Hgb 8.8, and Platelets 34. CMP was significant for BUN of 74mg/dL and Cr of 3.5mg/dL, Na 131 mmol/L, and K of 5.5mmol/L, Ca 8.3mg/dL (corrected for albumin of 2.2g/dL), Phosphorous 8.5 AST 413, and ALT of 227, LDH > 4000. BNP was 142 and troponin negative. She was given 1 dose of CTX 50mg/kg and a 20cc/kg NS bolus. Stool PCR was sent. She was given labetalol for her hypertension, started on maintenance IV fluids and transferred to the PICU for further management.

Rahul to summarize key elements from this case, this patient has:

• We have a 19-month old child with
• Diarrhea and emesis X 2 days
• No urine output for over 24 hours
• Bloody stool
• Petechiae on the neck and chest
• Anemia and thrombocytopenia

All of which bring up a concern for hemolytic uremic syndrome the topic of our discussion today

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

What are the key historical features in this child who presents with above?

• Bloody stool which alludes to an invasive diarrhea
• No urine output and an ill appearing state which points to a systemic inflammatory condition and end organ dysfunction.

Are there some red-flag symptoms or physical exam components which you could highlight?

• Presence of petechiae which are physical exam features of thrombocytopenia
• Her pallor which is a physical exam sign of anemia
• Hypertension which is related to her renal dysfunction

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

• Anemia
• Thrombocytopenia
• Elevated BUN and creatinine
• Elevated serum LDH
• The patient did not have hyperkalemia, or acidosis on initial presentation

OK to summarize, we have a 19 month old girl with:

• Anemia, thrombocytopenia, and renal failure. This brings up the concern for Hemolytic uremic syndrome →

Rahul Let's start with a short multiple choice question:

A 2-year old boy is admitted to the PICU with acute respiratory failure secondary to pneumococcal pneumonia. On day # 3 of admission, the nurse reports the patient appears pale and has petechiae on his chest. The patient also has not had urine output for > 12 hours and appears to be fluid overloaded. Of the following the lab findings would be most consistent with the above clinical findings in the patient?

• A) Elevation of serum haptoglobin
• B) Low serum lactate dehydrogenase (LDH)
• C) Negative Direct Coombs test
• D) Peripheral smear showing schistocytes
• The correct answer is D-Peripheral smear showing schistocytes.

Patient in the above case most likely has streptococcus pneumoniae associated hemolytic uremic syndrome commonly called as pneumococcal HUS, an uncommon condition, which accounts for 5% of all cases of HUS in children. A peripheral smear will show the presence of schistocytes (which consists of fragmented, deformed, irregular red blood cells). The schistocytes represent RBCs that are partially destroyed as they traverse through the blood vessels partially occluded by microthrombi. Smear may also show giant platelets due to the rapid platelet turnover from peripheral destruction. Because HUS is an intravascular hemolysis serum haptoglobin should be low. Serum LDH along with indirect bilirubin are typically elevated. The Direct Coombs test detects antibodies that coat RBCs and may allude to this pathology. In pneumococcal HUS where there is antigen-antibody interaction on RBC cell surface, the Direct Coombs test may be positive in 90% of the cases. A direct Coombs test is highly sensitive for pneumococcal HUS, but the degree of specificity is unclear.

A few points which I want to highlight classically on board exams, schistocytes look like helmet cells on blood smear. Also, presence of COOMBs positivity in the setting of hemolysis think about autoimmune hemolytic anemia (AIHA).

• Rahul As you think about our case, what would be your differential?

            The following may sometimes be difficult to differentiate from HUS

• Bacterial sepsis (History, clinical presentation with hemodynamic compromise and feature of distributive shock, fever with elevated WBC with neutrophil predominance, multiorgan presentation, source of infection, immunocompromised host etc)
• Disseminated intravascular coagulation (history of sepsis, drug, toxin eg snake venom, abnormal coagulation etc.)-In HUS the fibrinogen, PT, PTT are normal or slightly elevated and there is no active bleeding.
• Acute hemolysis from any other causes (drugs, toxins, warm-antibody, cold agglutinin disease, paroxysmal nocturnal hemoglobinuria etc.) -typical history, likely older patients, PNH post-viral in children.
• Hemophagocytic lymphohistiocytosis (HLH), acute macrophage activating syndrome (MAS), liver failure, TMA etc (good history, h/o JRA and other features may be helpful).
• Thrombotic thrombocytopenic purpura (older patient, neurological symptoms)
• The classic triad of hemolytic anemia, thrombocytopenia and renal failure is associated with hemolytic uremic syndrome can be seen on the spectrum of TTP — which adds fever and neurological symptoms to the diagnosis. In the pediatric population, TTP can be seen when children have acquired or congenital absence of ADAMS TS 13. Think of ADAMS TS 13 as a pair of scissors that cuts up vWF, an essential component of primary hemostasis. When you have a deficient or mutated ADAMS TS 13, which is a MMP, you end up having large vWF multimers which deposit in between endothelial cells which creates a consumptive thrombocytopenia and intravascular hemolysis.
• Pradip, do you mind building a framework between typical HUS versus Atypical HUS?
• Typical HUS is seen in patients with STEC diarrhea, or invasive pneumococcal disease, such as pneumonia. The atypical HUS is a term reserved for complement mediated HUS in which there is uncontrolled complement activation using the alternative pathway.

Rahul, before we go into the diagnostic and management framework can you shed some light on the pathogenesis of HUS?

The hemolytic uremic syndrome comes under an umbrella term called Thrombotic microangiopathy (TMA) syndromes. The clinical features of TMA include microangiopathic hemolytic anemia, thrombocytopenia, and organ injury. The pathological features are vascular damage that is manifested by arteriolar and capillary thrombosis with characteristic abnormalities in the endothelium and vessel wall.

Let’s breakdown the three pathogenesis or sub-diagnoses:

1. In STEC HUS (accounts for most of the HUS seen in children):
2. Enterohemorrhagic E coli expresses adhesin called intimin, allowing the Shiga Toxin to enter the bloodstream.
3. Once in the bloodstream the Shiga Toxin binds to globotriaosylceramide (Gb3, also known as CD77 or ceramide trihexoside) on endothelial cells, as well as to renal mesangial cells and epithelial cells.
4. After endocytosis, the toxin causes ribosomal inactivation leading to cell death.
5. Shiga Toxin is pro-inflammatory and pro-thrombotic and induces endothelial Von Willebrand factor resulting in thrombosis.
6. Multiple E Coli species produce the Shiga toxin but E Coli 0157:H7 is the most common in Europe and North America. S. dysenteriae Type 1 is an important cause of Shiga toxin HUS in other countries. STEC HUS is seen in younger children (3-5 years). Severe disease is seen in those with high white counts on initial presentation, female gender and younger age.

Pradip, what is the second subtype?

