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 of 17-year old with h/o of SLE and now acute liver failure.

Here's the case presented by Rahul:

A 17-year old teenage female year old presents to the PICU with acute liver failure. Important past h/o includes a diagnosis of SLE on therapy with prednisone, mycophenolate (cellcept), and plaquenil.

4 days prior to this admission, patient presented to an OSH with RUQ pain, vomiting (non bloody & no bilious), fever & malaise. Initially due to concern for "lupus Flare" patient was given steroids at the OSH.

At the OSH notable initial labs included a mild transaminitis and an INR of 1.5. She suddenly at the OSH developed fluid refractory hypotension and was started on a pressor. Due to continued worsening of her transaminitis well as a rising INR on her repeat labs she was referred to our tertiary PICU for further management.

Pertinent history also includes a negative urine pregnancy test. No recreational drug use, and only as needed use of Tylenol.

She now is in the PICU. She generally appears tired and ill. She is tachypneic on 4 LPM of nasal canulla and her oxygen saturation is 98%. She has a non-focal lung exam.

Her cardiac exam is notable for tachycardia, and pertinently no gallop, rub or murmur.

Her abdominal exam is non-focal except for mild discomfort on palpation of the RUQ with a palpable liver edge. Her extremities are cool with 3-4 capillary refill time. She is able to answer questions but intermittently doses off. No rash is noted.

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

• H/o of lupus and is on immunosuppressive medications
• New onset fever/malaise
• This sounds like a LUPUS flare as she has a clinical picture of generalized inflammation.

Rahul: Lets pause right here and take a look at key history and physical exam components in a patient who has a chronic auto-immune condition:

• Fever, malaise and feeling tired all signs of constitutional symptoms.
• She has abdominal pain and vomiting that could again be related to systemic inflammation but also an intra-hepatic lesion.

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

• This patient has signs of shock!
• Tachycardia with delayed cap refill and cool extremities
• Tachypnea
• & hepatomegaly which could indicate increased central venous pressures.
• Initially her outside presentation of fluid refractory shock is of utmost concern!
• Fluid refractory shock with multi organ presentation involving liver, kidney and the blood/coagulation systems
• All of these elements bring up a concern for some acute life threatening process such as sepsis, or even immune dys-regulation due to her h/o of Lupus
• To continue with our case, the patients labs were consistent with:Acute liver dysfunction (Elevated AST and ALT in the thousands, Total bilirubin 1.6, GGT 56) although the total bilirubin is not elevated to a degree I would expect.
• AKI (creatinine 2.18)
• An uptrending Coagulopathy with elevated PT and INR: PT 120 and a peak INR of 16
• Thrombocytopenia: Platelets < 50K
• She had a peak lactate 9.2
• and concurrent Metabolic acidemia: serum HCO3 7, and pH 7.18.
• A Pertinent negative: Normal serum ammonia <38 micromol/L (nl < 50)
• Finally, she had an elevated WBC 20.5K/ Hgb 9.7, Platelet 42. CRP 4.2/ESR 5

OK to summarize, we have: a 17 yr old female with SLE on mycophenolate (cellcept) who presents with fever, hypotension, AKI and liver dysfunction with severe coagulopathy, although we do not have other labs- This brings up the concern for acute macrophage activation syndrome (MAS) the topic of our discussion today.

• Let's start with a short multiple choice question:
• 12 year old male with h/o systemic onset juvenile idiopathic arthritis (JIA) presents with fever, rash, hypotension, acute respiratory distress with hypoxia. Mental status is normal. He also has acute kidney injury, transaminitis, coagulopathy, metabolic acidemia as well as anemia and thrombocytopenia. His liver and spleen are enlarged and he has scattered lymphadenopathy. The laboratory findings most suggestive of acute macrophage activation syndrome in this patient is:
• Erythrocyte Sedimentation Rate > 100
• ADAMS13 activity < 10%
• Serum Ferritin > 20, 000ng/mL
• Fibrinogen (> 500mg/dL)
• The correct answer is serum ferritin > 20,000ng/mL. Any patient with systemic JIA who presents with high fever, heptao-splenomegaly with evidence of multi-organ dysfunction should be considered to have the potentially life threatening complication of systemic inflammatory disorders: acute macrophage activation syndrome (MAS) unless proven otherwise. The 2016 Classification criteria for MAS was published (Ravelli A. et al. Ann Rheum Dis 2016; 75:481-489) requires a Ferritin > 684ng/mL and any two of the following:
• A platelet count < 181 X 109/L (181K)
• AST > 48units
• Triglycerides > 156 mg/dL
• Fibrinogen ≤ 360mg/dL

OK lets summarize, platelets less than 180K, fibronogen <360, transaminitis >AST 48 and hypertriglcyeridemia! Remember many of these values are acute phase reactants

Correct Rahul, also the above Laboratory abnormalities should not be otherwise explained by another patient condition, such as concomitant immune-mediated thrombocytopenia, infectious hepatitis, visceral leishmaniasis or familial hyperlipidemia.

Are there any other inflammatory mediators or subtleties you would like to highlight with this disease?

• A falling ESR, especially with a high CRP, is concerning for MAS and is secondary to low fibrinogen in the setting of consumptive coagulopathy.
• In the question, patient's ESR is elevated. Low or absent ADAMS T-13 activity is more suggestive of thrombocytopenic purpura (TTP), which is not the case here as mental status is preserved indicating no CNS involvement. In MAS there is typically consumption of fibrinogen not its elevation. The elevated ferritin (> 10,000ng/mL) along with other systemic findings in the patient in the question is highly suggestive of MAS. Additional labs that would suggest MAS include demonstration of hemophagocytosis in bone marrow or other tissue, elevated D-dimers, lactic acid dehydrogenase (LDH), triglycerides, low natural killer (NK) cell function, and elevated soluble IL-2 receptor levels.

Great highlight of the incorrect answers the pathophysiology of increased immune activation is key along with dysfibrinogenemia — this is likely due to microangiopathic consumption

Rahul can you briefly tell us a bit about macrophage activation syndrome?

• MAS is classified among the group of hemophagocytic lymphohistiocytosis (HLH), so HLH is the umbrella term.
• HLH includes familial HLH and secondary HLH. Secondary HLH is triggered by several causes, including infection, drugs, malignancy, and rheumatic disorder. Remember in our case the patient had Lupus
• In MAS A common hypothesis in MAS is that there is a defect in lymphocyte cytolytic activity, which means that lymphocytes are not able to kill cells appropriately.

Let's break down the pathophysiology a bit further.

1. There is a genetic predisposition, and that is to having increased macrophage responsiveness
2. There is some form of background inflammatory activity. What cytokines are elevated?
3. IL-6
4. IL-1
5. IL-18
6. What does IL-6 do?
7. Decreases NK cell function
8. So now you have bad T cell cytolytic function and decreased NK cell cytolytic function. What does this lead to?
9. Prolonged cell to cell interactions and amplification of a pro0inflammatory cascade.
10. So now we have genetic predisposition some background cytokine inflammatory activity with cytokine production and now we layer in the third element of the pathophysiology — A trigger!
11. What are triggers: acute on chronic inflammation & especially infection!
12. This trigger will be important to capture in our understand as management will be geared towards reversing this trigger. So where does the hemophagocytosis come about in the term hemophagocytic lymphohistiocytosis? Well, the cytokine storm results in activation of macrophages which are known as hemophagocytes. There's a particular cytokine IFN gamma that make macrophages angry and it is this response that can lead to multi-organ dysfunction.

Pradip, now with this summary let's dive into MAS and how it relates to HLH?

• MAS is a life threatening illness is a form of secondary hemophagocytic lymphohistiocytosis (HLH) and a common complication of rheumatologic conditions, such as systemic JIA. The occurence of MAS has been well reported in other autoimmune or auto-inflammatory conditions, such as, adult-onset and childhood-onset systemic lupus erythematosus, Kawasaki disease, and periodic fever syndromes.
• Characteristic clinical features of MAS are high, non-remitting fever, hepatosplenomegaly, generalized lymphadenopathy, central nervous system dysfunction and hemorrhagic manifestations.
• Typical laboratory abnormalities include pancytopenia, increased levels of ferritin, liver enzymes, lactate dehydrogenase, triglycerides, D-dimers and soluble interleukin 2 (IL-2) receptor α (also known as soluble CD25 (sCD25)), and decreased fibrinogen levels.
• A typical histopathological feature of MAS is the accumulation of well differentiated macrophages exhibiting hemophagocytic activity in bone marrow biopsy specimens or aspirates. Although the prevalence of MAS among patients with systemic JIA has been estimated to be ∼10%, recent reports suggest that subclinical MAS may occur in as many as 30–40% of patients with systemic JIA.
• MAS can result in progressive multiorgan failure and eventually a fatal outcome if unrecognized. Recent studies indicate a mortality rate of 8%. Early recognition of MAS is often challenging, given the lack of a single pathognomonic clinical or laboratory feature. Furthermore, histopathological features of hemophagocytosis may not be present in the initial stages and lack specificity for hemophagocytic syndromes. In addition, features of MAS may be difficult to distinguish from other conditions that may present with overlapping manifestations, such as flares of systemic JIA, lupus or systemic infections.
• MAS associated with SLE is rare and the incidence is about 0.9–4.6% but survival from MAS in febrile SLE patients who are admitted to the hospital ranges is 64% vs 97%.(p<0.001) in those without MAS. The odds of in-hospital mortality was 64.5, 95% CI: 7.6-544; p<0.001).

OK so HLH is the umbrella term and if a patient has signs and symptoms of acute inflammation + end organ dysfunction with a chronic rheumatological disease, you defintiely want to consider MAS. MAS in febrile SLE patients has a poor outcome.

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

• Sepsis with DIC or liver dysfunction
• Flare of systemic JIA, lupus or primary rheumatologic disease
• Remember cytokine release syndrome in patients who get CAR-T therapy is a form of MAS.

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

Initial labs include: CBC with diff, DIC panel, CMP, Ferritin, Soluble IL-2R. Blood/urine analysis/cultures. Patient in MOF, I would also trend lactates, blood gas, CMP and DIC panel at least every Q12 and as needed. Consult with rheumatology, infectious disease experts for their help with diagnosis and management. Given difficulty with distinguishing acute liver failure with DIC from MAS, factor V, VII and VIII levels (decreased in sepsis but not in liver disease) may be helpful. Additionally, PICU docs must be vigilant for neutropenic sepsis and opportunistic fungal infections, correct electrolyte imbalances, and use blood products to correct anemia, thrombocytopenia and coagulopathy.

• Alternative biomarkers for MAS—such as soluble IL-2 receptor, CD163, and IL-18—have shown promise. However, these tests are not universally available and generally have long turnaround times.
• It is important to r/o infection early but that may be difficult to do. I would send a viral panel which includes SARS COV-2 PCR
• Imaging: CXR, abdominal ultrasound, and echocardiography

Ferritin > 10K with evidence of hemophagocytosis in the bone marrow is most suggestive of MAS in a patient who has a presentation suggestive of MAS.

Pradip: If our history, physical, and diagnostic investigation led us to Macrophage activation syndrome (MAS) as our diagnosis what would be your general management of framework?

• Good basic PICU care with close attention to airway, breathing and hemodynamics. As modern medicine is a team sport consult with ID, rheumatology, hepatology etc. These patients typically need mechanical ventilation (On CMV use a high PEEP, low FIO2, low TV lung protective strategies). Patients may need HFOV for pulmonary hemorrhage. CVL, arterial lines should be placed. Avoid benzodiazepines for sedation, and prevent secondary kidney or liver toxicity (avoid nephrotoxic medications, dose antibiotics based on levels, avoid acetaminophen). As MAS is not readily distinguishable from sepsis-initial broad-spectrum antibiotics should be initiated.
• Although previously steroids/cyclosporine were the first line therapy: More recently, cytokine specific therapy with agents like anakinra an IL-1 receptor antagonist (2-4mg/kg s.c. every 6-24 hours) is rapidly effective. Anakinra blocks the biologic activity of both IL-1α and IL-1β by competitively inhibiting their binding to IL-1R. IV anakinra may be indicated if platelets < 20, neurologic symptoms and subcutaneous skin edema. A distinct advantage of anakinra is that the drug is less hepatotoxic, less immunosuppressive and has shorter half-life compared to etoposide or tocilizumab. Anakinra may help avoid steroids especially if diagnosis is not clear and there is a danger of masking lymphoma due to the steroids.
• Rahul its important to note that 2 other drugs (IL-1 beta receptor antagonist canakinumab and IL-6 inhibitor tocilizumab) while decreasing some of the clinical findings of MAS- such that patients may present with less fevers and hepatomegaly, as well as change lab features and the patient can thus have lower ferritin, lower fibrinogen, and lower CRP. Moreover, the excellent response of sJIA features to canakinumab and tocilizumab with simultaneous development of MAS features in some patients also suggests that the role of IL-1beta and IL-6 in MAS development might be limited
• In addition, plasma exchange and high-flow continuous veno-venous hemofiltration have shown promise. The use of extracorporeal cytokine removal therapies (CytoSorb) may show some selective efficacy in such patients with MAS.

That was a great summary, I would also advocate for treating the underlying cause!

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

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

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

Welcome to our Episode of 17-year old with h/o of SLE and now acute liver failure.

Here's the case presented by Rahul:

A 17-year old teenage female year old presents to the PICU with acute liver failure. Important past h/o includes a diagnosis of SLE on therapy with prednisone, mycophenolate (cellcept), and plaquenil.

4 days prior to this admission, patient presented to an OSH with RUQ pain, vomiting (non bloody & no bilious), fever & malaise. Initially due to concern for "lupus Flare" patient was given steroids at the OSH.

