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

I'm Pradip Kamat coming to you from Children’s Healthcare of Atlanta/Emory University School of Medicine

And I'm Rahul Damania from Cleveland Clinic Children’s Hospital and we are two Pediatric ICU physicians passionate about all things MED-ED in the PICU. PICU Doc on Call focuses on interesting PICU cases & management in the acute care pediatric setting so let’s get into our episode:

Welcome to our Episode featuring a 16-year-old male with high-grade fever & abdominal pain.

Here's the case:

• A 16-year-old male patient presents with high-grade fever, abdominal pain, and rash. The patient began experiencing a high-grade fever (102°F/38.9°C) and fatigue for the past 5 days. Over the past 2 days, he has developed diffuse abdominal pain, accompanied by vomiting and diarrhea. The patient also noticed a non-pruritic, maculopapular rash on his trunk and extremities yesterday. The patient has a history of mild asthma, controlled with a rescue inhaler. No history of hospitalizations, surgeries, or other significant medical issues. He uses an albuterol inhaler as needed for asthma symptoms. Up-to-date on all immunizations, including a COVID-19 vaccine booster 4 months ago. The persistence of the high-grade fever, worsening abdominal pain, the appearance of the rash, and the patient becoming increasingly lethargic led the family to seek medical attention urgently.
• Vital Signs on arrival: Temperature: 103.2°F (39.6°C) Heart rate: 135 bpm Respiratory rate: 24 bpm Blood pressure: 88/50 mmHg Oxygen saturation: 95% on room air
• The patient appears acutely ill, uncomfortable, and lethargic. There is a diffuse, non-pruritic, maculopapular rash on the trunk and extremities, with areas of petechiae. A cardiovascular exam reveals tachycardia and muffled heart sounds. Perfusion is 4-5 seconds peripherally. Respiratory exam demonstrates labored breathing with decreased breath sounds at the bases bilaterally. The abdomen is markedly distended, diffusely tender with rebound and guarding. Neurologically, the patient is somnolent but arousable to verbal stimuli, without focal deficits.
• Laboratory findings show elevated WBC, moderate anemia, thrombocytopenia, markedly elevated liver enzymes, and elevated creatinine. Inflammatory markers, including CRP and ESR, are significantly elevated. Imaging reveals bilateral pleural effusions on chest X-ray and a moderately enlarged liver with mild ascites on abdominal ultrasound. Blood cultures are pending, and COVID-19 PCR is negative.
• Patient received aggressive IV fluid resuscitation, antipyretics, and was started on broad-spectrum empiric antibiotics. Supplemental oxygen was administered via a high-flow nasal cannula to maintain adequate oxygen saturation.

To summarize key elements from this case:

• A 16-year-old male presents with a 5-day high-grade fever, abdominal pain, rash, and recent onset of lethargy.
• Exhibits tachycardia, hypotension, and respiratory distress.
• Labs indicate elevated WBC, anemia, thrombocytopenia, liver enzymes, creatinine, and inflammatory markers.
• Imaging reveals pleural effusions and liver enlargement with ascites.

Pradip, do you mind at this point giving me an idea of your thought process at this point and what you feel is the working diagnosis?

• The patient was admitted to the PICU because of a high fever, fast heart rate, low blood pressure, and difficulty breathing, which all suggest a quickly worsening, potentially life-threatening situation. Based on the details from this case, there are a few possible diagnoses we should consider:

• Severe bacterial infection such as septic shock secondary to complicated pneumonia- characterized by the sudden onset of fever, elevated WBC count, and hypotension on exam.

• Atypical presentation of appendicitis or cholecystitis - considering the patient's abdominal pain, distention, and elevated liver enzymes, albeit with nonspecific imaging findings.
• Toxic shock syndrome - suggested by the presence of fever, rash, and multiorgan involvement, including cardiovascular, respiratory, and hepatic manifestations.
• And finally, a systemic inflammatory process:
• This includes Multisystem Inflammatory Syndrome in Children (MIS-C) which is plausible given the patient's age, recent COVID-19 vaccination, and symptoms involving multiple organ systems, along with the elevated inflammatory markers. I would also add an atypical presentation of Kawasaki disease - while less likely due to the patient's age, it cannot be ruled out, given the fever, rash, and cardiovascular involvement.

This is a great differential, and as we narrow down what this patient might have, I think it is important for us to consider that if we have a branchpoint decision to make, what would be an appropriate pressor to use in this patient?

Sure! Let's talk about using cardiovascular agents in the context of this case. As a quick background, vasopressors are often necessary when a patient's heart or circulatory function isn't improving even after making sure even after fluid resuscitation is adequate. These medications work by influencing the biochemical and neurochemical pathways that help control blood vessel tone, contractility, and heart rate.