• Pneumococcal HUS (accounts for 5% of all HUS seen in children): Neuraminidase produced by the pneumococci cleaves the n-acetyl neuraminic acid from cell surface of platelets, RBC and glomerular cells and exposes the Thomsen Friedenreich (TF) crypt antigen. The TF antigen is typically hidden by the neuraminic acid. Once the TF antigen is exposed, preformed IgM antibodies bind to the TF antigen resulting in a cascade of events leading to hemolytic uremic syndrome.

Finally, let’s talk about atypical HUS.

Atypical HUS or complement mediated HUS accounts for approximately 10% of cases seen in children - what is the pathophysiology of this disease?

• In Atypical or complement mediated HUS the gain or loss of function mutations in complement regulatory protein results in uncontrolled activation of the alternative pathway of complement.
• Unlike the other two pathways of complement activation, the alternative pathway is constitutively active as a result of spontaneous hydrolysis of C3 to C3b.
• In the absence of normal regulation, C3b deposition on tissues may increase markedly, resulting in increased formation of the C5b-9 terminal complement complex (also called the membrane-attack complex) leading to endothelial injury and TMA.
• 30% of patients may not have any mutation in complement genes at presentation. 80% of patients present with a fulminant course (after acute URI or viral gastroenteritis). Low C3 with normal C4 indicates alternative pathway activation. Extra-renal manifestations such as seizures, hemiplegia, diplopia, blindness, coma, cardiac and lung involvement are also seen.
• Rahul: If you had to work up this patient with HUS, what would be your diagnostic approach?
• Before we get into this, lets create a mental model: 1) Show evidence of hemolysis, 2) find a source/cause and 3) determine severity of organ involvement
• Excellently said, Initial tests include CBC with differential, peripheral smear, DIC panel, Direct Coombs test.
• A comprehensive metabolic panel, serum LDH, serum haptoglobin, complement levels (C3 and C4), urinary NGAL.
• Blood culture, stool PCR/culture, respiratory culture from ETT
• Imaging and other diagnostics include: Chest radiograph, echocardiography, and renal ultrasound. Daily weights are highly recommended for the patient.
• Disease severity can be gauged by acidosis, hyperkalemia, LDH level and platelet count. Recovery of platelet count followed by decrease in LDH suggests improvement of hemolysis. Persistent hyperkalemia/acidosis suggests an urgent need for dialysis along with decreased UOP, fluid overload and weight gain.
• Other labs that may be needed on a case by case basis include ADAMTS-13 (needed for diagnosis of TTP) or complement 3 glomerulopathy (C3G) functional panel (Includes Complement Antibody Panel, Complement Biomarker Panel, Complement Pathway Panel). This will require great coordination between the nephrology, hematology, and ICU team.
• Pradip, If our history, physical, and diagnostic investigation led us to HUS as our diagnosis what would be your general management of the framework?
• After careful attention to airway, breathing circulation and good basic PICU care, supportive therapy is the cornerstone of the treatment of HUS patients admitted to the PICU.
• Let’s organize our management model into key PICU management components: fluid and electrolyte management, blood pressure control, transfusion thresholds, plasma exchange and antimicrobial
• Fluid, Electrolytes and Nutrition:
• Early volume expansion especially prior to development of acute kidney injury has been shown to have also proven to lessen the need for renal replacement therapy (RRT) as well as reduce central nervous system-associated complications.
• Once AKI develops, the intensivist will have to work with the nephrologist to provide dialysis. Typically at our institution this is done using CVVH although peritoneal dialysis can also be used.
• CVVH will help reduce volume overload, correct electrolytes, acidosis and allow provision of nutrition. We typically use citrate regional anticoagulation.
• Blood pressure control:
• Hypertension is common in HUS.
• Early use of titratable IV nicardipine especially for severe hypertension followed by transition to PO meds is recommended.
• Blood and platelet transfusion:
• Transfusion of pRBCs should be considered only in symptomatic children whose hemoglobin is < 7gm/dL.
• Platelet transfusion must be restricted to active bleeding or invasive surgical procedures.
• Transfusion of fresh frozen plasma also should be avoided unless there is active bleeding.
• You're absolutely correct, FFP which contains clotting factors & complement mediators may actually fuel your inflammatory cascade. A discussion with blood bank/hematology may be required to see if there is a role for "dextran washed RBCs" which removes more than 95% of plasma from donor pRBCs.
• Rahul, is there a role for plasma exchange in these patients?
• Plasma exchange:
• No role for...

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 Emory University,School of Medicine, Children’s Healthcare of Atlanta, Atlanta, GA.

Today's episode is dedicated to O2 delivery in the PICU. We would like to highlight in this episode Stanford University School of Medicine Pediatric Critical Care's LearnPICU website. The LearnPICU.com website Is dedicated to reviewing clinical topics related to pediatric critical care, and is an open access resources which Is widely accessed worldwide. The website has over 10,000 visits each month, and is managed by Dr. Kevin Kuo - Clinical associate professor of pediatrics pediatric critical care at Stanford University. Dr. Kuo has Been featured on our prior episode entitled seven habits of highly effective Picu fellows, and we are very excited to collaborate with his educational resources to provide you the listener a comprehensive educational experience.

Rahul, let's go ahead and get into today's case.

A 17-year old boy is admitted after he was struck by a car at slow speed while crossing the street.

He is has SPO2 of 98%, HR 98 bpm with a normal capillary refill and perfusion.

His blood gas at admission to the PICU reveals a ph of 7.3/PCO2 35/PaO2 196 mm Hg on 50% NRB with 100% O2 flowing at 12LPM.

His admission hgb is 10.5 gm%.

4 hours post admission, the nurses noticed that the patient is tachycardic to 150s, with a drop in his BP, delayed capillary refill, with cool extremities and increased output from the chest tube.

His SpO2 has decreased to 86% and PaO2 on his blood gas is now 65mm HG. He is found to have a POC Hgb of 6.8 mg/dL.

Let’s take this case and highlight key components of O2 delivery and O2 consumption.

Lets focus on O2 delivery first. Rahul What are the components of O2 delivery ?

 Pradip, O2 delivery is made of O2 content X Cardiac output

Simply put, O2 content is the amount of blood present in 100ml of arterial or venous blood. Its is denoted by CaO2 or CvO2 and its unit is mL O2 / dL blood or mL O2 per 100 mL of blood.

Before we introduce the complicated formula, let's just appreciate the variables within the equation.

Oxygen content is going to be a function of three variables:

This is going to be Hgb, Saturations on the hemoglobin also known as SaO2, and the amount of oxygen that is dissolved within the blood also known as your PaO2.

Pradip, Can you elucidate further about O2 content?

O2 content is given by the formula: CaO2 = (1.34X Hgb gm/dl X SaO2) + (0.003X PaO2)

Important points to remember about above formula is that the constant 1.34 (or 1.36 as given by some textbooks) is the amount of O2 in mL bound by one gm of Hgb and is called as the O2 carrying capacity of Hgb. In a healthy person say with 15gm% of Hgb, the O2 carrying capacity is about 15X1.34 = 20gm%.

Now many times amount of O2 bound to Hgb may not always reflect 100% saturation So we need to factor the % oxygen saturation into the oxygen carrying capacity of the Hgb.