At the OSH notable initial labs included a mild transaminitis and an INR of 1.5. She suddenly at the OSH developed fluid refractory hypotension and was started on a pressor. Due to continued worsening of her transaminitis well as a rising INR on her repeat labs she was referred to our tertiary PICU for further management.

Pertinent history also includes a negative urine pregnancy test. No recreational drug use, and only as needed use of Tylenol.

She now is in the PICU. She generally appears tired and ill. She is tachypneic on 4 LPM of nasal canulla and her oxygen saturation is 98%. She has a non-focal lung exam.

Her cardiac exam is notable for tachycardia, and pertinently no gallop, rub or murmur.

Her abdominal exam is non-focal except for mild discomfort on palpation of the RUQ with a palpable liver edge. Her extremities are cool with 3-4 capillary refill time. She is able to answer questions but intermittently doses off. No rash is noted.

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

• H/o of lupus and is on immunosuppressive medications
• New onset fever/malaise
• This sounds like a LUPUS flare as she has a clinical picture of generalized inflammation.

Rahul: Lets pause right here and take a look at key history and physical exam components in a patient who has a chronic auto-immune condition:

• Fever, malaise and feeling tired all signs of constitutional symptoms.
• She has abdominal pain and vomiting that could again be related to systemic inflammation but also an intro-hepatic lesion.

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

• This patient has signs of shock!
• Tachycardia with delayed cap refill and cool extremities
• Tachypnea
• & hepatomegaly which could indicate increased central venous pressures.
• Initially her outside presentation of fluid refractory shock is of utmost concern!
• Fluid refractory shock with multi organ presentation involving liver, kidney and the blood/coagulation systems
• All of these elements bring up a concern for some acute life threatening process such as sepsis, or even immune dys-regulation due to her h/o of Lupu

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

• Acute liver dysfunction (Elevated AST and ALT in the thousands, Total bilirubin 1.6, GGT 56) although the total bilirubin is not elevated to a degree I would expect.
• AKI (creatinine 2.18)
• An uptrending Coagulopathy with elevated PT and INR: PT 120 and a peak INR of 16
• Thrombocytopenia: Platelets < 50K
• She had a peak lactate 9.2
• and concurrent Metabolic acidemia: serum HCO3 7, and pH 7.18.
• A Pertinent negative: Normal serum ammonia <38 micromol/L (nl < 50)
• Finally, she had an elevated WBC 20.5K/ Hgb 9.7, Platelet 42. CRP 4.2/ESR 5

OK to summarize, we have: a 17 yr old female with SLE on mycophenolate (cellcept)

• Who presents with fever, hypotension, AKI and liver dysfunction with severe coagulopathy. Although we do not have other labs- This brings up the concern for acute macrophage activation syndrome (MAS) the topic of our discussion today.
• Let's start with a short multiple choice question:
• 12 year old male with h/o systemic onset juvenile idiopathic arthritis (JIA) presents with fever, rash, hypotension, acute respiratory distress with hypoxia. Mental status is normal. He also has acute kidney injury, transaminitis, coagulopathy, metabolic acidemia as well as anemia and thrombocytopenia. His liver and spleen are enlarged and he has scattered lymphadenopathy. The laboratory findings most suggestive of acute macrophage activation syndrome in this patient is:
• Erythrocyte Sedimentation Rate > 100
• ADAMS13 activity < 10%
• Serum Ferritin > 20, 000ng/mL
• Fibrinogen (> 500mg/dL)
• The correct answer is serum ferritin > 20,000ng/mL. Any patient with systemic JIA who presents with high fever, heptao-splenomegaly with evidence of multi-organ dysfunction should be considered to have the potentially life threatening complication of systemic inflammatory disorders: acute macrophage activation syndrome (MAS) unless proven otherwise. The 2016 Classification criteria for MAS was published (Ravelli A. et al. Ann Rheum Dis 2016; 75:481-489) requires a Ferritin > 684ng/mL and any two of the following:
• A platelet count < 181 X 109/L (181K)
• AST > 48units
• Triglycerides > 156 mg/dL
• Fibrinogen ≤ 360mg/dL

Ok, let's summarize: platelets less than 180K, fibronogen <360, transaminitis >AST 48 and hypertriglcyeridemia! Remember many of these values are acute phase reactants

• Correct, Rahul, also the above Laboratory abnormalities should not be otherwise explained by another patient condition, such as concomitant immune-mediated thrombocytopenia, infectious hepatitis, visceral leishmaniasis or familial hyperlipidemia.
• Are there any other inflammatory mediators or subtleties you would like to highlight with this disease?
• A falling ESR, especially with a high CRP, is concerning for MAS and is secondary to low fibrinogen in the setting of consumptive coagulopathy.
• In the question patients ESR is elevated. Low or absent ADAMS T-13 activity is more suggestive of thrombocytopenic purpura (TTP), which is not the case here as mental status is preserved indicating no CNS involvement. In MAS there is typically consumption of fibrinogen not its elevation. The elevated ferritin (> 10,000ng/mL) along with other systemic findings in the patient in the question is highly suggestive of MAS. Additional labs that would suggest MAS include demonstration of hemophagocytosis in bone marrow or other tissue, elevated D-dimers, lactic acid dehydrogenase (LDH), triglycerides, low natural killer (NK) cell function, and elevated soluble IL-2 receptor levels.

Great highlight of the incorrect answers the pathophysiology of increased immune activation is key along with dysfibrinogenemia — this is likely due to microangiopathic consumption

• Rahul can you briefly tell us a bit about macrophage activation syndrome?
• MAS is classified among the group of hemophagocytic lymphohistiocytosis (HLH), so HLH is the umbrella term.
• HLH includes familial HLH and secondary HLH. Secondary HLH is triggered by several causes, including infection, drugs, malignancy, and rheumatic disorder. Remember in our case the patient had Lupus
• In MAS A common hypothesis in MAS is that there is a defect in lymphocyte cytolytic activity, which means that lymphocytes are not able to kill cells appropriately.
• Lets break down the pathophysiology a bit further.

1. There is a genetic predisposition, and that is to having increased macrophage responsiveness
2. There is some form of background inflammatory activity. What cytokines are elevated?
3. IL-6
4. IL-1
5. IL-18
6. What does IL-6 do?
7. Decreases NK cell function
8. So now you have bad T cell cytolytic function and decreased NK cell cytolytic function. What does this lead to?
9. Prolonged cell to cell interactions and amplification of a pro0inflammatory cascade.
10. So now we have genetic predisposition some background cytokine inflammatory activity with cytokine production and now we layer in the third element of the pathophysiology — A trigger!
11. What are triggers: acute on chronic inflammation & especially infection!
12. This trigger will be important to capture in our understand as management will be geared towards reversing this trigger. So where does the hemophagocytosis come about in the term hemophagocytic lymphohistiocytosis? Well, the cytokine storm results in activation of macrophages which are known as hemophagocytes. There's a particular cytokine IFN gamma that make macrophages angry and it is this response that can lead to multi-organ dysfunction.

Pradip, now with this summary let's dive into MAS and how it relates to HLH?

• MAS is a life threatening illness is a form of secondary hemophagocytic lymphohistiocytosis (HLH) and a common complication of rheumatologic conditions, such as systemic JIA. The occurence of MAS has been well reported in other autoimmune or auto-inflammatory conditions, such as, adult-onset and childhood-onset systemic lupus erythematosus, Kawasaki disease, and periodic fever syndromes.
• Characteristic clinical features of MAS are high, non-remitting fever, hepatosplenomegaly, generalized lymphadenopathy, central nervous system dysfunction and hemorrhagic manifestations.
• Typical laboratory abnormalities include pancytopenia, increased levels of ferritin, liver enzymes, lactate dehydrogenase, triglycerides, D-dimers and soluble interleukin 2 (IL-2) receptor α (also known as soluble CD25 (sCD25)), and decreased fibrinogen levels.
• A typical histopathological feature of MAS is the accumulation of well differentiated macrophages exhibiting hemophagocytic activity in bone marrow biopsy specimens or aspirates. Although the prevalence of MAS among patients with systemic JIA has been estimated to be ∼10%, recent reports suggest that subclinical MAS may occur in as many as 30–40% of patients with systemic JIA.
• MAS can result in progressive multiorgan failure and eventually a fatal outcome if unrecognized. Recent studies indicate a mortality rate of 8%. Early recognition of MAS is often challenging, given the lack of a single pathognomonic clinical or laboratory feature. Furthermore, histopathological features of hemophagocytosis may not be present in the initial stages and lack specificity for hemophagocytic syndromes. In addition, features of MAS may be difficult to distinguish from other conditions that may present with overlapping manifestations, such as flares of systemic JIA, lupus or systemic infections.
• MAS associated with SLE is rare and the incidence is about 0.9–4.6% but survival from MAS in febrile SLE patients who are admitted to the hospital ranges is 64% vs 97%.(p<0.001) in those without MAS. The odds of in-hospital mortality was 64.5, 95% CI: 7.6-544; p<0.001).

OK, so HLH is the umbrella term and if a patient has signs and symptoms of acute inflammation + end organ dysfunction with a chronic rheumatological disease, you defintiely want to consider MAS. MAS in febrile SLE patients has a poor outcome.

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

• Sepsis with DIC or liver dysfunction
• Flare of systemic JIA, lupus or primary rheumatologic disease
• Remember cytokine release syndrome in patients who get CAR-T therapy is a form of MAS.
• Pradip: If you had to work up this patient with MAS what would be your diagnostic approach?
• Initial labs include: CBC with diff, DIC panel, CMP, Ferritin, Soluble IL-2R. Blood/urine analysis/cultures. Patient in MOF, I would also trend lactates, blood gas, CMP and DIC panel at least every Q12 and as needed. Consult with rheumatology, infectious disease experts for their help with diagnosis and management. Given difficulty with distinguishing acute liver failure with DIC from MAS, factor V, VII and VIII levels (decreased in sepsis but not in liver disease) may be helpful. Additionally, PICU docs must be vigilant for neutropenic sepsis and opportunistic fungal infections, correct electrolyte imbalances, and use blood products to correct anemia, thrombocytopenia and coagulopathy.
• Alternative biomarkers for MAS—such as soluble IL-2 receptor, CD163, and IL-18—have shown promise. However, these tests are not universally available and generally have long turnaround times.
• It is important to r/o infection early but that may be difficult to do. I would send a viral panel which includes SARS COV-2 PCR
• Imaging: CXR, abdominal ultrasound, and echocardiography

Ferritin > 10K with evidence of hemophagocytosis in the bone marrow is most suggestive of MAS in a patient who has a presentation suggestive of MAS.

• Pradip: If our history, physical, and diagnostic investigation led us to Macrophage activation syndrome (MAS) as our diagnosis what would be your general management of framework?
• Good basic PICU care with close attention to airway, breathing and hemodynamics. As modern medicine is a team sport consult with ID, rheumatology, hepatology etc. These patients typically need mechanical ventilation (On CMV use a high PEEP, low FIO2, low TV lung protective strategies). Patients may need HFOV for pulmonary hemorrhage. CVL, arterial lines should be placed. Avoid benzodiazepines for sedation, and prevent secondary kidney or liver toxicity (avoid nephrotoxic medications, dose antibiotics based on levels, avoid acetaminophen). As MAS is not readily distinguishable from sepsis-initial broad-spectrum antibiotics should be initiated.
• Although previously steroids/cyclosporine were the first line therapy: More recently, cytokine specific therapy with agents like anakinra an IL-1 receptor antagonist (2-4mg/kg s.c. every 6-24 hours) is rapidly effective. Anakinra blocks the biologic activity of both IL-1α and IL-1β by competitively inhibiting their binding to IL-1R. IV anakinra may be indicated if platelets < 20, neurologic symptoms and subcutaneous skin edema. A distinct advantage of anakinra is that the drug is less hepatotoxic, less immunosuppressive and has shorter half-life compared to etoposide or tocilizumab. Anakinra may help avoid steroids especially if diagnosis is not clear and there is a danger of masking lymphoma due to the steroids.
• Rahul its important to note that 2 other drugs (IL-1 beta receptor antagonist canakinumab and IL-6 inhibitor tocilizumab) while decreasing some of the clinical findings of MAS- such that patients may present with less fevers and hepatomegaly, as well as change lab features and the patient can thus have lower ferritin, lower fibrinogen, and lower CRP. Moreover, the excellent response of sJIA features to canakinumab and tocilizumab with simultaneous development of MAS features in some patients also suggests that the role of IL-1beta...

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 in Atlanta, GA.Today we are going to present a case of a 3 year old presenting with bilateral hyper-flexed wrists.

Here is Rahul with our case:

A 3 yo previously healthy M presents to the emergency department after his mother noted his wrists becoming completely stiff and flexed. Despite several attempts to stretch out his wrist, his mother was unable to place them back into position. She brought him to the ED for further evaluation. Importantly, mother denies any trauma or injury. Mom notes that this happened once before one month ago. The episode lasted 10 min and self-resolved. She did not seek medical attention at that time. Patient has no history of bleeding, bruising or chronic medical conditions. His immunizations are UTD. Family hx was relatively unremarkable however the mother states that she gets admitted to the hospital for Kidney Stones 4-5 times per year. She usually follows with a urologist. Though she is on diuretic therapy for recurrent renal stones, she denies that her son has any access to these medications & also denies any ingestion. She does state that patient is a picky eater and does not drink milk but will eat cheese often with 4-5 cups of juice. Mother denies any recent upper respiratory tract symptoms, vomiting, constipation, urinary abnormalities or changes in gait.