It's crucial to understand how these vasoactive agents work and their specific pharmacological properties, as well as how the patient's own response to their critical illness might impact how they react to the drug. Also, it’s important to note that a patient's critical condition can also influence drug clearance, so the effects we read about in textbooks might not be exactly what we see at the bedside.

Let’s organize the decision of which pressor to choose by going thru each of the potential vasopressor options we have in our armamentarium, how they work, and the pros & cons of each one.

That sounds like a great idea, but before we get into that when it comes to shock one of the classical teachings which we think about is to categorize the shock as cold shock where the patient has cool extremities, delayed capillary refill, and poor perfusion versus warm shock where the patient is flushed, has flash capillary refill, and hyperdynamic perfusion. Can you shed some light on this cold vs. warm shock characterization?

That's an interesting question! Classically, we've been taught to think about shock in terms of cold and warm categories. As you alluded to, cold shock is typically associated with cool extremities, delayed capillary refill, and poor perfusion, while warm shock is characterized by flushed skin, rapid capillary refill, and hyperdynamic perfusion. However, recent guidelines have moved away from relying solely on these bedside clinical signs to categorize septic shock in children. The 2020 Surviving Sepsis Campaign International Guidelines for the Management of Septic Shock and Sepsis-associated Organ Dysfunction in Children suggest not using these clinical signs in isolation to label septic shock as "warm" or "cold." This recommendation stems from the weak recommendation and very low quality of evidence supporting this classification. Instead, it's crucial to take a more comprehensive approach when evaluating and managing shock in pediatric patients, considering a variety of factors beyond these traditional bedside signs.

Interestingly, an article published in PCCM in 2021 entitled, ‘Clinical Classification of Cold and Warm Shock: Is there a signal in the noise?’ played a bit of a devil’s advocate on the Surviving Sepsis guidelines — in fact, it brought up, the fact that this may be a bit of an uncomfortable recommendation as we frequently rely on our bedside assessments to drive care. It also noted that we are subject to bias, and at times, it’s hard for us to understand what portion of the assessment is true ‘signal’ vs. ‘noise.’

You've brought up a great point! It's important to remember that skin blood flow, as determined by factors like capillary refill time and extremity temperature, may not accurately represent the true state of a patient's circulation. This is because various organs, such as the muscles, gut, coronary, renal, and brain, all have their own unique autoregulation processes.

Interestingly, research has shown that there's no clear benefit to choosing a vasoactive agent based on the traditional classification of "shock type." In a study comparing vasoactive choices and clinical outcomes, investigators found that factors like extremity temperature, capillary refill, and pulse strength were the primary drivers for clinicians to categorize a patient as having warm or cold shock. Pulse pressure and diastolic blood pressure, however, didn't play a significant role in this decision-making process.

Even more fascinating, when the study simulated random allocations of shock type, the vasoactive agent choices were just as likely to match these random classifications as the ones made by clinicians. This finding further emphasizes the need to move beyond the traditional "warm" or "cold" shock categorization and focus on a more comprehensive approach when evaluating and managing pediatric shock patients.

In summary, selecting the right pressor for pediatric patients involves several challenges, including a lack of standardization in clinical examination, discordance between shock elements, and individual variability in response to medications. Additionally, skin perfusion might not accurately reflect vital organ perfusion and optimal therapeutic hemodynamic goals for children are unknown. Recognizing trends in surrogates of CO and constantly reevaluating are at least some mitigation strategies that we can consider to address these challenges.

Let’s go thru a quick multiple-choice question to really kick off our rapid review of pressors:

A 14-year-old with toxic shock syndrome due to osteomyelitis and Staphylococcus aureus bacteremia presents with tachycardia (heart rate of 133 bpm), hypotension (blood pressure of 82/25 mmHg), and tachypnea (respiratory rate of 30 breaths/min). Clinical exam reveals diffuse erythema, bounding pulses, and flash capillary refill. After aggressive fluid resuscitation and central venous catheter placement, his blood pressure slightly improves to 90/21.

Which vasoactive infusion should be initiated? A. Dobutamine B. Dopamine C. Norepinephrine D. Epinephrine E. Milrinone

Rahul, in this particular case, the most appropriate choice of vasoactive infusion would be option C, Norepinephrine. The patient is presenting with toxic shock syndrome, which often involves a distributive shock characterized by vasodilation and low systemic vascular resistance. Norepinephrine, a potent α-adrenergic agonist, helps increase vascular tone and subsequently improves blood pressure. It also has some β-adrenergic effects, which can aid in supporting cardiac function. Given the patient's hypotension and the clinical context, Norepinephrine seems to be the most suitable option to address the patient's hemodynamic instability.