The final element is to understand that some oxygen is dissolved in the plasma and is calculated using a constant 0.003 X PaO2. Typically 100ml of arterial blood with a saturation of 100 will contain 100 X 0.003 = 0.30ml of dissolved oxygen.

Rahul can you calculate the pre-decompensation oxygen content in the above case?

The above patients hgb pre-decompensation = 10.5gm%. His room air saturation 98% and his PaO2 is 196.

CaO2 = (1.34X10.5X0.98) + 0.003 X 196 = 13.7 + 0.58 = 14.2ml O2/dL blood.

Great - what is the post decompensation CaO2.?

The post decompensation CaO2 can be estimated using same formula as above: CaO2 = (1.34 X 6.8 X0.86) + (0.003 X 65) = 7.8 + 0.195 = 7.9 O2/dL blood.

Exactly So if you see the pre and post bleed O2 content just with a drop in Hgb from 10.5 to 7.5gm/dL: There is almost a 38% decrease in patients O2 content (8.83/14.2 = 62%,)

What is the best strategy to increase the patients O2 content?

First we can increase the patients FiO2 from 50% to 100% (immediate bedside action). We can get consent from family to order blood for transfusion.

Increasing FiO2 will result in an CaO2 = (1.34 X 6.8 X1 ) + (0.003 X 65) = 7.8 + 0.195 of about 9. O2/dL blood.

If we transfuse to a hgb of 10gm% with no increase in FiO2: we will get an CaO2 of (1.34X10X0.86) + (0.003 X 65) = 11.52 + 0.195 = 11.71 ml O2/dL.

The summary of this is to understand that modulating the patients hemoglobin via transfusion gives greatest bang for your buck in terms of optimizing O2 content

Exactly. Now, there is some value of increasing PaO2 in patients with acute severe hgb (say a Hgb of < 3gm/dL). Placing a child on 100% FIO2 NRB or placing child in hyperbaric chamber (diving & increasing PaO2) can increase CaO2 significantly. This is rarely used however may be indicated in patients who present with severe anemia with difficulty finding blood for transfusion due to antibody development etc.

Except for acute severe symptomatic anemia,Hgb should not be the sole criteria to transfuse to improve O2 content. In fact recent studies report that liberal policy of transfusion may be associated with increased mortality compared to a more restricted (transfused only if Hgb < 7gm/dL). So you want to assess the clinical picture fully and identify, intervene, and reassess.

Rahul, can you create a mental model related to O2 content in the blood for our listeners?

Absolutely, I would like to create 2 mental models:

As we reviewed, the variables in the oxygen content equation are:

1. Hgb
2. SaO2
3. PaO2
4. So how do we measure these clinically?
5. Well, in order to get the Hgb you order a CBC
6. In order to get your SaO2 you would place the patient on a pulse oximeter
7. In order to obtain your PaO2 to you or draw an ABG

Thus, your total oxygen content can be thought of as CBC, pulse ox, an ABG.

This is great - What’s another way to think about CaO2?

You can think about CAO2 by visualizing a car.

Many of us have heard that hemoglobin is the car which carries oxygen throughout our body. So the car and its frame represents hemoglobin. The wheels on the car represents the saturations. Four wheels on a car, for binding sites on hemoglobin. And finally thinking about a car needing to travel on a fluid road, helps you remember that PaO2 is the dissolved O2 in the plasma.

Pradip, we also talked about Venous oxygen content. How is that calculated?

CvO2 is similar to CaO2 and it is calculated using the formula: 1.34XHgbXSvO2 + 0.003 X PvO2

Typically, mixed venous O2 sat is used instead of SaO2 and PVO2 is used instead of PaO2. The blood gas is typically obtained from a central venous line with tip at SVC-RA junction.

Now thtat we have defined CaO2 and CvO2 lets talk about the other component of O2 delivery and that is CO. remember DO2 = CaO2 x CO.

Exactly, going into our Car analogy:

Hgb representing the frame SaO2 being the wheels on a car and PaO2 being the fluid road which the car travels on,

Remember that a car cannot run without a motor. SO what is that motor? It is CO.

So just to summarize DO2 = CaO2 x CO.

So Rahul, what is the AVO2 difference?

It is The difference between CaO2 and CvO2 can be used as a measure of the adequacy of O2 delivery. Typically in a normal patient the CaO2 is about 20.5 mL O2/dL and the CVO2 is about 14.5mL O2/dL giving us an AVDO2 of 5mL O2/dL. The normal range is 4-6mL O2/dL.

A decrease in DO2 will lead to higher O2 extraction and therefore a higher AV O2 difference. A lower AV O2 difference is seen when there is decreased O2 extraction such as in cyanide toxicity or sepsis.

Rahul, lets shift gears to the next heading of our talk O2 consumption or VO2 - can you introduce this to us?

VO2 is the amount of oxygen consumed by the tissues per minute. Certain condition can result in low VO2 such as hypothermia in the absence of shivering sedation/paralysis, coma, brain death, cyanide poisoning etc. Increased VO2 is seen with fever, pain, shivering, increased work of breathing, positive inotropes etc. VO2 (mL/min) is given by (CaO2-CvO2) X cardiac output, which uses the reversed Fick equation. VO2 = CI X AVDO2. IN ARDS or sepsis, VO2 may continue to increase even as DO2 increases above normal values. VO2 remains supply dependent to much higher levels of DO2 leading to pathologic supply dependency. The exact reason for this pathologic supply dependency is unknown.

Pradip, help us understand O2 Extraction a bit more?

It is important to understand that the DO2 in humans is around 620+/- 50mL/min per square meter. The O2 consumption in humans is typically in the range of 120-200mL/min per square meter. The body normally extracts only about 25% of the oxygen delivered to the tissues overall. O2 extraction (ERO2) is given by DO2/VO2 = 25%. OR AVDO2/CaO2. O2 extraction can vary by organ-the heart, brain extract a lot of oxygen but the kidneys, liver utilize little oxygen.

Global impairment in oxygen delivery can thus be determined by monitoring central venous oxygen saturation (measured at SVC-RA junction with a central venous line) or mixed venous oxygen saturation (measured with a Swan Ganz catheter at the pulmonary artery).

Normal ScvO2 = 70-75% reflecting an O2 extraction of 25%

It is important to note that in humans: O2 consumption or VO2 is independent of O2 delivery or DO2.

As the oxygen delivery decreases (or as oxygen demand increases), the body responds by extracting more oxygen and hence, the mixed venous saturation (ScvO2) or its oxygen saturation of blood at the SVC-RA junction gradually decreases to reflect this increasing oxygen extraction. However, the body can only extract so much oxygen and eventually, a critical extraction threshold (critical point of oxygen delivery) is met and cellular metabolism becomes anaerobic with the subsequent production of lactate. I would advise listeners to visit learnpicu.com to see an important graph drafting the relationship between DO2 and VO2.

An important component of oxygen delivery is Cardiac output: Rahul can you tell us the components of cardiac output?