Upon presentation to the ED, his vital signs were stable. His physical exam is normal except for Bilateral hands in flexion with digits on flexion as well. After some resistance the examiner was able to extend hands. There were no abrasions or signs of cutaneous injury in his bilateral hands. Full range of motion of elbow and shoulder as well as full range of motion of ankle and knee as well as hip. Prior to drawing blood for a diagnostic work-up the patient undergoes an EKG which shows some artifact but is notable for a prolonged QTc interval of 560.

To summarize key elements from this case so far, we have a toddler with

• Bilateral hyper-flexion of the wrists which seem to be in a tonic state and is recurrent
• A family history of renal metabolic disease.
• and finally, an EKG abnormality.
• Rahul one key pertinent negative at this stage is that there is no trauma & patient has full range of motion at other large joints
• Rahul, let's transition to key history and physical elements when you think about bilateral wrist flexion.

1. This is an interesting chief complaint, however I would tailor my history to assess for trauma as this seems to be a primary MSK issue.

• The key feature here is that the patient has bilateral wrist involvement which brings up the concern for an underlying systemic cause such as an electrolyte abnormality, connective tissue disorder, or muscular abnormality. The family history of recurrent kidney stones points more towards a familial renal or electrolyte problem.
• I would ask about any trauma related to skin wounds. As this patient is in a tonic state, I would worry about tetanus.
• I would also get a good dietary history as excessive juice consumption may have limited nutritional value.

1. On physical exam, I would look for any other MSK abnormalities with this bilateral wrist flexion. Especially if we are heading down the route of nutritional abnormality, electrolyte disturbance or renal anomaly, I would like to assess for any bowing of the legs, joint flaring, any metacarpal shortening, or rib abnormality.

Pradip, I would love to hear more about the emergency room diagnostic work-up in this patient...

• To continue with our case, the patients labs were consistent with:
• A very low ionized calcium of 2.2 (normal 4.4-5.4mg/dl). Also, his total serum Ca was low — < 5mg/dL (Nl range 8.9-10.4mg/dl) with a relatively normal albumin.
• His CMP was notable for an elevated Alkaline Phosphatase at 963 with normal liver function and bilirubin.
• The rest of his electrolytes, renal function, and CBC were normal. As the primary concern was regarding calcium homeostasis, a PTH was sent and revealed a markedly elevated value of 823 pg/mL and his 25 Vitamin D level was low at 3.6 ng
• A urine Ca:Creatine ratio was elevated and finally a radiological joint survey of wrists showed osteopenia, physeal widening consistent with the final impression bringing up concern for rickets.
• The patient was given 60mg/kg of calcium gluconate and was transferred to the PICU for closer diagnostics & monitoring in the setting of severe hypoCa.

OK to summarize, we have:

• A 3 year-old M with bilateral hyper-flexed wrists due to severe hypocalcemia in the setting of hypovitaminosis D.
• Rahul Let's start with a short multiple choice question very relevant to PICU:
• A 5 year boy is admitted PICU with acute respiratory failure secondary to poly-trauma sustained after being involved in a motor vehicle collision in which the boy was an unrestrained passenger. After initial resuscitation with normal saline, the patient received rapid infusion of 4 units of packed red cells for hemorrhagic shock and a Hgb of 3gm% over a very short period of time. The patient is started on phenytoin for seizure prophylaxis due to traumatic brain injury. After initial resuscitation and stabilization, the patient develops an abnormal rhythm on the monitor and is now hypotensive. His blood gas drawn post transfusion is notable for a metabolic alkalosis and an ionized ca of 2. The hypotension and abnormal rhythm improves with IV repletion of calcium gluconate.
• The most likely explanation for the patients hypocalcemia is
• A. Pancreatic injury
• B. Citrate chelation of Ca
• C. Sepsis
• D. Phenytoin
• The correct answer to this question is (B) Citrate Chelation of Serum CaCitrate intoxication is a frequent complication after massive blood transfusions and often presents itself as metabolic alkalosis. The reason this term comes about is due to the conversion of citrate, which is applied as an anticoagulant in blood bags, to bicarbonate, and this conversion happens, predominantly in the liver. So, Stored blood is anti-coagulated using citrate (3 g/unit of RBC), which chelates calcium.
• Typically a healthy adult, the liver metabolizes 3 g of citrate in 5 min. Infusion rates greater than 1 unit of RBC over 5 min, or liver dysfunction, increase citrate concentration and lowers plasma ionized calcium.
• To highlight our other answer choices, we do not have enough evidence to suggest that there is injury to the pancreas at this stage and acute pancreatitis does not cause hypocalcemia this quickly. Although in a relatively subacute setting, acute pancreatitis can lead to hypocalcemia. This is primarily due to auto-digestion of mesenteric fat by activated pancreatic enzymes resulting in release of free fatty acids which form calcium salts, transient hypoparathyroidism and hypomagnesemia.
• While hypocalcemia can be seen in sepsis and critical illness in general and the etiology is usually multifactorial. In sepsis, the effect of the bacteremic state and the inflammatory mediators on PTH secretion and function can result in hypocalcemia.
• Phenytoin is known to cause hypocalcemia by altering the bone and mineral metabolism. It increases impairs normal Vitamin D metabolism, which in turn lowers the calcium absorption from gut and causes hypocalcemia. This effect is unlikely to be seen with use of phenytoin in a patient with normal renal function.

• As we have talked about a few presentations of hypocalcemia thus far as well as calcium homeostasis — but I do want to highlight some subtle but clinically relevant findings in hypocalcemia, namely petechiae - this is because Ca is integral in platelet metabolism and when you have low ica, platelets will have decreased activation and thus you will have physical exam findings related to primary hemostasis. Second, remember that hypocalcemia in neonates may present as stridor.
• 'LETS CONCLUDE OUR PODCAST WITH DIAGNOSTIC WORK-UP & MANAGEMENT FRAMEWORKS. If you had to work up our patient with hypocalcemia, what would be your diagnostic approach?
• Rahul one way to approach any patient with hypocalcemia is to measure serum PTH level. You can then divide causes associated with elevated PTH level & causes associated with low PTH levels.
• In general when serum Ca is low, PTH level should go up by triggering release of Ca and phosphate from the bones as well as absorbing Ca from the kidneys. PTH also will trigger formation of 1,25 dihydroxyvitamin D formation which increases intestinal absorption of Ca and phosphate.
• So if you have have Hypocalcemia and a high PTH level: think of PTH resistance, calcium loss or calcium intake/absorption problems. PTH resistance (endorgan resistance, missense mutations in PTH or hypomagnesemia). Pseudohypoparathyroidism (X-linked dominant) can present with physical findings that variably include short bones, short stature, a stocky build, early-onset obesity and ectopic ossifications, as well as endocrine defects that often include resistance to parathyroid hormone (PTH) and TSH. Patients with PTH resistance usually have high serum phosphate levels.
• Ca loss can be acute (sepsis, acute pancreatitis, TLS and even respiratory alkalosis) OR Chronic causes include renal disease, hyperPhosphatemia and metastases.
• A common cause of poor calcium uptake and poor management of calcium homeostasis is deficiency of or resistance to vitamin D.
• Hypocalcemia and Low PTH level: Can be congenital as in DiGeorge syndrome or acquired causes such as HIV infection, autoimmune, destruction of PTH glands after surgery or radiation. Infiltration of gland with cancer, sarcoidosis, or iron or copper deposition.
• Alright listeners, this can be very confusing with arrows etc. so lets summarize with a conceptual framework. Remember PTH physiologically increases Ca concentration and decreases Phosphate concentration. So if you have hypoparathyroidism, which means that your PTH levels are low, you will have hypoCa & hyperPhosphatemia. With calcium homeostasis disorders take it back to the normal parathryoid axis and then branch out from there
• Exactly Rahul, so how does Vitamin D get integrated into this pathophysiologic or diagnostic framework?
• Vitamin D Deficiency: Could be genetic or acquired: Enzyme deficiencies or Vitamin D receptor problems.
• Common causes include: obesity, malabsorption, and poor exposure to sunlight and problems with nutritional intake which also could be important given "picky eating" behavior in our patient. A toddler typically doesn't consume non dairy sources of calcium (beans/green leafy vegetables)-thus exacerbating poor calcium absorption caused by Vitamin D deficiency. Babies who breast feed and are not supplemented with Vitamin D, those who are premature or if mother had Vitamin D deficiency- can also have Vitamin D deficiency.
• I do want to call out Vitamin D deficiency 2/2 malabsorption as this is frequently tested on boards in the context of cystic fibrosis and the exocrine insufficiency which can occur along with Celiac disease where you get VIt D insufficiency due to intestinal failure.
• Exactly Rahul, whether you're talking about PTH or Vitamin D, to be comprehensive, A good approach for labs would be to send some basic labs such as CBC, CMP, Urine analysis, blood gas, ionized calcium. Labs such as ionized Ca, serum calcium, magnesium, potassium etc help to fix abnormal values quickly which should be the # 1 priority while a search for diagnosis is being made.
• A consult with endocrine as well as nephrology services may help with other labs that need to be sent. The help of our friendly PICU nutritionist is invaluable to get detailed dietary history as well as to make dietary suggestions.
• Let's go into the clinical relevance of these labs which you will get...
• Labs to determine underlying cause include:
• PTH: Key value to investigating cause of hypocalcemia as we have described above.
• Serum phosphate: High level indicates end organ resistance or renal disease. Low value with high PTH suggests secondary hypoparathyroidism such as Vit D deficincy.
• Alkaline phosphatase- a bone turnover marker (elevation in patient with hypocalcemia suggests vitamin D deficiency),
• 25-hydroxyvitamin D (major circulating form of vitamin D and best marker of vitamin D status).
• The blood 25-hydroxyvitamin D level corresponds with vitamin D intake and activity; the half-life of 25-hydroxyvitamin D is 2 to 3 weeks, as compared with a half-life of 4 to 6 hours for 1,25-dihydroxyvitamin D. (hence 25-hydroxy Vit D is measured).
• amylase, lipase(for suspected pancreatitis), CPK (if suspect muscle breakdown), urine ca:creatinine ration (to determine abnormal renal calcium excretion and renal tubular reabsorption)
• Adrenocorticotropin, cortisol, and thyroid-stimulating hormone, for suspected polyendocrine failure
• Rahul we mentioned in our case the imaging and EKG as part of the presentation, what are salient points with regards to these diagnostic tests?
• Imaging studies: x-ray of metaphysis of a long bone (such as wrist or knee). Hand images may show shortened fourth and fifth metacarpals and suggest pseudohypoparathyroidism type 1a. In hypoparathyroidism, skull x-ray may show intracerebral calcifications (such as basal ganglia calcifications). Chest radiograph to evaluate for rachitic rosary.
• EKG: Prolonged QT interval on electrocardiogram as a result of ST-segment lengthening.
• Consult with genetics if there is suspicion for a genetic cause.
• In our patient: The total as well as serum ionized ca are low. there is appropriately elevated PTH as well as alkaline phosphatase, normal serum phosphate level, low 25 hydroxy vitamin D points to severe Vitamin D deficiency due to poor nutritional intake. (Nutritional Rickets)
• If our history, physical, and diagnostic investigation led us to hypocalcemia due to Vitamin D deficiency what would be the management frame work?
• Initial focus should be on providing good basic PICU care. Attention to airway, breathing and hemodynamics should be a priority in such patients.
• Before diving into diagnostics, every attempt to correct abnormal values must be made and the levels frequently reassessed.
• Calcium: If symptomatic or severe, EKG changes: can use 10% calcium gluconate or calcium chloride as boluses followed by calcium gluconate infusion, which should be titrated to maintain normal serum ionized ca levels.
• Remember listeners that ca is a divalent cation so which other divalent cation would you want to also make sure is within reference range in your hypocalcemia management? You got it, magnesium. If patient has hypomagnesemia -correct magnesium concurrently, since hypocalcemia is refractory until magnesium deficiency is corrected.
• You got it! So shifting back to our ca replacement management approach once patient can tolerate PO, they should be given calcium carbonate.
• For patient with vitamin D deficiency or hypoparathyroidism: Supplementation with Vitamin D analogues: 1,25-dihydroxycholecalciferol (calcitriol), or Vitamin D3.
• One thing to watch for as this childs calcium normalizes is the "hungry bone syndrome" a condition in which there is paradoxical worsening of hypocalcemia after initiation of vitamin D therapy. This condition is thought to be due to rapid bone-mineral uptake by the demineralized skeleton, and management may require very high doses of calcium, as well as occasional therapeutic doses of calcitriol (1,25-dihydroxyvitamin D), the active form of vitamin D.
• How do we follow up on such patients and monitor their response to therapy: Follow blood levels of calcium, phosphate, 25-hydroxyvitamin D, PTH, and alkaline phosphatase and the urinary calcium:creatinine ratio approximately 4 weeks after the initiation of treatment and at monthly intervals until resolution of laboratory abnormalities. Most children will show improvement in about 3 months of their radiological abnormalities.
• Pradip where can our listeners read more information about hypocalcemia ?
• Rahul I would highly recommend that our listeners read the Case by Virkud Y et al published in NEJM 2020 (N Engl J Med 2020;383:2462-70. DOI: 10.1056/NEJMcpc2027078)
• Also chapter 71 page 126-pages 877-878 of the latest edition of Furhmanns and Zimmerman's textbook of Pediatric Critical care has information on hypocalcemia.
• Chapter 30, pages 930-933 Lucking et al. Pediatric Critical care Text and Study Guide Second edition volume 1.
• These references will be in the show notes

Alright to summarize today's take home points — remember that when you have hypocalcemia you care going to be twitchy. Remember the mnenonic CATS go NUMB which reviews the...

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 16 year old with fever and a rash.