What would be the pros and cons of using NE in a distributive shock picture?

The pros of using Norepinephrine (NE) in distributive shock include its potent vasoconstrictive effects, which are beneficial in shock states characterized by excessive vasodilation. NE also possesses inotropic activity at the myocardial β1-adrenoceptor, supporting cardiac function without significant chronotropic effects, as its low binding affinity for β2-adrenoceptors limits its impact on heart rate. Additionally, NE increases venous tone, facilitating increased venous return, and generally has little effect on pulmonary vascular resistance in patients with normal pulmonary vasculature.

This is very helpful, what about the cons of NE use?

There are cons to using NE in distributive shock as well. Its use should be limited to situations with adequate intravascular volume, as improper use can decrease end-organ perfusion and lead to ischemia, particularly in the kidney and gut. In patients with pulmonary hypertension or increased muscularization of the pulmonary vasculature, NE may increase pulmonary vascular resistance and right ventricular afterload. Furthermore, extravasation of NE can cause severe tissue necrosis, so it should be infused only through central venous sites. If extravasation occurs, treatment with the α-adrenergic antagonist phentolamine can help manage the affected area.

In summary, NE, commonly viewed as a vasoconstrictor, remember also has a high affinity for cardiac β1-adrenoceptors due to its role as a neurotransmitter in sympathetic nerves. This enables it to produce inotropic actions alongside increased vascular resistance. With minimal effect on β2-adrenoceptors, it also has little impact on the atrial pacemaker. In adult studies of cardiogenic shock, NE has been shown to be superior to Epi.

Alright, the next pressor we want to highlight is epinephrine, and to effectively talk about this, let’s contrast it to NE.

Epinephrine and NE differ in their actions on adrenergic receptors and their effects on various circulations. Epinephrine acts on all adrenergic receptors, with low infusion doses primarily impacting β1 & 2-adrenoceptors. It is initially used in postarrest settings but it can typically be transitioned to another vasoactive depending on the clinical state. In contrast to NE, epinephrine has hemodynamic and metabolic effects to keep in mind. At low to moderate doses, epinephrine redirects increased cardiac output towards skeletal muscles and away from splanchnic and renal circulations.

Adding to our discussion, it's worth noting that epinephrine has different effects on coronary perfusion depending on the infusion dose. At lower doses, it can reduce diastolic blood pressure due to its β2-adrenergic effect, while still increasing systolic blood pressure with its positive inotropic effect. This leads to increased pulse pressure. However, the rise in contractility and heart rate also increases myocardial oxygen demand, which in turn boosts coronary blood flow.

At higher infusion doses, epinephrine increases systemic vascular resistance, leading to increased afterload. This, combined with an increased heart rate, significantly elevates myocardial oxygen demand, which is not favorable for patients with cardiogenic shock.

Alright, so here’s a quick active-recall question.

Which vasopressor acts on the alpha-1 receptor that is structurally similar to epinephrine and elevates the SVR and PVR?

• If you said Phenylephrine, you’re absolutely correct!
• Phenylephrine, similar to NE, causes significant arterial vasoconstriction and thus elevates SVR and PVR. It has no inotropic properties; therefore, if cardiac function is impaired, cardiac output may be reduced by the increase in afterload even though the blood pressure increases.

At this juncture, it's essential to underscore a fundamental principle: whenever vasopressors come into the conversation, concurrently, we should be discussing access. Given that these vasopressors have the potential to inflict considerable peripheral and systemic harm if they inadvertently leak into the soft tissue, securing a central line access becomes a vital priority. It's not just important—it's an absolute necessity for effective team coordination and patient safety! These children likely will need an arterial line to see beat-to-beat changes in BP.

Alright, to wrap up this episode, let’s do a quick rapid review of common vasopressors in the PICU.

Ready Pradip?

Yes! Let’s do it!

1. Let’s talk about Dopamine

2. What is Dopamine's mechanism of action?

3. It's a dose-dependent effect:
4. Low dose (1–5 mcg/kg/min) → Renal/splanchnic vasodilation, natriuresis via a D1 receptor effect.
5. As you increase the dose, it has more B and alpha effects → typically at 5–8 mcg/kg/ min, you will see an Increased inotropy, whereas at a high dose (> 10 mcg/kg/min) you will see increased SVR, PVR.

Please note, that there is little to no evidence to support the use of renal low-dose dopamine in children with shock and typically we go for the direct-acting vasoactive agents.

Let’s talk about Dobutamine next:

What's the mechanism of...