Rahul: CO (liters per minute) = HR(beat per minute) X SV(mL). Cardiac output is typically indexed to BSA. CI is given as CO/BSA

Listeners need to remember that newborns and children with heart disease cannot increase stroke volume and are therefore heart rate dependent to increase cardiac output. Any rate or conduction anomalies can affect heart rate as in myocarditis, arrhythmias or poisoning.

SV is amount of blood pumped at each contraction and is dependent on preload, pump function and afterload.

Preload is the stretch of the cardiac myocytes just prior to contraction. Left ventricular end-diastolic volume, which is the volume of blood in the (L) ventricle just prior to contraction is the best surrogate marker of systemic preload. Preload is decreased in hypovolemia, hemorrhagic shock and cardiac tamponade.

Stroke volume is also determined by cardiac contractility which is defined as the extent of shortening that occurs in cardiac myocytes when stimulated independent of preload or afterload. It a function of cardiac muscle performance. Echocardiographic measures of shortening fraction and ejection fraction are typically used as estimates of contractility. Listeners need to remember that multiple factors affect contractility such as catecholamines as well as optimization of the so called cardiac lytes:- calcium, magnesium and potassium. contractility is decreased in cardiogenic shock, drugs/toxins or cardiomyopathy.

Afterload: is defined as the force opposing the contraction of the left ventricular myocytes during systole. Increased or decreased SVR can affect afterload in shock states

In the next section Lets us discuss the assessment of O2 delivery & consumption clinically at the bedside where it matters.:

How can you assess oxygen delivery and consumption at the bedside?

A physical exam we can assess peripheral perfusion, heart rate, blood pressure, urine output, and mental status.

Serial arterial blood gases, measures of serum lactate, SmVO2 (if available as SmvO2 requires pulmonary artery catheter), ScvO2, measure of Hgb, SaO2 can be obtained. A rise in lactate with falling ScVO2 or SmvO2 suggest anaerobic metabolism. A rising base deficit, persistent acidosis, decreasing pH may suggest declining DO2 in the right circumstances.

Blood lactate can be used as an indirect measure of perfusion. A temporal trend is more valuable than a single number. Rate of production and clearance is affected by liver metabolism.

Rahul, any serum biomarkers for assessment of cardiac function ?

Paige: B-type Brain natriuretic peptide (BNP):, troponin (specific to myocardium) Troponin increase is seen in myocarditis, pericarditis, coronary injury or occlusion, and sepsis. BNP is released in response to ventricular wall stress due to volume or pressure overload. High levels of circulating BNP have been correlated with congestive heart failure states—a trend over time is likely the most helpful for the clinician

Pradip, what can you tell us about Near-infrared spectroscopy?

NIRS helps assess the systemic and regional O2 transport. NIRS is commonly used, particularly in patients with CHD, as a means of trending regional DO2 or as a surrogate for mixed venous O2 saturation or systemic DO2. Frequently used on patients undergoing VA ECMO. Rahul, how can we improve oxygen delivery?

We can give patient a blood transfusion (although not ideal unless hgb < 7gm%) increase FIO2 to increase SAO2. We can decrease VO2 by reducing fever/catabolic states, treating infection, treating agitation with sedation/paralysis, cooling (while avoiding shivering), inducing coma etc. We can also decrease VO2 by early intubation if necessary in a patient with severe respiratory distress. Avoiding vasopressors can also decrease myocardial oxygen requirement and O2 consumption.

Pradip How can we tackle O2 consumption?

Let’s break this down in a systems based manner:

1. Resp:
2. Reduce respiratory distress by supporting using Ni or Inv MV
3. Reduce arrythmia as this can increase VO2 but also derail CO and thus DO2
4. Reduce pain agitation fever seizure or shivering. At times you may not have a great clinical assessment of subclinincal status so consider placing eeg on patient or intiating...

Acute pulmonary Hypertensive Crises.

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 7 month old boy ex-26 week premature infant with acute hypoxemia, bradycardia episodes, poor perfusion

Here's the case:

A 7 month old ex-26 week male was transferred from the outside hospital to our PICU for tracheostomy evaluation. Patient was intubated on second day of life. He had a prolonged course, on inhaled Nitric Oxide for first 2-3 months of life in the setting of severe pulmonary hypertension, requiring HFOV for a prolonged period of time. Failed extubation attempts multiple times. Received steroid burst x2. BPD settings trialed (lower rate, longer iTime, high PEEP, larger TV) without improvement. At time of transfer he was in PRVC mode on the ventilator — TV ~10ml/kg, 50%, PEEP 8, rate 28 (Peak pressures 27-32). Patient received albuterol Q4 for bronchospasm/wheezing and pulmicort BID. Patient was deeply sedated with morphine and midazolam. Interstitial lung disease panel was negative. ECHO showed: systolic septal flattening, moderate RV hypertrophy with normal systolic functioning. Patient was not on any PH medications at transfer. Patient is also on furosemide, hydrochlorothiazide and spironolactone.

Patient has completed a course of antibiotics for klebsiella tracheitis from a ETT CX a week prior to admission to our picu. Patient tolerated feeds via an NJ tube.

The team continues to evaluate his case as the Patient continues to have episodes of acute desaturation, tachycardia, cool extremities and poor perfusion.

To summarize key elements from this case, we have a 7month old who is ex-26 week premie

• Patient has BPD and is on high vent settings and failing extubation
• Abnormal echocardiogram with flat septum and hypertrophied Right ventricle
• Episodes of cold shock-tachycardia, poor perfusion, and cool extremities
• Hypoxia

All of which bring up a concern for acute pulmonary hypertensive crisis

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

What are key history features in this infants who presents with an acute pulmonary hypertensive crisis

• Prematurity
• BPD

Remember BPD is defined by a requirement of oxygen supplementation either at 28 days postnatal age or 36 weeks postmenstrual age.

Are there some red-flag symptoms or physical exam components which you could highlight?

• Presence of cold shock: tachycardia, cool extremities and poor perfusion
• Hypoxia
• Cardiac exam will reveal a bounding right ventricle, prominent loud single S2
• Although not obvious in this patient: some patients can have a palpable liver, cardiac gallop, peripheral edema and jugular venous distention

S2 heart sound represents the closure of the PV very close to AV — In pulmonary hypertension this PE sign is seen with equal right and left ventricular pressures.

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

• Respiratory acidosis (PCO2 > 100)
• CMP, CBC are normal
• BNP < 100, serum lactate normal

Echocardiography findings in these patients can show tricuspid regurgitation. We can estimate right ventricular systolic pressure on echo and, by extension, systolic PAP (sPAP), by using tricuspid regurgitant (TR) jet velocity in combination with other echocardiographic findings. Using the modified bernoulli principle 4 x TR jet velocity squared, we can estimate the sPAP. If sPAP >2/3 systemic sBP with severe flattening or posterior bowing of the interventricular septum the patient can be diagnosed with severe pHTN.

Pradip, what if the patient had a PDA on echo — what would you see?