Here's the case:

A 16 year old F presents to the PICU with generalized weakness, fever and a diffuse rash**.** Three days prior to admission she stated that she was feeling lightheaded and the day after she started having frequent non-bloody diarrhea. She states that she has otherwise been healthy, no sick contacts or travel, and the only change in her life was her menstrual cycle which ended a few days before her symptoms started. She says that about two weeks ago, she went to her primary care physician to get an in-grown toe nail drained, but was able to recover after some analgesia and antibiotics for a week. On day of admission her mother brings her into the ED as she says her rash continues to progress. Her mother states that the rash looks like a sunburn. Mother noticed on day of admission that her daughter now had red injected eyes bilaterally without discharge, and was becoming increasingly confused with her fevers. Of note, the patient has also has had decreased oral intake as she says her mouth quote hurts when she swallows. She has had no sore throat, congestion, dysuria, or headache. She presents to the ED febrile to 39 C and tachycardic to 130 bpm. She is ill appearing and has orthostatic vital signs. Her exam is notable for palpable diffuse myalgia, oropharyngeal hyperemia, diffuse erythroderma, and conjunctival injection. She is noted to have a hyperdynamic precordium and faint crackles bilaterally. Her L toe is mildly erythematous with no discharge, necrosis or pain to palpation. Acute resuscitation and diagnostics are begun and patient is transferred to the pediatric intensive care unit.

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

• Hx of a fever and multisystem involvement including GI manifestations, myalgias, confusion, mucositis, and rash
• This is in the setting of a local drainage procedure and course of antibiotics.
• In addition, she presents now with fever, hypotension, and tachycardia.
• These elements so far bring up a broad differential but for now we can agree that it seems that she has signs of acute inflammation or infection throughout her body.

nsition into some history and physical exam components of this case.

1. If we take a step back, what are key history features in a child who presents with fever & rash?

• Understanding the characteristics of the rash, the evolution, and progression of the rash is important.
• In the setting of myalgias, fever, headache, and rash you should think of assessing for any recent travel as tick-borne illnesses commonly present with this symptomatology.
• You also want to assess for recent antibiotic exposures, sexual history, and surgical history - in our case, our patient had a recent procedure on her toe

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

• Absolutely, when a child presents with fever and a rash, it is important to stratify two major elements:

1. You want to assess the degree of toxicity in relation to the symptomatology:
2. Lethargy, irritatbility, altered sensorium, poor perfusion, pallor or cyanosis may indicate serious illness.
3. Understanding the duration of fever in the setting of suspected total body inflammation is important, however the importance of the heigh of fever in predicting the risk of serious illness is unclear.
4. We will visit a differential a bit later in this podcast, however I do want to highlight that the presence of tachycardia and tachypnea in any patient with fever and rash suggests the possibility of sepsis.
5. When you notice these red-flag symptoms it is important to focus on resuscitation and treatment rather than pursuing diagnostics.

• To continue with our case, our patients labs were consistent with:
• An AKI - with her creatinine being three times the upper limit of normal.
• A transaminitis and indirect hyperbilirubinemia.
• Thrombocytopenia
• Pyuria on UA with negative LE or nitrites.
• And finally, an elevated CPK at 2000 units/L.
• Looking ahead in this case, our patient had negative serologies for RMSF, leptospirosis, measles.

Ok, to summarize, we have:

• 16 yo F who presents with fever, diffuse erythroderma, signs of systemic inflammation, and multi-organ dysfunction all of which bring up concern for Toxic Shock Syndrome, the topic of our discussion today.
• Let's start with a short multiple choice question:
• A patient presents with fever and rash and concern for Staphylococcal Toxic Shock Syndrome. Which of the following describes the mechanism of pathogenesis behind this diagnosis?
• A. Increased TLR-4 binding with LPS.
• B. Endotoxin production.
• C. Increased MHC II binding with T-cell receptor.
• D. Cytokine release of TGF-beta and IL-10.
• The answer is C. Increased MHC II binding with T-cell receptor. Staphylococcal Toxic Shock Syndrome characteristically has a TSST-1 exotoxin which is present in all of menstrual cases toxic shock syndrome and about half the non-menstrual cases of toxic shock syndrome. The interaction and stabilization between the antigen presenting cells and T-cell receptors cause a massive cytokine storm and thus this superAg can be one of the major virulence factors behind the multi-system involvement we see in toxic-shock-syndrome. Interestingly, one of the cytokines which is released in this syndrome is TNF and this inhibits neutrophil function. Data suggests that TSST-1 in addition to TNF do not engender Staph to have a purulent response and this may be due to lack of PMN recruitment.
• As you think about our case, what would be your differential?
• This is an interesting differential however given her symptomatology and disease progression I would focus my differential to infectious entities first. These include but are not limited to:
• Disseminated Meningococcemia ( type of rash, lack of meningismus)
• Rocky Mountain Spotted Fever (type of rash, exposure/travel history)
• Leptospirosis (type of rash/ exposure to rodents feces and urine)
• Dengue fever (bleeding besides arthralgias and rash)
• Typhoid fever
• Now Staph Scalded skin syndrome may have similar nomenclature and pathogenesis as TSS however they are slightly different. A review article published in Clinical Infectious Diseases in 2006, highlighted key differences between SSS and TSS. These included:
• Age — as patients with TSS are older with a median age of 12 years compared to 4 years with SSS.
• Presence of bullae that rupture with light pressure (i.e. are nikolsky sign +) due to SSS's exofoliative toxin.
• And lack of mucous membrane involvement which can stratify this from TSS and other severe exfoliative skin conditions.
• Sepsis or septic shock due to other pathogens is important to have at the top of your differential. Gram negative, fungal pathogens, or culture negative sepsis may clasicilly not be associated with rash but making the empiric diagnosis at the bedside upon presentation is key.
• Ok so we covered differentials related to fever and rash that are infectious in nature. Are there other broad categories to consider?
• Yes, inflammatory causes are important to also pursue:
• Drug reactions may have fever, systemic symptoms, and dermatological involvement. These include Steven Johnsons syndrome (SJS), Toxic epidermal necrolysis (TEN), or DRESS syndrome.
• I would also add COVID-19 related multi inflammatory syndrome to our differential and its close mimicker Kawasaki disease.
• Especially when a child presents with a prodrome of fever for 5 days and systemic signs of inflammation, you should think about Kawasaki disease and also its severe manifestations, namely myocarditis.
• That was a great differential. Before we continue, we want to revisit some key points from our case that narrowed our differential to Staphylococcal Toxic shock syndrome and cover some brief points regarding this condition:
• Firstly, we classically are tested in board exams of the retained tampon leading to TSS however in actuality menstrual cases of TSS are on the decline. This decrease may be explained by the withdrawal of highlight absorbent tampons and the absence of polyacrylate rayon-containing products from the market. Nonetheless, doing a pelvic exam is important to assess for retained tampons.
• At least half of reported Staphylococcal TSS cases are not related to menstruation and thus a variety of clinical circumstances can be associated. In our case, post procedure or surgical wound infections can be a trigger but the literature also cites burns and even respiratory infections such as the flu. In a report of 5300 TSS cases over a decade, the proportion of TSS cases following surgical procedures increased from 15 percent to about 27 percent. The case-fatality rate for non menstrual TSS was 5%.
• Secondly I want to highlight Streptococcal TSS. Surgical triggers may be common in history but in diving into the literature it seems that Streptococcal TSS has more of a virulent nature. These patients present with:
• Myonecrosis and a necrotizing fasciitis picture often with no visible break in the skin.
• They can have coagulopathy liver dysfunction and ARDS
• Typically you will isolate GAS from a normally sterile site but I wanted to highlight this phenomena as these patients can present with vascular collapse!

Let’s conclude by going through a diagnostic and management framework for TSS:

• If you had to work up this patient with TSS, what would be your diagnostic approach?
• Routine blood tests:
• CBC'd
• CMP
• Lactate
• Blood gas
• & coagulation studies is where I would start
• In our case with myositis getting a CK is reasonable
• Microbiological testing including 2 sets of blood cultures, UA, urine cultures, and as mentioned blood cultures will be important.
• I would also consider getting a wound culture if there is a surgical site abnormality along with inflammatory markers.
• Key point It is important to do a pelvic exam and nasopharyngeal exam to isolate any foreign or retained bodies as you want to really establish source control
• Of note, blood and sterile site cultures are positive for S. aureus in <5% of toxic shock cases, and testing for TSST is typically an academic exercise.
• If our history, physical, and diagnostic investigation led us to Toxic Shock Syndrome as our diagnosis what would be your general management of framework?
• Great question, I first off want to say that there have been none to very few randomized trials or evidence-based guidelines defining treatment regimens.
• You will not go wrong in the early stages to parallel the management of septic shock. This includes:
• Aggressive fluid resuscitation use of vasopressors or inotropes
• Initiation of broad spectrum antibiotics
• Supportive measures such as mechanical ventilation or renal replacement therapy when indicated. In a paper published in Annals of IM in 2005, renal dysfunction and central nervous system involvement are common and may occur more often in non menstrual TSS
• I think a key element here is to support end organ dysfunction and also treat the underlying cause - in this case it is the source control.
• What antibiotic regimen would you recommend:
• Clindamycin with Vancomycin can be an initial therapy.
• Studies have cited that the addition of clindamycin as a protein synthesis inhibitor can have the potential to suppress toxin production. Clindamycin is often added for its in vitro ability to suppress toxin production as well as evidence that clindamycin may reduce mortality in patients with streptococcal toxic shock syndrome. This was well defined in an older study published in 1997 which showed toxic shock syndrome toxin-1 (TSST-1) production is completely inhibited by clindamycin in logarithmic and stationary phase growth.
• Excellent review on this, I would also encourage clinicians to consult Pediatric Infectious Disease as their invaluable expertise & following of culture data is crucial.
• Once you get culture data, you can narrow to more MSSA tailored antibiotics like:
• Nafcillin or oxacillin
• Is there a role for IVIg?
• No trials evaluating use in staphylococcal toxic shock syndrome have been identified. However there have been case reports showing efficacy in streptococcal toxic shock syndrome. In vitro data shows that Staph aureus superantigens are less effectively inhibited by IVIG than streptococcal Ag. The Red Book suggests that there could be a potential role for IV Ig in patient with fluid refractory TSS as IVIg may play a role in neutralizing toxin. You should consider this in patients who are critically ill, unresponsive to fluid resuscitation, an undrainable infection, pulmonary edema, and oliguria.
• And finally to add, Use of corticosteroids therapy is controversial. There seems to be a potential survival benefit in animal models.
• Invitro studies show that dexamethasone suppresses TSST-1-induced cytokine production. In a study published in 1984 in JAMA, early adjunctive treatment with corticosteroids may be associated with reduced severity and duration of toxic shock syndrome symptoms but not decreased mortality. The current AAP Red Book does not mention a role for steroids.

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 PICU Doc On Call Mini-Case series. In this episode, we present a 15 year old girl who is admitted for shock after returning from her recent travel to NIgeria.

Here's the case:

13y F with no significant past medical history presents with 4 days of fever, headache, watery, non-bloody diarrhea, non-bloody, non-bilious emesis, decreased PO intake with worsening myalgias, fatigue, and weakness. She had traveled with her mother to Nigeria earlier this month and returned a week ago. Over the weekend mom consulted her pediatrician who prescribed an antiemetic without significant improvement of her symptoms. Once patient progressed to becoming light headed and weak, the mom decided to bring her to ED where she was found to be have tachycardia and hypotension. She required 3 L of crystalloid resuscitation was started an epinephrine continuous infusion and transferred to the PICU. Patient was found to have acute kidney injury with an elevated Cr, as well as a primarily direct hyperbilirubinemia and associated anemia and thrombocytopenia.

Her other history elements were notable for fever and difficulty breathing. Prior to traveling to Nigeria she did receive travel vaccinations and took mefloquine prophylaxis. She also had a negative COVID screen. While in Nigeria she denies exposure to animals, raw food intake, and only recalls that she may have had a few mosquito bites but this was well after returning from Nigeria until 7 days prior to presentation to the ED.

She presents to the PICU with hypotension, tachycardia at 160 bpm, tachypnea, and normal saturations. Her physical exam is notable for cool peripheral extremities, RUQ tenderness, and bilateral crackles.

She had no murmurs or gallops on her initial exam. Pertinently, she had no rash, lymphadenopathy or scleral icterus.

• This is a teenage girl who has fever and constitutional symptoms after returning from travel abroad
• She now presents with fluid refractory shock, tachycardia that is out of proportion to dehydration and signs of end-organ failure.
• Notable negatives include: No LNadenopathy, hepatosplenomegaly, or a rash
• Synthesizing these symptoms together → we are thinking that this picture may be related to a contracted infection or inflammatory condition related to her travel.
• 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 fever and shock after a recent travel outside the US (Nigeria-West Africa)

• Diarrhea and emesis days before presentation
• High Fever with no rash
• Mental status is maintained although she did have an headache
• Light headed and weakness are symptoms suggestive of dehydration and even shock
• Physical exam findings of importance here include- patient presenting with tachycardia, signs of poor perfusion such as delayed cap refill, cool extremities, hypotension. It is unique that even though she has RUQ pain there is no jaundice.

2. Are there some red-flag symptoms or physical exam components which you could highlight in a

patient with the above history and recent travel.

• Weakness, light-headedness, shock, tachycardia, poor perfusion, fever and evidence of multi-organ dysfunction are suggestive of an acute and possibly life threatening infection acquired during travel. Given her travel to West Africa: I would be worried about falciparum malaria, dengue fever, typhoid fever, and cholera. Other diseases to be concerned about especially given her travel h/o include leptospirosis, chickungunya, Crimean-Congo hemorrhagic fever, African tick bite fever etc. I would be also concerned about bacterial sepsis with a source such as the kidney, bowel, or intrapelvic organs.
• To continue with our case, the patients labs were consistent with:
• Anemia 11/33, thrombocytopenia 12, and leukopenia WBC 4.55 with 92% segs. On her smear her RBC morphology was described as normal.
• Elevated BUN and creatinine with no acidemia
• Elevated liver enzymes (AST/ALT and Tbilirubin). Although her synthetic liver function was preserved
• Elevated lactate, a BNP of 309 and troponin of 11.5.
• Given her fever and travel history the ED team also sent a blood culture (large volume) and a thick and thin smears for malaria. In the PICU after consulting with ID service , we sent GI PCR, Dengue serology IgM and IgG) and NS-1 antigen.
• We also did an EKG, ECHO (given her tachycardia and shock).
• The lab personnel called to report that a malarial parasite was seen at 0.8% on the smear. The ID attending who examined the smear confirmed multiple ring forms in cells which goes along with Plasmodium falciparum, but unable to exclude different types of Malaria. A PCR for speciation of type of malaria was also sent.

OK to summarize, we have a:

• 13 yo female who presented with, fever, shock, and multi-organ dysfunction with a h/o recent travel. Given the findings of falciparum malaria on her blood smears, we confirm a diagnosis of falciparum malaria in this patients. Although her parasitemia level is < 5%, her clinical presentation of shock, AKI suggests she has severe malaria.
• Let's start with a short multiple choice question:
• A patient with severe Falciparum malaria who presents in shock, AKI and a parasite level of 10%, and inability to keep PO medications due to emesis, which of the following in the initial drug of choice?
• A. Quinidine
• B. Artemesin
• C. Artensunate
• D. Doxycycline
• Correct answer is C. Artensunate given IV. As recommended by the CDC as well as the American Academy of Pediatrics' Red book. IV Quinidine is no longer available in the US.
• Artemesin can be used if patient can tolerate PO while awaiting IV Artensunate. Drugs like doxycycline are slow acting antimalarials that would not take effect until well after 24 hours and are not effective in severe malaria. Other PO medications which can be used include artemether-lumefantrine (Coartem™) because of its fast onset of action as well as atovaquone-proguanil (Malarone), quinine, and mefloquine. As for any malaria treatment, the interim regimen should not include the medication used for chemoprophylaxis if possible.
• As you think about our case, what would be your differential?
• Broadly speaking you want to think about other causes of fever, and shock with multiorgan dysfunction in a traveler returning to the US, I would think of
• Sepsis (pyelonephritis, pneumonia, ruptured appendicitis, ovarian abscess etc.): Negative blood culture
• Leptospirosis (no exposure to rodent or food contaminated with rodents urine or feces. No conjunctivitis, rash or jaundice)
• Typhoid fever (GI PCR would confirm)
• Dengue (no rash or muscle/joint or eye pain
• Chickungunya (no joint pain or rash, argues against this)
• Ebola (lack of conjunctivitis, DIC/hemorrhage)
• Food poisoning and hypovolemic shock (fever would be unlikely)
• Always think of SARS-COV-2 especially in this child who is not vaccinated. Her presentation with fever, GI symptoms and shock could be a manifestation of MIS-C. (SARS CoV-2 Ab negative)
• Rahul if a patient develops a fever or symptoms 21 days after travel to a foreign country certain disease such as dengue, rickettsial infections, Zika virus infection, and viral hemorrhagic fevers are unlikely, regardless of the traveler’s exposure history.
• Infectious causes may be further narrowed by pretravel vaccinations and chemoprophylaxis, although neither approach is 100% effective like our patient who did not take her mefloquine correctly. The incubation period (time to onset of malaria symptoms) in most cases ranges from as soon as 7 days after being bitten by an infected mosquito to about 30 days and is shortest for P falciparum and longest for P malariae
• If you had to work up this patient with severe malaria what would be some of the lab investigations you would send:
• Fever in a returning traveler requires a good history and a physical examination. Besides a complete blood count with differential, comprehensive metabolic panel, CRP, Procal, blood Cx (large volume), UA/UCx and in a patient with shock and poor perfusion- I would send a lactate, get a chest radiograph, EKG and an echocardiograph.
• After consulting with infectious diseases: I would send thick and thin (to speciate type of parasite) blood films to test for malaria parasite. The thick film allows for concentration of the blood to find parasites that may be present at low density, whereas the thin film is most useful for species identification and determination of the density of red blood cells infected with parasites. If initial blood smears test negative for Plasmodium species but malaria remains a possibility, the smear should be repeated every 12 to 24 hours during a 72-hour period, ideally with at least 3 smears. Serologic testing (rapid diagnostic test or RDT) generally is not helpful. PCR is most useful to confirm species of malaria. If there is diarrhea and vomiting then a GI PCR and testing for SARS-COV-2 maybe useful. If there are respiratory symptoms respiratory viral panel which includes SARS-COV-2 must be performed. Serologic testing for dengue, chikungunya, leptospirosis and rickettsioses may be required. If there is fever with abdominal pain or tenderness- suspect acute cholangitis (stones, liver flukes), liver abscess (pyogenic or amoebic)-may need ultrasound, blood cultures or stool examination. Practitioners to keep in mind that the returning traveler may present with ruptured appendicitis, UTI/pyelonephritis, pancreatitis etc). These conditions need to be sought with appropriate lab and imaging.

To summarize - thick smears finds the parasites whereas thin is for species identification

• If our history, physical, and diagnostic investigation led us to severe malaria as our diagnosis what would be your general management of framework?
• Let me reiterate that a patient is said to have severe malaria if the patient's parasite load is ≥ 5% or the patient has any of the following:
• Impaired consciousness, Seizures, Circulatory collapse/shock, Pulmonary edema or acute respiratory distress syndrome (ARDS), Acidosis, Acute kidney injury, Abnormal bleeding or disseminated intravascular coagulation (DIC), Jaundice (must be accompanied by at least one other sign) and Severe anemia (Hb <7 g/dL).
• Cerebral malaria, characterized by altered mental status and manifesting with a range of neurologic signs and symptoms, including generalized seizures, signs of increased intracranial pressure (confusion and progression to stupor or coma), and death
• Any patient with severe malaria requires admission to the PICU as there can be rapid decline in the patients clinical status. Initial management of airway, breathing followed by resuscitation with balanced intravenous fluids should be started. Frequent checks as well as correction of glucose and electrolyte imbalances is recommended as well as close monitoring of urine output.
• Rahul our patient had mild cardiomegaly on CXR, mildly depressed cardiac function (LV and RV) on echo and mild elevation of her BNP and troponin. Can you shed some light on myocardial depression in patients with severe malaria?
• Pradip-initially our patient presented in shock so a quick echo done at bedside revealed some mild-moderate cardiac dysfunction with no pericardial effusion. An EKG revealed diffuse ST segment elevation. Patient was on epinephrine and MIlrinone for her cardiac dysfunction. Her echo+ekg findings along with elevated biomarkers were strongly suggestive of malarial myocarditis. Mainstay of treatment consists of hemodynamic cardiac support and treatment of the underlying malarial infection. We saw gradual improvement of her cardiac function with malaria therapy. In fact a cardiac MRI done prior to discharge was completely normal.

A recent paper by Kotlyar et al in PCCM journal (2018; 19:179–185) reported on myocardial function and Injury by echocardiography and cardiac biomarkers in African Children with severe plasmodium falciparum malaria. The authors reported from their echocardiographic data that most children (96.2%) with severe P. falciparum malaria have normal EF despite some elevation of the cardiac biomarkers. Although there was evidence for myocardial injury (elevated cardiac troponin I), this did not correlate with cardiac dysfunction.

• Pradip Let's go into specific elements of management, how would you treat severe malaria
• CDC malaria clinicians are on call 24/7 to provide advice to healthcare providers on the diagnosis and treatment of malaria and can be reached through the CDC Malaria Hotline
• For severe malaria: IV artensunate is the drug of choice . If patient is able to take PO, the patient should be treated with artemether-lumefantrine (Coartem™) because of its fast onset of action, or atovaquone-proguanil (Malarone). When IV artesunate arrives, immediately discontinue the oral medication and start parenteral treatment. Each dose of IV artesunate is 2.4 mg/kg. A dose of IV artesunate should be given at 0, 12, and 24 hours. Patients on treatment for severe malaria should have one set of blood smears (thick and thin smear) performed every 12–24 hours until a negative result (no Plasmodium parasites are detected) is reported. If, after the 3rd IV artesunate dose, the patient’s parasite density is >1%, IV artesunate treatment should be continued with the recommended dose once a day for a maximum of 7 days until parasite density is ≤1%. Doses given at 0, 12, and 24 hours count as 1 day, which means up to 6 additional days. Clinicians should proceed with full course of oral follow-on treatment as above as soon as parasite density ≤1% and the patient is able to tolerate oral medications.
• Intravenous artesunate is safe in infants, children, and pregnant women in the second and third trimesters. The only formal contraindication to IV artesunate treatment is known allergy to IV artemisinins.
• All persons treated for severe malaria with IV artesunate should be monitored weekly for up to four weeks after treatment initiation for evidence of hemolytic anemia.
• As for any malaria treatment, the regimen selection should not include the medication used for chemoprophylaxis.
• Previously, CDC recommended exchange transfusion be considered for certain severely ill persons. However, exchange transfusion has not been proven beneficial in an adequately powered randomized controlled trial. In 2013, CDC conducted an analysis of cases of severe malaria treated with exchange transfusion and was unable to demonstrate a survival benefit of the procedure. Considering this evidence, CDC no longer recommends the use of exchange transfusion as an adjunct procedure for the treatment of severe malaria.

This concludes our PICU Mini case Series Episode on Fever and shock in the PICU patient after recent travel . 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!

• More information can be found
• Thwaites G and Day Nicholas PJ. Approach to fever in the returning traveler. N Engl J Med 2017; 376:548-560
• AAP Red Book 2021. Page 493-503
• Gupta et al, "Malaria and the Heart: JACC State-Of-The-Art Review." J Am Coll Cardiol. 2021 Mar, 77 (8) 1110–1121,
• Kotlyar S, Olupot-Olupot P, Nteziyaremye J, et al.Assessment of Myocardial Function and Injury by Echocardiography and Cardiac Biomarkers in African Children With Severe Plasmodium falciparum Malaria. Pediatric Critical Care Medicine 2018; 19:179–185

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 9 year old girl with worsening seizures in the setting of an electrolyte abnormality.

Here's the case:

A 9 year old girl presents to the ED with increased frequency of seizures, dehydration and listlessness. She has h/o of global developmental delay, congenital hydrocephalous (with VP shunt in place with her last revision 3 years prior, and seizure d/o treated with Leviteracetam. She usually has one or two focal seizures per day but on day of admission she had multiple prolonged seizures which were also generalized tonic clonic in semiology. Per her caregiver, the patient usually eats by mouth and mother typically gives her 3 cups of water daily. There is no history of diarrhea but patient has had 2-3 bouts of non-bloody non-bilous emesis on day of presentation. Looking at her growth chart, the patient has also lost ~ 2KG of her weight in the last 3 months and has had poor follow up with her PCP. In the ED she has a hypovolemic shock picture as she is hypothermic, tachycardic, tachpneic, and hypotensive with appropriate saturations. Blood gas is notable for a mild metabolic acidosis. Patient receives abortive seizure rescue. A head CT showed no increased in hydrocephalus, no mass or hemorrhage and a shunt series confirms patency of her VP shunt. Most pertinently to this case, her serum sodium on her RFP was undetectable at a value of = >200mEQ/dL; this was confirmed by a repeat lab draw and POC value. Other notable findings included an elevated Cr for age, an elevated BUN and a microcytic anemia. Patient was given a NS bolus, had cultures drawn, was started on broad spectrum abx therapy, stabilized and sent to the PICU.

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

• A history of GDD with epilepsy and shunted hydrocephalus.
• A stigmata of cachexia.
• And a presentation of hypovolemic shock secondary to decreased intake, increased loss, and potential underlying concern for sepsis.
• The most important element of this case is her extreme hypernatremia
• All of these factors in this case point to our topic of discussion today → the approach to hypovloemic hypernatremia 2/2 to dehydration.
• Let's transition into some history and physical exam components of hypovolemic hypernatremia?

1. Key history features in patients who present with Hypovolemic HyperNa include:

• Increased losses such as emesis
• Decreased intake, and in this setting potentially lack of access to free water
• Listlessness which could be related to cerebral hypoperfusion
• Increase in seizure frequency due to increased rapid depolarization of Na channels in the brain and fluid shifts
• And weight loss → all of these factors were seen in our case.
• Of note if this patient was a neonate considering a high-pitched cry in the setting of hyperNa & dehydration could be a subtle history finding.

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

• Our patient is Non verbal and has global delay secondary to a remote neurological insult
• She may not have intact ability to communicate or vocalize thirst.
• Apart from her mucous membranes, dry cracked lips, decreased skin turgor that can be described as doughy, and prolonged capillary refill, I think it is important to highlight her hypotension - as BP is one of the last vital signs in pediatrics to be abnormal in intravascular volume depletion. To me, this really stratifies this patient into severe dehydration and potentially septic shock.

This is a great point — understanding % volume loss and its correlation to vital sign and PE anomalies is key. Remember a sensitive marker for dehydration in pediatrics is tachycardia and a late finding if you are primarily dealing with dehydration is hypotension. This indicates that counter-regulatory responses are unable to maintain adequate systemic vascular resistance (SVR) and that there is a significant loss of intravascular volume. In our patient, we also noticed her weight loss on presentation which not only brings up the concern for malnutrition but it also serves as an adjunct measure of dehydration. In fact, in a 2009 paper assessing dehydration in pediatrics it was noted that the gold standard for confirming the diagnosis of hypovolemia in children is comparison of body weight before and after rehydration.