Rahul, when you see Predominantly right-to-left shunting across the PDA suggests suprasystemic sPAP. And as a result these patients can be hypoxemic

Ok, to summarize, we have:

• A 7-month ex-26 week premie infant old with shock with signs of poor perfusion +bounding right ventricle and loud single second heart sound, which brings us to the concern for acute pulmonary hypertensive crises.
• Let's start with a short multiple choice question:

The best treatment for an acute pulmonary hypertension crises in an six month old ex-26 week with premie without congenital heart disease who is mechanically ventilated secondary to RSV bronchiolitis is

A) Sildenafil

B) Hypoventilation

C) Milrinone

D) Sedation and paralysis

Rahul the correct answer is D sedation and paralysis. Although not a choice the I would recommend giving 100% O2 which is a potent vasodilator preferably with bag-mask hyperventilation (which causes alkalemia and causes pulmonary vasculature vasodilatation). Of the choices given in the above question none will be helpful in an acute PH crises although they are frequently used to treat PH in children. Milrinone is a PDE-3 inhibitor (increases cAMP) where as sildenafil is a PDE-5 inhibitor (increases cGMP). Hypoventilation will increase PCO2 which is a potent stimulus for PH crises. If available nitric oxide could be used.

To summarize, acute pHtn you have to think about the pulmonary vasculature — which is responsive to changes in 02, pH, and Co2.

As you think about our case, what would be your differential?

• Cold shock (although the in patients without PH-the cardiac exam will not reveal a loud single S2 or hyperdynamic right ventricle
• "Tet spell"-cyanotic spells typically seen in infants with congenital heart disease with a VSD such as tetralogy of fallot. deoxygenated blood is shunted across fro the right to the left across the VSD due to increased PVR. Cardiac exam may reveal reduced intensity or no murmur (as the murmur due to right ventricular outflow tract obstruction is proportional to the blood flow to the pulmonary circuit).
• We should also be vigilant of obstruction/Kinking of ETT in a patient resulting in hypoxia, bradycardia and cardiac arrest- which may look like a PH crises

Remember due to inc RV afterload you are going to have impairment of forward flow thus clinically presenting with hypoxemia and signs of poor perfusion

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

Really you don't need any investigation during an acute crises especially in a patient with h/o PHTN, h/o chronic lung disease, BPD or an infant with known cyanotic heart disease. Once patient is stable- consider chest radiograph (to check ETT tube position), blood gas for adequacy of ventilation. If patient is febrile then a CBC with differential + blood culture should be considered. An EKG may show RAH, RVH, ECHO may reveal findings suggestive of PH such as enlarged RA/RV, increased RV pressure, systolic flattening of the septum.

Rahul: What is the pathophysiology of an acute PHTN crises?

A pulmonary hypertensive crisis occurs when the pulmonary vasculature presents such a high resistance that there is little or no preload to the left ventricle and a massive, unsustainable afterload to the failing right ventricle. This can be triggered by multiple causes including parenchymal lung disease, Fever,pain, anxiety, tracheal suctioning, hypovolemia, increased cardiac demand, acidemia, aspiration, GE reflux, accidental interruption of prostanoid infusion. The acute massive loss of left ventricular preload and right ventricular afterload results in a drop in systemic cardiac output and coronary blood flow. Decreased coronary flow causes worsening right ventricular function. The higher than systemic right ventricular pressure pushes the interventricular septum into the left ventricle and that further worsens left ventricular filling. A vicious cycle ensues resulting in worsened left ventricular performance, syncope, bradycardia, and asystole.

• Once this point is reached, it is rare that cardiopulmonary resuscitation will successfully return sufficient cardiac output without significant multiorgan damage.
• If our history, physical, and diagnostic investigation led us to acute PH crises as our diagnosis what would be your general management of framework?
• Although PH management depends on the underlying cause-during a acute PH crises the following can be tried:
• If patient is on the ventilator-bag-mask ventilation with 100% O2 will vasodilate the pulmonary vasculature. O2 is a potent vasodilator and hyperventilation will decrease the PCO2 also causing vasodilation
• Bolus of sedation (decreases sympathetic drive) and a dose of NMB such as rocuronium will further relax the vasculature
• Nitric oxide can be used (start at 20-40ppm) if available-as it is a direct pulmonary vasodilator (works by increasing cGMP), causes selective pulmonary vasodilation (improves VQ matching as well as PVR)
• Great rahul - further, Correct metabolic acidosis using NAHCO3
• Treat bradycardia and hypotension
• Use fluid bolus if patient is dehydrated or over diuresed.
• After acute crises is mitigated - consideration for anti-reflux therapy of treatment of infection should be highly considered. A short course of steroids can also be used to decrease inflammation although these may not help in an acute crises.
• We have used epoprostenol (PGI2) infusion more to treat acute PH rather than in a crises. Typically started at 2ng/kg/min and slowly increased by 2ng/kg/min to a max of 9-11ng/kg/min.

OK to summarize, long term management focuses on modulating NO pathway, endothelin pathway, and prostacyclin pathway.

Are there any recent publications related to acute PH crises?

• We have posted references on our website picudoconcall.org (should NOT go through all below but just say posted in our shownotes)
• Lau EMT, Giannoulatou E, Celermajer DS, Humbert M. Epidemiology and treatment of pulmonary arterial hypertension. Nat Rev Cardiol. 2017 Oct;14(10):603-614. doi: 10.1038/nrcardio.2017.84. Epub 2017 Jun 8. PMID: 28593996.
• Hansmann G. Pulmonary Hypertension in Infants, Children, and Young Adults. J Am Coll Cardiol. 2017 May 23;69(20):2551-2569. doi: 10.1016/j.jacc.2017.03.575. PMID: 28521893.
• Krishnan U, Feinstein JA, Adatia I, Austin ED, Mullen MP, Hopper RK, Hanna B, Romer L, Keller RL, Fineman J, Steinhorn R, Kinsella JP, Ivy DD, Rosenzweig EB, Raj U, Humpl T, Abman SH; Pediatric Pulmonary Hypertension Network (PPHNet). Evaluation and Management of Pulmonary Hypertension in Children with Bronchopulmonary Dysplasia. J Pediatr. 2017 Sep;188:24-34.e1. doi: 10.1016/j.jpeds.2017.05.029. Epub 2017 Jun 20. PMID: 28645441.
• Del Pizzo J, Hanna B. Emergency Management of Pediatric Pulmonary Hypertension. Pediatr Emerg Care. 2016 Jan;32(1):49-55. doi: 10.1097/PEC.0000000000000674. PMID: 26720067.

Rahul, where can more information can be found:

• Fuhrman & Zimmerman - Textbook of Pediatric Critical Care Chapter 53: Diseases of the Pulmonary Circulation by Zhang H et al.
• Rahul what are the key objective take-aways:

1. Acute PHTN crises is a life threatening event that requires immediate therapy using oxygen, sedation+paralysis, inhaled nitric oxide, prevention of bradycardia and hypotension.
2. A multidisciplinary team approach with specialists from cardiology, pulmonary teams are needed in the management of patients with PH in the picu. Intensivists should understand the triggers for acute PH crises and try to avoid these triggers to prevent such crises.