• To continue with our case, the patients labs were consistent with:
• Severe Hypernatremia
• Elevated BUN and Cr which point to an AKI
• And interestingly mild anemia → this could be a nutritional aberrancy such as iron deficiency anemia or anemia of chronic disease in the setting of her complex underlying condition but it also brings up the concern for hypovolemic shock secondary to bleeding. Pertinently she had no signs of external or internal bleeding, but it is important to stratify this element as your resuscitation efforts — i.e. whether you would give crystalloid or colloid can be guided by this subtlety.

Correct, it is important to highlight that in the setting of dehydration Hct values would be increased. In a 2006 Study in Transfusion, Valeri and colleagues concluded that the Hct values in hypovolemic anemic patients are elevated because the plasma volume does not increase to achieve the normovolemic anemic state.

OK to summarize, we have:

• 9 year old with global developmental delay who has emesis, dehydration and a serum Na of 200 mEq/L. This brings to the topic of our discussion today namely hypernatremia in the PICU.
• Let's start with a short multiple choice question: 15 year old with h/o diabetes insipidus presents with a serum Na of 175mEq/L. 4 months ago his serum Na was 140mEq/L. Currently patient is obtunded with decreased skin turgor, fever and a blood pressure of 140/80 mmHg. Patient has been stressed due to school work and been non compliant with his DDAVP resulting in polyuria for almost 5 days.
• Treatment goal for this patient is

a. Reduce serum sodium concentration to normal in first 12 hours

b. Reduce serum sodium concentration to normal in 24 hours

c. Reduce serum sodium concentration to 150 mEq/L in 24 hours

d. Reduce serum sodium concentration by 10 mEq/L in 24 hours

The correct answer is d. Reduce serum concentration by 10-12 mEq/L in first 24 hours; you can also think of this as not correcting the sodium more than 0.5 meQ/L per hour → thus in 24 hrs you should not lower the sodium by more than 12. I think listeners should remember that it is important to gradually lower the sodium in patients who have developed hypernatremia slowly over a period of days especially when Na is > 165mEq/L. Pradip, why is this?

• Patients with hypernatremia develop idiogenic osmoles to protect the brain from dehydration within hours. Numerous fatal cases of cerebral edema and herniation have occurred with rapid correction over a 24-hour period, leading to recommendations for correction over no less than 48 hours. General trend is for slow correction over 48 hours.

A mnemonic that can be useful is high to low the brain will blow; i.e. if a patient has chronic hypernatremia that is corrected too acutely, you have the potential to develop cerebral edema. In a landmark study published in NEJM in 2015, the authors concluded that rapid correction of hypernatremia can lead to cerebral edema to the relative inability of the brain to extrude idiogenic osmoles. Furthermore a study published in pediatric emergency care in 2013 showed that serum sodium correction rate > 0.5 mEq/L/hour was associated with increased risk of mortality and convulsion in neonates with hypernatremia dehydration admitted to neonatal intensive care unit.

Rahul: what would be some of the anatomic changes seen in the brain due to the resultant hyperosmolarity from hypernatremia?

• Anatomic changes seen with the hyperosmolar state include loss of volume of brain cells with resultant tearing of cerebral vessels due to local ECM shear stress forces. As you have an imbalance in frank starling capillary mechanics and subsequent flow through your cerebral vasculature, you may also see capillary and venous congestion, subcortical or subarachnoid bleeding, and interestingly, venous sinus thrombosis.

I'd like to make a big point about the phenomena of sinus venous thrombosis as this has been well described in Pediatric Review articles. Taking it back to the basics, Virchow's triad gives us a framework on how to think about mechanisms of thrombosis. During hypernatremic dehydration at a micro-level there is endothelial stress and subsequent injury which can subsequently lead to venous sinus thrombosis. These patients can present with altered mental status, severe headache, and seizures.

Rahul, that was a great framework → as we conclude our podcast, Iets hone in on three areas: a schema in understanding hypernatremia, a diagnostic approach, and finally a management framework.

In general, how do you think about hypernatremia?

• I think Pradip one easy way to approach hypernatremia is to think of it as a water loss problem or a salt gain problem. Hypernatremia can exist as any of the following 3 scenarios, and these are all correlated to total body water.
• First, low total body water: Patients with a low total body water and hypernatremia have a loss of water in relative excess of sodium losses. This can occur from vomiting and diarrhea or renal losses from osmotic diuresis.
• Second Normal Total body Water: Loss of water occurs without excessive sodium losses in some conditions → these patients are going to be relatively euvolemic. Extrarenal losses result from increased respiratory losses as may occur with tachypnea, hyperventilation, or mechanical ventilation with inadequate humidification are examples of this phenomena.
• We also think about further insensible loss scenarios such as transcutaneous losses associated with fever, burns, extreme prematurity, or use of phototherapy or radiant warmers in the neonate without adequate water replacement. In general, another well-described cause of euvolemic hypernatremia is DI which can be a podcast in and of itself!
• Finally we think about increase in total body sodium and subsequent total body water: Usually from iatrogenic causes such as administration of Na HCO3, hypertonic saline or improperly concentrated infant formula.
• In a 2017 systematic review the authors looked at acute sodium toxicity due to dietary intake. They cited factors such as social media challenges and even charities that advocated eating small amount of salt to empathize with Syrian refugees. They concluded that a lethal dose of <5 teaspoons of salt ingested acutely can lead to pediatric fatality.
• If you had to work up this patient with hypernatremia what would be your diagnostic approach?
• I would highly suggest getting a nephrology consult in this patient.
• A comprehensive metabolic panel, Urine analysis
• Urine analysis especially of the first urine specimen preferably prior to rehydration to determine specific gravity
• If you are suspecting DI, getting urine Na and electrolytes may be indicated
• In this our patient case, she presented with increased seizures and altered sensorium, thus A CT scan of the head is recommended to evaluate for hemorrhage and shunt malfunction.
• Due to hypothermia a blood culture, urine CX, a CBC with diff, CRP and procal would be useful. As this child has concern for increased catabolism in the setting of failure to thrive and lack of access getting a CPK to rule out rhabdomyolysis as a cause of intrinsic AKI would be useful.
• Finally a renal US may be necessary based on laboratory and urinary findings.

I like this list Pradip, totally agree that a coordinated effort with nephrology can help in this setting as these patients may have renal dysfunction and there can be a collaborative effort in tracking electrolytes after we choose the appropriate rehydration fluid management. I would also recommend tracking weights as a part of your initial diagnostic plan!

• Our history physical and investigational undertaking has led us to severe hypernatremia as our diagnosis what would be your general management of framework?
• Patient needs to be adequately resuscitated to correct hypotension, protection of airway, and if necessary AEDs to control of seizures. Continuous EEG monitoring must be considered especially if patient is intubated. Most importantly, correction of underlying disease process giving rise to hypernatremia should be the goal. In our case it was dehydration due to lack of access to free water.
• Gradual correction of serum hypernatremia ~ 12-15 mEq/L/day. Frequent monitoring of serum Na(Q2 hr initially), as well as close eye on UOP
• As hypernatremia is toxic to the beta islet cells, their dysfunction can lead to associated hyperglycemia.
• Estimated deficits, ongoing maintenance requirements, and additional excessive losses must be accounted for in calculations of the amount of fluid replacement required. In general 2-2.5 times maintenance IVF fluids usually with NACl is necessary especially with severe dehydration.
• In a precise academic approach calculating the free water deficit may be helpful:
• The equation is:
• 0.6 x wt (kg) x [(current Na+/140) – 1] = this gives you liters of fluids:
• In acute dehydration you can take this fluid deficit and resusicate 50% of the volume you calculate over the first 12 hrs, and the remaining in the next 24 hrs could be a potential management strategy.
• If patient has central DI: Vasopressin, DDAVP along with replacement of UOP may be needed.
• In hypernatremic dehydration, the intracellular fluid moves into the extravascular space due to hypernatremia hence the patients dehydration may be underestimated.
• If patient has renal failure dialysis may be necessary

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 and we come to you from Children's Healthcare of Atlanta Emory University School of Medicine. Today's episode is dedicated to the rational use of antibiotics in the PICU

We are delighted to be joined by two brilliant Pediatric clinical pharmacists Ms Whitney Moore and Ms. Stephanie Yasechko from Children's Healthcare of Atlanta.

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

• Case

An 8-year-old female (24 kg, 130 cm) with PMH significant for severe persistent asthma and history of multiple PICU admissions presents to the ED with swelling, redness and inability to bear weight in her (L) lower leg.

Patient had just finished soccer practice the evening prior to her ED visit when she first noticed swelling and redness of her left lower leg. She also had a fever as well as some non-bloody, non-bilious emesis. Her past h/o is significant for poorly controlled asthma with multiple admissions to the PICU.

Upon arrival to the ED, patient's BP was hypotensive, tachycardic, and tachypneic. She was given two 20 mL/kg NS boluses, and blood cultures were drawn in addition to a CBC, BMP, and UA.

Labs were notable for an elevated white count, lactate, and serum Cr. Patient was given a dose of antibiotic, and transported to the PICU for further workup and management.

Whitney and Stephanie welcome to PICU Doc on call.

Thanks Rahul and Pradip for having us. Neither one of us have any financial disclosures or conflicts of interest.

We want to divide today's discussion into 3 segments- antibiotic selection, transition into dosing and end with therapeutic monitoring

Whitney, what are some of the factors to consider prior to choosing an antibiotic regimen in our patient case with a preliminary diagnosis of cellulitis of the left lower extremity with possible sepsis?

• Whitney: First and foremost you want to consider your host so really diving deep into the patient’s past medical history and secondly we should consider the likely pathogens that are causing the patient’s infection. In this case given the invasive nature of her infection and recent hospital admissions I would start Vancomycin and Cefepime. Once blood cultures results are back, we can then tailor or narrow her antibiotics based on susceptibilities.

Stephanie what are some of the other factors to consider prior to starting antibiotics in this patient?

• Other things to consider include her multiple previous hospitalizations, significant exposure to broad-spectrum antibiotics, whether or not she is immunocompromised, the presence of chronic conditions like lung disease, ventilator/trach dependency, and if patient was a resident of a long term care facility. Additionally any history of organ or bone marrow transplant or malignancy with use of chemotherapy/radiation, and/or a history of growth of multiple drug resistant organisms.

This is an important point - infectious disease is not just about the relevant pathogen or "bug" but it is also about understanding the host status!

Stephanie -why vancomycin and cefepime in this case?

• In this patient the major pathogens to consider include: P. aeruginosa (give her multiple previous PICU admissions).
• Also she has extensive cellulitis which necessitates antibiotic coverage against Methicillin resistant staph aureus (MRSA) and Streptococcus pyogenes . So our options in this case include vancomycin for broad-spectrum gram positive coverage, and generally either piperacillin/tazobactam or cefepime for broad-spectrum gram negative and pseudomonal coverage.
• As you can see by patient’s Scr, it appears that she is presenting in AKI since we have no history of her having any type of renal impairment at baseline; therefore, to minimize additional AKI risk, cefepime would be our most appropriate choice for the time being. There is literature that shows us that the combination of vancomycin and piperacillin/tazobactam specifically has a much higher risk of AKI than other nephrotoxic combinations and should be avoided if possible.

Whitney lets now transition from abx selection to dosing — how would you dose vancomycin and cefepime in our patient case?

• An appropriate dose of vancomycin to start out here would be 15 mg/kg, with a maximum of 1000 mg. However, instead of scheduling a defined frequency, pharmacy would recommend a x1 dose, and check a level in a couple of hours in patients who present with any type of unstable renal function. However, traditional vancomycin dosing in patients with normal renal function is either 20 mg/kg/dose IV every 8 hours or 15 mg/kg/dose IV every 6 hours with a max of 1000 mg/dose.
• Cefepime is traditionally dosed at 50 mg/kg/dose IV every 8 hours; however, since our patient has AKI, we should calculate her CrCl or estimated GFR to renally adjust the dose. As you all know there are a couple of equations we could use to calculate her clearance. But the modified Bedside Schwartz equation is the gold standard for pediatric patients. Once the GFR or CrCl is calculated we can then adjust the dose for her AKI.

I think this is a great time to start to highlight the importance of collaboration between the intensivists, nursing & the pharmacy team. These children already are tenuous and as we treat with broad spectrum abx it is important to also consider the side effects such as nephrotoxicity of broad spectrum antibiotics.

As we discussed specifics of dosing of Vanc and Cefepime, Stephanie, if we take a step back what are some of the other factors to consider prior to antibiotic dosing?

• In terms of selecting the most appropriate dose, we always want to consider factors like age, weight, renal/hepatic function, as well as the area in the body we wish to penetrate (CNS, bone, blood, etc.).
• Additionally, it is very important to identify whether or not the patient is currently receiving continuous renal replacement therapy(CRRT), plasma exchange, ECMO, or fluids and/or diuretics, because all of these can affect drugs quite significantly from a pharmacokinetic standpoint.
• Lexicomp (available either as a paper-back or online) is the gold standard for pediatric dosing. And of course your clinical pharmacist specialist is always available to help with dosing references, and can provide recommendations on how to most appropriately dose your specific patient

Whitney how would you monitor the patient given evidence of AKI and the need for a nephrotoxic antibiotic such as vancomycin?

• Depending on the severity of the renal dysfunction, the vancomycin level can be checked anywhere from 8-24 hours post administration
• A therapeutic steady-state drug concentration is generally reached after the administration of about 3-4 doses (or 4 to 5 half-lives). The therapeutic goal trough level is 10-15 mcg/mL for all infections, except for those harder to penetrate areas like the CNS or the heart. In these cases the target trough is higher at 15-20 mcg/mL.