This concludes our episode on acute pulmonary hypertensive crises. 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 hosted by myself 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. My name is Pradip Kamat.

My name is Rahul Damania, a current 3rd year pediatric critical care fellow. We come to you from Emory University School of Medicine-Children's Healthcare of Atlanta.

Today's episode is very special as we are going to be discussing 7 Habits of Highly Effective PICU fellows. As many trainees, both residents and fellows are settling into the year, We wanted to make a special podcast which highlights some key, high value habits Which can make the pediatric critical care experience very fruitful longitudinally!

We are delighted to be joined by Dr. Kevin Kuo and Dr. Paige Stevens.

Dr. Kuo is a Clinical Associate Professor, Pediatrics - Critical Care as well as the Program Director, Pediatric Critical Care Fellowship at Stanford University. Notably, Dr. Kuo is also the site creator and editor of the informational & well-known PICU website learnpicu.com- which accumulates over 10K views a month. Dr. Paige Stevens is a PCCM fellow at Stanford University and is here to provide the trainee perspective.

Dr. Kuo and Dr Stevens - we are delighted to have you. Welcome to PICU doc on call podcast.

• Dr Kuo or Stevens: Thank You Pradip and Rahul for having us on PICU Doc on Call. We have no relevant financial disclosures or conflicts of interest.

Our episode will be a series of actionable steps which can optimize your passion and performance in the PICU. This episode was inspired by the very famous book: The 7 Habits of Highly Effective People by Steven Covey which is an international bestseller.

To start with our episode, Dr. Kuo, do you mind highlighting the 7 Habits which we will cover:

• KK: Sure, here they are:
• From Dr. Covey's book we wanted to start with Begin with the End in Mind as the first habit
• Second, Embrace a Growth Mindset
• Third, Eat a Piece of Humble Pie Daily
• Fourth, Remember the ABCs
• Fifth, Put on Your Own Oxygen Mask First
• Sixth, Be Aware of the Meta
• Seventh, Sing in the Rain

Awesome, I can't wait to get into each of these. Dr. Kuo can you start us off with the first habit — Begin with the End in Mind?

• Dr. Kuo: sure
• 3 years goes by very quickly - what do you want your career to look like, what skills do you want to have gained, what things do you want to accomplish by the end of your three years, where do you want to work when you finish (academic vs community)?
• Be honest with what your interests and career goals are - i.e. not everyone needs to be an R01 funded basic scientist (although that is certainly needed and a wonderful career path).
• This is also great advice for people interviewing for fellowship. If you have a clear idea of who you want to be at the end of training, it will be easier to find a program that is going to help you get there. If you don’t know, you might want to choose a program where fellows go on to successfully do a broad range of things well.

Excellent approach and mindset especially for residents applying for PICU and matching in a few short months.

Dr. Stevens: What about the Growth Mindset?

• PS: Starting with the Growth Mindset is to
• Be active in the continual process of self-reflection and evaluating your strengths and areas for growth- use those ILP’s and conversations with your mentors.
• Be active in the continual process of seeking out feedback from others. You may not always be able to see the full perspective so seek it out from everyone you interact with.
• When you find areas for improvement after self-reflection or receive feedback from others, embrace a growth mindset and a desire to incorporate that feedback and enact change.

This habit reminds me of a great book known as Mindset: The New Psychology of Success by Carol Dwek, a PhD psychologist who has transformed the way we think about personal development, resilience, and optimism — definitely a trainee read.

Dr. Kuo, as you grow your experience as an attending what does the third habit, Eat a Piece of the Humble Pie mean to you?

• Dr Kuo:
• In the ICU we are constantly asked to be a "Jack of all Trades" ranging from a pulmonologist, to a cardiologist, to a nephrologist, to a transplant specialist, to a proceduralist... Our division chief Tim always says, "The minute you think you know it all is the day you should retire." You can't know it all and, at the end of the day, knowing and admitting what you don't know and asking for help is one of the most important things you can do.
• Additionally, even the things you think you know now (ie blood transfusion for EGDT in sepsis, looking for UTI's in RSV etc) could very well change during your years in practice.
• Approach each day with an eagerness to learn from those around you: your patients, your colleagues, your trainees, your RNs, RTs, Child Life specialists, Chaplains, etc. Ties into Covey’s “Seek first to understand, then be understood.”

Thank you for highlighting this invaluable characteristic — as ICU is a team sport humility and ego sublimation is paramount to success.

Lets transition to some productivity and self-compassion techniques - our next two habits are Remember the ABCs & Put your Own Oxygen Mask on — Dr. Kuo can you go into the prioritization of Airway Breathing Circulation in a bit more detail pls?

1. Dr Kuo: Remember the ABCs

• Just like in a resuscitation where you must prioritize the ABCs above all else, learning the art of prioritization is a skill that will go a long way in all aspects of your clinical skills and career.
• Concept of 4 quadrants (Covey): important/unimportant/urgent/nonurgent quadrants. There will always be something more that needs to be done, the real art comes in choosing your next step wisely

1. Dr Stevens: Put on Your Own Oxygen Mask First

• In order to best care for others, you need to care for yourself.
• Get in the habit of practicing self-compassion – we see and experience all sorts of challenging things in critical care- at the end of the day, we can only do our very best, continually learn, and the rest really isn’t in our hands.
• This includes building up all aspects of your life both inside and outside of medicine: relationships, finances, staying healthy: sleep, exercise, nutrition, mental health, spiritual health
• Also, surround yourself with people who can help put your oxygen mask on in case of emergencies like family/friends/spiritual community etc

This is great - lets do a quick re-cap thus far: End in Mind, Growth Mindset, Humble Pie, ABCs and O2 mask on first!

Lets round this episode off with our last two. Dr. Kuo what does Be Aware of the MEta mean to you?

1. Dr Kuo: Be Aware of the Meta

• Coming into fellowship, you’re probably worried and thinking about what induction meds to use for that intubation, how to run that code, putting in the line, when to start CRRT or cannulate for ECMO etc. -You’ll almost certainly learn that during fellowship. The “meta” is all the stuff that might not be strictly medical nor made explicit and includes things like: interpersonal interactions-ie picking up on the cue that the nurse/parent/RT etc is worried about something, team dynamics- ie facilitating autonomy for each level of learner on your team, how to run efficient yet helpful rounds, learning when/how to speak in a meeting, thinking about the meaning of the work we do, etc.) Long after you’ve learned most of the explicitly “medical” things, the meta often can be some of the most challenging and humbling parts of what we do.
• To get the most out of your training, take a step back and look at the bigger picture (“meta”) going around you. That, at least in my experience, is where more of the challenges and conflict arises and is the tougher part of the job as you get to be a more seasoned attending.
• Push yourself to see things from others' perspective and to see yourself from others' perspectives.
• Take time to recognize the “meta” of what we do. We have the privilege of taking care of children and families during the most difficult times in their lives. Take a moment to recognize the WOW factor of that privilege.

This is such a great point highlighting humanism in medicine - especially during this pandemic we have come to realize the meta in our care for children.

This has been an awe inspiring podcast today - Dr. Stevens - can you go into our last habit?

1. Dr. Stevens: Sing in the Rain

• Even though there will be challenges, remember to have fun!
• For me, these are the absolute best years of medical training. Yes, the hours may be long but you’re finally getting to do what you want to do. You’re immersed in an environment where you are constantly learning and growing. There are new challenges all the time and, even though things can be nerve wracking, you still have the backup of your attendings. You have great colleagues who you'll remember and may be friends with for the rest of your life.
• People who have fun are fun to be around. You'll be a better team leader, teacher, doctor, consultant, etc. if you find ways to make things fun.

This was an enlightening discussion - lets do a brief summary of each of today's habits:

• Begin with the End in Mind as the first habit
• Second, Embrace a Growth Mindset
• Third, Eat a Piece of Humble Pie Daily
• Fourth, Remember the ABCs
• Fifth, Put on Your Own Oxygen Mask First
• Sixth, Be Aware of the Meta
• Seventh, Sing in the Rain

Rahul-Dr Kuo Paige: What are your tips for first year fellows starting their PICU fellowship

Rahul: Especially during these challenging times due to the COVID-19 pandemic when its seems like there is no end, We advise the fellows to stay reslient and Remember these 7 habits of highly effective fellows. As budding intensivits we are on the path of life-long learning, and this episode allows for us to form a network and lead by example!

This concludes our episode today on 7 Habits of Highly Effective PICU Fellows 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 hosted by me Pradip Kamat and my cohost 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 with a 15 year old Male having hypotension and bradycardia.

Here's the case presented by Rahul:

A 15 year old M presents to the PICU after sustaining an acute trauma. The patient was brought to the ER by his family after being on a boat and lifting a heavy object. He did not fall, sustain any head or extremity trauma, but did feel an achy non-radiating back pain shortly after the event. His grandmother states that the patient kept complaining about the back-pain and over the next few hours the patient became increasingly fatigued and flushed in the face. The patient was able to move his arms and legs and still walk, however family became concerned when the patient had abdominal fullness and was unable to urinate properly. He presents to the emergency department for further evaluation. In the emergency department he is noted to be awake however intermittently sleepy. His vital signs are notable for a HR of 58 bpm and a blood pressure of 85/60. He has 3/5 motor strength in his lower extremities with decreased sensation in his feet. Patellar reflexes are 1+ bilaterally. Rectal tone is normal. Acute resuscitation is begun for this patient.

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

• Acute trigger
• Back pain
• Vital sign instability and lower motor neuron signs.
• All of which bring up a concern for a spinal cord injury.
• Let's transition and discuss some history and physical exam components of this presentation:

1. What are key history features in a child who presents with hypotension and bradycardia?

• As our worry is primarily spinal cord in etiology you would want to ask about trauma — this could be blunt or penetrating trauma
• You also would like to ask about the nature of the injury and scene. It is especially important to inquire with the pre-hospital providers about the nature of the injury and the patient course in transport. Besides our normal ABCs, it is important to ask the care taken regarding spinal cord restriction (such as use of a cervical collar or backboard)
• Another high yield history component when you think about hypotension and bradycardia is to assess for Numbness, weakness, or changes in bowel or bladder habits. In this case the patient had abdominal fullness which maybe due to bladder dysfunction.

This is a great summary of key history findings for patients who present with hypotension and bradycardia as it relates to spinal cord issues. Remember that patients who have Down's syndrome may have a predilection to have lax ligaments especially in the upper verterbrae. As a result, you should have an increased index of suspicion if a Down's Syndrome patient presents with hypotension and bradycardia in the presence or absence of trauma. In a study published in 2017 in Neurocrit Care it was estimated that about 20% of patients with Trisomy 21 may have atlantoaxial instability.

A great point which you just highlighted. Remember that when you approach hypotension and bradycardia, it is also important to focus on cardiac etiologies:

Bradycardia directly pulls down the cardiac output, potentially causing shock, and especially if you have a blunted vasoconstrictor response you can couple this bradycardia with hypotension.I do not want to delve too much out of the scope of today's episode but there is a wide differential for bradycardia but specifically related to history you should consider intoxication as a cause of bradycardia and hypotension.

• This includes:
• Beta-blocker or calcium-channel blocker.
• Central alpha-2 agonist (e.g., clonidine, dexmedetomidine, guanfacine).

Going back to our case, are there some red-flag symptoms or physical exam components which you could highlight when you approach?

Yes, in this patient who we suspect spinal cord injury, we would like to perform a comprehensive neurological exam:

• Motor strength should be tested especially in the lower extremities
• Key muscle groups should be tested to determine level of injury
• Knee extensors are at L3
• Whereas your triceps and biceps can be assessed C5-C7.

On physical exam, this patient had a flushed face, and this could be related to an Interruption of sympathetic chain causing a horner's syndrome like presentation.

Recall that Horner's Syndrome is a triad of ptosis, miosis, and anhidrosis which can present as facial flushing.

During this spinal cord assessment it is important to perform a rectal exam to check for perianal sensation and rectal tone

• If at least 1 is normal in the acute setting, this suggests a sacral-sparing injury and thus an incomplete injury with the potential for some motor recovery

Other physical exam components includes assessing for priapism in male patients. Priapism in male patients may be present from abrupt loss of sympathetic tone to pelvic vasculature, causing a high-flow arterial priapism.

This is a great review of history & physical components for hypotension and bradycardia as a presentation of spinal cord injury — I think the key point here is to remember that this presentation is related to a loss of sympathetics and thus unopposed vagal tone which leads to the acute symptamology of Distributive shock with hypotension and bradycardia

To continue with our case, the patients labs were consistent with:

• Blood gas consistent with a metabolic acidosis
• A lactic acid of 4.6 mg/dL
• His coagulation panel and basic metabolic panel was within normal limits
• EKG was notable for sinus bradycardia with no evidence of heart block.

I would also like listeners to note that in patient with high cervical spinal cord injuries, the presence of hypercarbia suggesting hypoventilation may prompt for the need for early intubation

What did the imaging show in this patient?

• After stabilization, our patient underwent CT showing an T2 spinal cord injury. There was an associated T5 vertebral fracture.

Interesting this may have been related to his boat trauma. Remember listeners, that CT is very sensitive for defining bone fractures in the spine. Because CT is more sensitive than plain films, patients who are suspected to have a spinal injury and have normal plain films should also undergo CT. CT also has advantages over plain films in assessing the patency of the spinal canal. CT also provides some assessment of the paravertebral soft tissues and perhaps of the spinal cord as well, but is inferior in that regard to MRI.