To summarize, those "hard to reach areas" such as the blood brain barrier or the heart — we should ensure a higher trough in order for us to reach therapeutic effect.

Stephanie, what are important points regarding trough monitoring for vancomycin?

• Trough monitoring represents a therapeutic controversy within the pharmacy community, as recent vancomycin dosing guidelines have changed to now recommend area under the curve (AUC) guided monitoring as the most efficacious and safe way to monitor the drug given its narrow therapeutic range and increased nephrotoxic risk with trough monitoring.
• Here at our institution, we have not yet fully incorporated this new monitoring technique. We are reserving AUC monitoring for patients with MRSA bacteremia or unable to achieve therapeutic troughs with traditional dosing.

This is a great practical example, as the bedside staff it is important to optimize communication as antibiotic troughs are time sensitive.

Now that we have discussed vancomycin, Stephanie what about dosing and monitoring of cefepime in our patient?

• Cefepime, does not require therapeutic drug monitoring, so determination of an appropriate dose is dependent on CrCL, and it is important to recognize that continuous adjustments may need to be made as renal function improves or declines.
• Refer to Lexicomp for all renal dose adjustments. Rule of thumb, if CrCL > 50, a patient can be dosed normally. Anything less should be evaluated.

Let's wrap up this section by summarizing some important dosing points for Vancomycin and Cefepime. Whitney, as your patient improves how would you approach de-escalation of abx?

• There are two important points I want you to remember when dosing vancomycin and cefepime. First, is knowing the maximum dose of each medication. Cefepime we max the dose at 2000 mg per dose, and our initial starting dose maximum for vancomycin is 1000 mg, as mentioned. We can go up to 1250 but only after we have drawn levels and need to. But knowing the maximum dose is an important point to consider when dosing a large patient because you don’t want to exceed an adult dose. The second important point I want you to remember is calculating the patient’s clearance and adjusting the dose and/or frequency based on the patients renal function if needed.
• Now, in regards to de-escalation of antibiotics, once the patient is no longer septic, with a resolved AKI, and cultures and susceptibilities have resulted, the team will determine if a full treatment course is warranted or not. If it is, then broad-spectrum antibiotics can be discontinued, and we can narrow to an antibiotic that the patient's pathogen is susceptible to.

This is an important point — narrowing broad spectrum antimicrobials optimizes antibiotic stewardship.

As we build on our case, Stephanie, if the blood culture grew Methicillin sensitive staph Aureus (MSSA) what antibiotic would be used and how will it be dosed?

• When a patient's blood culture is positive for MSSA, it is considered an invasive infection. Most common sources of bacteremia include endocarditis, skin and soft tissue infections, intravascular catheter infections, bone and joint infections, pneumonia, etc. and in 25% there is no source.
• MSSA can give rise to sepsis syndrome and septic shock with a mortality of 10-20%.
• We typically use nafcillin or oxacillin 2 gm IV Q4 hours or even an infusion. One retrospective study reported that continuous oxacillin was an effective alternative to intermittent oxacillin for the treatment of infective endocarditis caused by MSSA and may improve microbiological cure.
• Cefazolin can also be used. Patients who cannot be treated with beta-lactams, should be administered vancomycin or daptomycin. For uncomplicated bacteremia, a two week regimen is used. For complicated infection we typically do a 4-6 week course.
• Finally, understanding that patients who have toxic shock syndrome from staphylococcal species, Clindamycin has been shown to have bacteriostatic effects and reduce production of bacterial toxins!

Key points: MSSA likes to form a biofilm especially on internal hardware, and continuous oxacillin may be an effective option for treatment prior to consider removing the hardware for source control.

Our final portion of this podcast relates to specific clinical scenarios. We will be covering broad spectrum therapy for specific patient populations. We will cover anti-microbial coverage for patients who have:

1. Hematologic malignancies
2. Solid organ transplant on immunosuppression
3. Neontal sepsis
4. Sickle cell

and ...Children with:

1. VP shunts
2. Perforated appendicitis
3. Lemierre's disease
4. ...and finally the undifferentiated, critically ill, child.

Whitney lets start with patients who have an underlying hematologic malignancies. What would be an initial empiric anti-microbial regimen for these patients?

• We typically use Cefepime, or zosyn, for gram negative coverage to cover bugs like pseudomonas & enterobacteriaceae. And for enhanced Gram positive coverage for your staph and strep we add vancomycin especially if there is presence of a central line associated bloodstream infection (BSI), or if the patient has severe mucositis, a skin and soft tissue infection, pneumonia or is hemodynamically unstable).
• If the patients fever continues with no source identification by about day 5 (4 to 7 window), consider adding an antifungal agent like micafungin or caspofungin. And if patient happens to already be on an antifungal for prophylaxis, consider adding voriconazole.

And what about the the patient who has a solid organ transplant on immunosuppression who presents with septic shock?

• In transplant patients or those on immunosuppression we should first consider the fact that some immunosuppressive medications are known to be nephrotoxic and interact with other medications. Second thing we should consider like I mentioned before is our host. If they are immune compromised they will need broader coverage. Therefore, the most appropriate choices would be vancomycin and cefepime. If the patient continues to clinically decompensated, then it would be appropriate to add on that antifungal coverage with micafungin.

This is an important point - immuno-suppresants may compound end organ dysfunction and further, may have key drug interactions, such as CYP enzymes, which may alter your antimicrobial or antifungal kinetics.

Stephanie, let's continue with our specific patient populations which antibiotics would we consider in neonatal sepsis?

• Ampicillin +Cefotaxime OR Ampicillin +gentamicin but given shortage of cefotaxime we should consider ampicillin with ceftazidime.
• We want to cover Group B streptococci, E Coli and other gram negatives along with listeria species.
• Discontinue antibiotics if cultures are negative after 48 hours and suspicion for infection is low based on inflammatory markers.

(Stephanie) What about the patient with fever, headache, altered sensorium concerning for bacterial meningitis, can you also comment on the patient with ventriculoperitoneal shunt infection and brain abscess?

• So in this scenario, it is essential to select antimicrobials that penetrate the CNS. Therefore, generally speaking, an appropriate selection would be vancomycin and ceftriaxone. The more inflamed the meninges are, the greater CNS penetration you are going to get with vancomycin. We would also add metronidazole for brain abscess to vancomycin and ceftriaxone to cover for anaerobic organisms.

The addition of Vancomycin combined with Ceftriaxone especially in patients who have meningitis and no hardware is important in overcoming resistant S. Pneumo strains.

Whitney, what is our coverage for perforated appendicitis with sepsis?

• For a perforated appendicitis with sepsis, piperacillin/tazobactam (Zosyn) is our preferred agent. Also the combination of Ampicillin +gentamicin + metronidazole can be used. When thinking of appendicitis you want to cover for your GI bugs like klebsiella, proteus, bacteroides and other anaerobes.
• One thing to note when thinking about gut coverage is clindamycin's resistance to B. fragilis is increasing and is up to 60% worldwide, therefore, it’s no longer recommended for intra-abdominal infections.

Stephanie, What about neck abscesses and septic thrombophlebitis (such as Lemierre syndrome)

• A beta-lactamase resistant beta-lactam antibiotic (ampicillin/sulbactam) is recommended as an empiric therapy due to case reports of treatment failures with penicillin secondary to beta-lactamase producing F. necrophorum.
• Antibiotics should of course be tailored to the culture results and susceptibility data when available.
• Alternative options include clindamycin or metronidazole for patients with significant clinical allergy to beta-lactams. Clindamycin is preferred (for head, neck and lung anaerobic infections) as it has activity against metronidazole-resistant organisms such as actinomycetes and peptostreptococci.

(Allen BW, Anjum F, Bentley TP. Lemierre Syndrome. [Updated 2020 Dec 4]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK499846.)

It is important for us to highlight that the likely microbe associated with Lemierre's is Fusobacterium necrophorum!

Whitney, lets conclude with our final patient population. What is your typical coverage in patient with Sickle cell disease who presents with sepsis, or acute chest syndrome?

• Levofloxacin is our agent of choice in this scenario to provide routine bacterial coverage as well as atypical coverage. Traditionally we would have done a 3rd generation cephalosporin, but we try to avoid the empiric use of ceftriaxone due to the association with life threatening hemolysis after administration.

Though this incidence is rare, it is important to understand that CTX can cause intravascular hemolysis in these patients who already have compromised Oxygen delivery due to their anemia.

Alright Stephanie, we have reached the end of our episode today... but I have one more question, as a fellow, when I am on call and we have a previously healthy child who presents to the PICU who is critically ill and hemodynamically unstable, what antibiotics should we consider ?

• Once again, the concept of where exactly we think the source of the infection is will drive antibiotic selection with the goal of providing the best empiric therapy for the most likely pathogen(s). In a previously healthy patient who has really had no recent hospitalizations or antibiotic exposure, we could start with ceftriaxone. If the patient, however, has MRSA of PSE risk factors, at that point we would then need to broaden to vancomycin and either cefepime/ceftazidime/or piperacillin/tazobactam.

To take this episode home, remember to consider host status, source of infection, and likely microbes prior to initiation of broad spectrum therapy!

Whitney and Stephanie thank you so much for your expertise on common bugs and drugs — this was a great discussion, and we value your expertise. What are your take home clinical pearls for anti-microbials in the PICU..

Stephanie: Your clinical pharmacist can always help with choice of antibiotics as well as dosing and monitoring, especially in critically-ill children with AKI or hepatic dysfunction.

Whitney: The...

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

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

Today's episode is dedicated to How to Read And Critically Review a Paper not only for the Journal club presentation at the fellows conferences but also for use in your clinical practice as a pediatric intensivist.

We are delighted to be joined by Jocelyn Grunwell, MD, PhD. Dr. Grunwell is an Assistant Professor of Pediatrics-Pediatric Critical Critical Care at Emory University School of Medicine in Atlanta, GA. She is a K-scholar with research interests in mitochondrial dysfunction in critical illness, the airway immune response in pediatric acute respiratory distress syndrome, and near-fatal asthma. She is on twitter @GrunwellJocelyn.

Rahul: Dr Grunwell welcome to picu doc on call. We are delighted to have you on our podcast today to discuss how to read & critically review a manuscript.

Grunwell: Thank you Rahul and Pradip for having me on PICU DOC on Call. I have no conflicts of interest or financial disclosures.

Q1. Rahul: Dr Grunwell: Why should a pediatric intensivist (whether in training or as a faculty) read journal articles?

Grunwell: There are several reasons you might want to read journal articles, and your reading should be tailored to your goals. For example, first, you may want to learn more about a clinical topic to understand how to diagnose, treat or manage a disease. 2nd you may want to find the best evidence for how to treat a patient. 3rd, you may want to learn about the basic biology or mechanisms of a disease. Finally, you may want to identify gaps in a particular field of research to develop a research plan and write a proposal to explore a new research area.

Q2: Dr Grunwell: Where do you find manuscripts relevant to intensivists?

First, I would like to suggest that the learners and faculty in pediatric critical care make a habit of reading at the very least the abstracts in various pediatric journals even if they don't have the time to read an entire article. I generally go to Pediatric Critical Care Medicine, Critical Care Medicine, Critical Care Explorations, Pediatrics, Journal of Pediatrics, NEJM, JAMA Pediatrics, and the family of American Thoracic Society journals on a weekly basis. You can set-up your account so that the table of contents of these journals will be emailed to you. There are apps available, such as ReadQxMD, where you can be alerted to new content of interest to you. You can sign up and follow the accounts of several journals of interest to you on Twitter. There is also a useful, free website sponsored by Dr. Hari Krishnan called picujournalwatch.com in which Dr Krishnan has journal articles well-organized. The website is constantly updated to show the latest manuscripts relevant to our field. You can keep your articles organized by topic in software such as EndNote. Also doing a search on PubMed, OVID etc. can also be helpful to find latest information on a topic. Talking to a medical library scientists is very useful to structure a systematic search for articles or to get a article from a journal that is not available at your institution.

Q3: Dr Grunwell can you define the term level of evidence?

Grunwell: the term level of evidence - or traditional hierarchy of evidence - refers to what degree that information can be trusted based on the study design.

The most common question is related to therapy or an intervention. Levels of therapy are typically represented as a pyramid with systematic reviews or meta-analyses positioned at the top of the pyramid followed by well-designed randomized control trials, and then observational studies. Observational studies include cohort studies or case-control studies. Case studies, laboratory-based studies with animal or in vitro models (aka: preclinical studies), and consensus or expert opinion lie at the bottom of the pyramid hierarchy. Based on this pyramid structure of evidence, the message is clear: Not all evidence and information is equivalent.

Q3. Pradip: Dr. Grunwell what is a critical appraisal of a manuscript and how does it help us?

Grunwell: Critical appraisal is the systematic evaluation of clinical research papers and it is used to judge the article's trustworthiness, its value and relevance in a particular context. Critical appraisal helps you to systematically evaluate whether:

• The study addresses a CLEARLY FOCUSED QUESTION
• The study uses VALID METHODS to address this question
• The valid results of the study are IMPORTANT
• The VALID, IMPORTANT results are APPLICABLE to your patients or population

So the goal of learning critical appraisal helps you:

• identify the most relevant papers
• distinguish evidence from opinion, assumptions, misreporting, and beliefsP
• assess the validity of the study
• assess the usefulness and clinical applicability of the study
• recognize any potential for bias.

Q4. Dr Grunwell what are some of the key components of the appraisal process of a manuscript?