OK, to summarize, we have:

• A 15 yo M who presents after trauma with hypotension, bradycardia, facial flushing and bladder dysfunction. This brings up the concern for spinal or neurogenic shock, the topic of our discussion today.
• Let's start with a short multiple choice question:
• After a MVA, a 16 yo M presents with a HR 50 and MAP 45. Patient is obtunded, gurgling, and resuscitation efforts are begun. His hypotension does not improve with fluid resuscitation. A diagnosis of neurogenic shock is suspected. Stimulation of which of the following receptors is most likely to benefit this patient acutely?

1. nicotinic ach receptors
2. muscarinic ach receptors
3. vasopressin -2 receptors
4. alpha-1 receptors.

The correct answer is D. alpha-1 receptors. Remember that patients with neurogenic shock are devoid of sympathetics. Thus, you want to initiate sympathomimetics early. Some patients may require continuous infusion of norepinephrine, phyenlephrine, or dopamine.

As you think about our case, what would be your differential?

• First off I would make a distinction between Conus medullaris syndrome & Cauda Equina Syndrome.
• To start, the Conus medullaris is the terminal end of the spinal cord. If damaged, these children will have UMN weakness.
• They make have impaired sphincter control early, and Disturbances in urination
• Older children may be able to communicate a feeling of saddle anesthesia.

Pradip, what about cauda eqina syndrome?

Great question. So the Cauda equina is the lumbar and sacral roots caudal from the conus medullaris. These patients are going to have multiple nerves affected and may also have progressive incontinence.

In fact, studies have shown that Finding of urinary retention (post void residual > 100-200 mL) has 90% sensitivity for cauda equina syndrome.

A key distinction between the two is that cauda equaina syndrome in general has an asymmetric weakness with primarily LMN signs. These patient are going to have urinary retention that presents later from the onset of injury.

OK, to summarize, Conus medullaris syndrome you damage spinal cord, think early onset issues of bowel and bladder with UMN vs CE syndrome you have more damage of peripheral nerve roots and you in general will have a progressive inconitence with UMN signs.

RAHUL, I have also heard of this acronym, SCIWORA. What is this clinical entity?

SCIWORA stands for Spinal Cord Injury WithOut Radiographic Abnormality (SCIWORA)

In the pediatric population this differential is greater concern in pediatric population due to laxity of ligaments and weaker muscles

In this disorder, there is No discernible fracture on conventional films or computed tomography scans however patients may have spinal cord injury or on exam neurological deficits. The Mechanism is transient subluxation, stretching, or vascular compromise.

Finally, let's contrast neurogenic shock with spinal shock — this is a subtle distinction clinically but has been described in the literature Rahul can you shed some light on that?

• Spinal Shock Syndrome with a temporary loss of neurologic function and tone below a level of an acute lesion
• Presents as flaccid paralysis, loss of sensation, loss of deep tendon reflexes, and urinary bladder incontinence
• Spinal reflexes often return in a predictive manner with the reflexes in the genital region among the first to reappear
• Spinal shock, when accompanied by hemodynamic compromise with loss of vasomotor tone, is generally going to be known as neurogenic shock. Neurogenic shock typically occurs in patients with a T5 injury and above however can be seen in any lesion throughout the spinal cord.

If our history, physical, and diagnostic investigation led us to neurogenic shock related to acute traumatic spinal cord injury as our diagnosis, what would be your general management of framework?

• We have made a key theme today regarding the interruption of autonomic pathways in the spinal cord causing decreased vascular resistance and bradycardia. As such, your management should be focused on resuscitation and re-initiation of sympathetic tone in the form of vasopressors.
• Remember that Patients with traumatic spinal cord injury may also suffer from hemodynamic shock related to blood loss and other complications.
• An adequate blood pressure is believed to be critical in maintaining adequate perfusion to the injured spinal cord and thereby limiting secondary ischemic injury.
• Bradycardia caused by cervical spinal cord or high thoracic spinal cord disruption may require external pacing or administration of atropine. However in studies atropine has not been shown to completely reverse neurogenic shock.

What about steroid use in spinal cord injuries?

• Methylprednisolone is the only treatment that has been suggested in clinical trials to improve neurologic outcomes in patients with acute, nonpenetrating TSCI. However, the evidence is limited, and its use is debated.
• In animal experiments, administration of glucocorticoids after a spinal cord injury reduces edema, prevents intracellular potassium depletion, and improves neurologic recovery - this is especially true within the first eight hours after injury.
• In 2013, based upon the available evidence, the American Association of Neurological Surgeons and Congress of Neurological Surgeons stated that the use of glucocorticoids in acute spinal cord injury is not recommended. Use of glucocorticoids in this setting appears to be declining.
• Let's focus our management on the vasopressor use — as mentioned prior, vasopressors should be considered in cases of neurogenic shock esp if there is failure to respond to crystalloid, and no alternative diagnosis for hypotension.
• Your go to agents are going to be those that have a-lpha 1 activity to reestabllish vasomotor tone:
• Norepinephrine or Phenylephrine are your medications of choice in this setting
• Note phenylephrine may cause reflex bradycardia as this is a pure alpha one agonist.

In terms of prognosis:

• Adult studies have cited: 10%-20% of patients with spinal cord injuries do not survive to hospitalization.
• Most recovery starts within the first few weeks and plateaus in the first 3-6 months
• Better prognosis for ambulation include
• Younger age, decreased severity of impairment, incomplete injury, and lower level of injury

This is a great time for us to highlight the multi-disciplinary effort that goes into caring for these children. It is important in the acute setting to work closely with neurosurgery, ortho, neurology, and the critical care team and further in the subacute setting involving the rehabilitation team.

• Leading causes of death in children with spinal cord injury are respiratory conditions and pnuemonia so working closely with speech therapy for oromotor function is imperative in management.
• I would advise trainees and anyone interested to consider reading chapter 34 entitled shock states in Fuhrman & Zimmerman - Textbook of Pediatric Critical Care to review the hemodynamic patterns seen in our discussion of neurogenic shock.

This concludes our episode on Neurogenic shock. 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 hosted by myself Pradip Kamat and my cohost Dr. Rahul Damania. Stay tuned for our next episode! Thank you!

References:

Powell A, Davidson L. Pediatric spinal cord injury: a review by organ system. Phys Med Rehabil Clin N Am. 2015 Feb;26(1):109-32. doi: 10.1016/j.pmr.2014.09.002. PMID: 25479784.

Farrell CA, Hannon M, Lee LK. Pediatric spinal cord injury without radiographic abnormality in the era of advanced imaging. Curr Opin Pediatr. 2017 Jun;29(3):286-290. doi: 10.1097/MOP.0000000000000481. PMID: 28306628.

Yue JK, Tsolinas RE, Burke JF, Deng H, Upadhyayula PS, Robinson CK, Lee YM, Chan AK, Winkler EA, Dhall SS. Vasopressor support in managing acute spinal cord injury: current knowledge. J Neurosurg Sci. 2019 Jun;63(3):308-317. doi: 10.23736/S0390-5616.17.04003-6. Epub 2017 Mar 1. PMID: 28252264.