I generally ask 3 preliminary questions when I look at a paper:

1. What was the research question and why was the study needed? ( After a brief background about the topic under study, the paper's introduction should clearly state the research question and the hypothesis.)
2. What was the research design? (For example, is this a primary or secondary study; If primary, then was it a laboratory experiment, clinical trial, survey, observational, or a case series study? If secondary, then was it a review or a clinical guideline, decision analyses, or economic analyses)?
3. Was the research design appropriate to the question? It can be helpful to categorize the study into a therapeutic, diagnostic, prognostic, randomized control trial, qualitative, an epidemiologic/descriptive study, or a meta-analysis. There are evidence-based medicine worksheets that can help you structure a formal review and make sure you consider all aspects of the study. These worksheets can be found in many different languages at the Centre for Evidence-Based Medicine at The University of Oxford in the United Kingdom under Critical Appraisal Tools. The web address will be in the show notes (https://www.cebm.ox.ac.uk/resources/ebm-tools/critical-appraisal-tools) The Evidence-Based Medicine Toolbox from Toronto, Canada also have critical appraisal worksheets and resources to learn evidence-based medicine. This link will also be available in the show notes? https://ebm-tools.knowledgetranslation.net/.

OK to summarize, understand the question and the study design and then assess whether the appropriate design was used to answer a central question!

Q5. Dr Grunwell what is a general framework of how we should approach a manuscript?

Dr Grunwell: In order to explain the structure of a scientific paper, I use the analogy of a story. Think about your favorite fairy tale: there is a beginning - where the scene is set and the characters are introduced; there is a middle - where the action happens, and there is an ending - where there is a lesson learned or a moral of the story. By analogy, every scientific paper has an introduction - where you set the background and importance of the question and introduce the subject matter - the who, the what, and the why of the study). The middle of the article is where the action happens - you explain how you did the study in the methods section and what happened (what you found) in the results section. Finally, the article has an ending where you discuss the results within a larger context of other studies by comparing and contrasting, noting similarities and explaining discrepancies to other work, and acknowledging limitations. Finally you make a conclusion based on your results - can you recommend this therapy or diagnostic study for your patients?.

I really like the story analogy as this really frames our next segment of how to systematically read a scientific paper.

Q6. Dr Grunwell: What is the first step in the critical appraisal of the scientific paper?

A good first step would be just to skim through an article (start with the abstract) to understand the aims, key data and conclusions. Early considerations as you are skimming through the manuscript)-

• Main question - Relevant? Interesting?
• Original topic - Address a gap? Clear & easy to read?
• Conclusions consistent with the evidence presented?
• Do the experiments/data address the main question?
• Is there a disagreement with current consensus & is this disagreement justified by the data gathered?
• Do the Tables & Figures tell the story/add to the paper?

This is a bird's eye view to get yourself oriented.

Dr. Grunwell, in general, how does the introduction help you as you critically appraise a manuscript?

Grunwell: When we look at the introduction we can formulate the problem

Define who the question is about? (how would I describe a group of patients similar to this one)

Define which maneuver you are considering in this patient or population and if necessary, a comparison maneuver: (drug treatment vs. standard therapy or placebo)

Define the outcome: Reduced mortality, length of stay, better quality of life cost savings, etc.

Q7 Pradip: As you read further after your broad overview how do you identify areas for improvement or major flaws in study design?

Dr Grunwell: I would encourage listeners to closely look at Tables, figures and images— What story are these data telling you? Can you recreate the story from the data presented WITHOUT reading a single word of the text? You should be able to follow the experimental argument and draw conclusions based solely on the evidence presented in the tables and figures.

Some things to watch for:

Are the authors drawing a conclusion that is contradicted by the author’s own statistical or qualitative evidence.

Are they using a discredited or flawed method?

• how are they sampling a population, do they have appropriate controls, how precise are their measurements, was the analysis conducted in a systematic manner?
• Are they asking a valid question?

-Are the authors ignoring a process that is known to have a strong influence on the area under study?

Asking questions which correlate to the author's point of view is essential.

Correct, using this process it is important to summarize the research question by:

• Stating the main question addressed
• and Summarizing the goals or objectives.
• This helps to conceptualize the research, and allows focus on the successful aspects of the paper.

Transitioning to the methods section of a paper, Do Grunwell how do we assess the quality of the methods used in a study?

I guess the real question is whether the study in question is original and what does the new research add to the scientific literature? For example, is this a continuation of a large study or field of research.Does it address previous methodological shortcomings? Will numerical results add significantly to a meta-analysis?

Is the study population different?

Is the clinical issue important enough, or does there exist sufficient doubt in key-decision makers, to make new evidence ‘politically’ desirable?

Dr Grunwell as we assess the methods section how do we narrow in on the population of interest and specifically relate the methodology and paper to our patient cohort whom we serve clinically?

This is a great question. I would think about whether the patients

1. Are the subjects more, or less, ill than who you see?
2. Are the subjects of a different ethnicity, live a different lifestyle, from your own patients?
3. Did the subjects receive more, or different, attention during the study that you can give your patients?
4. Unlike most patients you care for, did the subjects have nothing wrong with them apart from the condition being studied?
5. Did the subjects have potentially confounding exposures similar to your patients?

To summarize a central theme of our episode thus far is to read a paper with a perspective on how this applies to your setting - in our case it is critically ill children

Lets transition and talk about the layers of bias which may be present in the results or even discussion portion of the manuscript, Dr Grunwell can you highlight the sources of bias in a study?

Bias occurs when there is a systematic difference between the results from a study and the true state of affairs. Bias is often introduced when a study is being designed, but can be introduced at any stage. Appropriate statistical methods can reduce the effect of bias, but may not eliminate it. Increasing the sample size does not reduce bias.

We need to look at the treatment group and control group very closely to make sure both are treated equally.

Selection bias: can result from incomplete randomization. So patients included in the study are not representative of the population which you intended to analyze.

Performance bias can result from systematic differences in care received by the intervention and control groups because either the participant or the researcher know what group they were assigned - so there are differences in care received other than the intervention being compared

Exclusion bias refers to systematic differences in withdrawal or participants from a study arm. For example, there may be more withdrawals from the intervention compared to the placebo arm of a trial due to side effects; alternatively, there may be more withdrawals from the placebo arm of the trial compared to the intervention arm due to lack of improvement in clinical condition.

Detection bias is the systematic differences in outcome assessment between groups. Blinding (or masking) of outcome assessors may reduce the risk that knowledge of which intervention was received, rather than the intervention itself, affects outcome measurement.

Alright listeners lets summarize the various types of bias — selection is due to incomplete randomization, performance bias involves a lack of blinding, exclusion bias refers to the element of attrition, and detection bias refers to the impact the intervention has with respects to the control.

Dr Grunwell what are the preliminary statistical questions which need to be addressed in a manuscript?

Grunwell: Three statistical questions should be addressed:

First, there should be a sample size calculation to determine the power to detect a true difference between groups

–To calculate a sample size, there needs to be a defined amount of difference between 2 groups that is a clinically significant effect

–You will need to know the Mean and Standard deviation (or variance) of the principal outcome variable

Second, the study must be continued for long enough for the effect to be reflected in the primary outcome.

Third, the completeness of follow-up should be high. For example, < 70% follow-up may be sub-optimal. You can make an assessment of completeness by looking at the rate of withdrawal from the study (some reasons for low completeness include suspected adverse reaction, loss of motivation, loss to follow-up (moving from study area), or death).

Dr Grunwell lets conclude our podcast by going into how do you evaluate the Results and Discussion section of a manuscript?

The results should tell us what was discovered or confirmed. I make sure to see if it tells a coherent story. The authors should describe in simple terms what the data show and refer to statistical analyses such as significance and goodness of fit. Its should evaluate observed trends.

Explains significance of results to a wider understanding. Outcome should be a critical analysis of the data collected.

How do you look at the conclusion of a study?

The conclusion should basically reflect upon whether or not the aims are achieved. Conclusion should not have surprises in them and should be evidence-based. It typically is short and relates directly to the question and outcome.

Dr Grunwell this was a wonderful summary and discussion today — what our resources our listeners can utilize to improve their understanding about research methodology:

How to read a paper by Trisha Greenhalgh

Users' Guide to medical literature by Gordon Guyatt

I also would recommend writing science by Joshua Schimel.

I always give my fellows a paper by my undergraduate research mentor, Professor George M. Whitesides titled the "Whitesides' Group: Writing a Paper" in the journal Advanced Materials.

I recommend that PCCM fellows keep reading papers in PCCM and CCM journal - at the very least peruse through the abstracts especially when they are busy on-service, etc. Structured and interactive journal clubs can help practice critical appraisal skills.

A community approach is definitely essential in staying current on new research?

Dr. Grunwell we appreciate your insights on today's podcast, as we wrap up, would you mind highlighting your personal pearls with respect to critical appraisal of manuscript ?

1. To develop a new habit, such as skimming abstracts and journal articles, its best to start small. For example, choose 1-2 journals to peruse and get the table of contents emailed to you.
2. Be curious and start a journal club and try using the critical appraisal templates or worksheets when assessing the article. Make the journal club a fun and social experience.
3. Learning new skills takes practice, and any investment you make in learning critical appraisal skills will help you become a better writer, researcher and clinician.
4. Tables and figures should stand alone and tell the story. Invest time in trying to understand what the evidence supports in the article by interpreting the information in the tables and figures yourself before reading the text of the paper in its entirety.

We went through a systematic process on how to collect, organize, synthesize & apply journal articles from manuscript to bedside! Having close collaboration with your medical librarian is essential along with a curiosity to learn is essential to optimize your evidence based knowledge and stay up to date on the literature

This concludes our episode today on how to read a paper. We thank Dr Jocelyn Grunwell for her expertise on this topic. We hope you found value in this short podcast. We welcome you to share your feedback & place a review on our podcast. PICU Doc on Call is co-hosted by me Pradip Kamat and myself Dr. Rahul Damania.

Stay tuned for our next episode! Thank you

References:

How to read a Paper 5th Edition by Trisha Greenhalgh. Wiley Blackwell publishers

White J....

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 PICU Mini-Series Episode a 10 month old who is intubated for acute respiratory failure secondary to RSV bronchiolitis.

Here's the case:

A 10-month-old full-term infant girl old is intubated for acute respiratory failure secondary to RSV bronchiolitis. Patient was brought to the ED by parents on day 3 of her illness with h/o cough, congestion and worsening respiratory distress. She has had increasing WOB and grunting. After assessment in the ED where the patient had a brief trial of HFNC, she was intubated with a 4.0 ETT due to persistent hypoxemia. Pertinently, her viral panel was positive for RSV, and the patient was transferred to the PICU. In the PICU, patient was ventilated using PRVC: Set TV of 90cc (patient is 11KG), PEEP 6, PS 10, and FIO2 40%. Throughout her course, she was mechanically ventilated and sedated for about a week. She required a continuous infusion of rocuronium due to decreased lung compliance and high peak pressures. Patient weaned on her ventilator settings by ICU day 7 and the decision to move towards extubation was made.

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

• 10 month old with acute respiratory failure secondary to RSV infection and with a secondary bacterial infection due to H.Influenza.
• Had about a six day course on the ventilator requiring sedation and NMB
• and now we are at the discussion of extubation readiness.Rahul, do you mind summarizing the patient's peri-extubation course?

Sure Pradip, so on day 6 of hospitalization our patient was weaned to low mechanical ventilator settings. The chest radiograph, which initially showed evidence of interstitial pneumonitis and atelectasis now improved and the patient had improved secretion burden. The patient was on ceftriaxone throughout the hospital course as her ETT cx with which grew Hemophilus Influenzae.

• What about the patient's neurological status?
• The patient was initially on fentanyl, dexmedetomidine and a rocuronium infusion — a day prior to considering extubation, the patient was off of the continuous rocuronium infusion oxygenating and ventilating well. The patient prior to extubation was wide awake and appropriate during the morning sedation holiday.
• Any other important clinical markers?
• Yes, the patient's clinical exam including lung exam was reassuring. The patient underwent a pressure support trial PEEP 5, CPAP 10 and had a normal respiratory effort with exhaled of about 5 mL/kg. The RT, however mentioned that the patient did not have a "leak" when performing the leak test. The finally the patient was given a few doses of furosemide for diuresis prior to extubation.
• Awesome, today's episode we really want to focus on extubation readiness however prior to this discussion, can we take a step back and talk about some red-flag symptoms which led to intubation for this patient?
• This patient had severe respiratory distress which progressed to failure.
• The tachypnea, decreased mentation, and grunting were key signs that the patient was progressing to endotracheal intubation.
• Grunting is important to highlight as this refers to the child generating auto-PEEP to combat the atelectasis present in bronchiolitis.
• Remember that a child's chest wall has a high compliance and a decreased propensity for outward elastic recoil — this in essence reduces FRC and thus there is a more balance towards the inward recoil of the long (closing capacity). The highly compliant chest wall and the natural inward recoil of the infant lung creates a propensity towards atelectasis and subsequent impairments in breathing. Low FRC can also create increase PVR which can thus imbalance optimal cardiopulmonary interactions.

OK let's transition to our topic of discussion by a quick summary:

• A 10 month old after 6 days of MV is now ready for extubation.
• Let's start with a short multiple choice question:
• In children deemed ready for extubation by clinicians, which of the following is most likely to be associated with reintubation?
• A) High breath by breath variability
• B) Failed Pressure Support trial
• C) Duration of mechanical ventilation
• D) No leak around the ETT prior to extubation
• Correct answer is A. Pediatric extubation failure rate ranges from 2-20%. Although extubation failure is usually multifactorial, High respiratory variability during spontaneous breathing trials is independently associated with extubation failure in children.
• A recent paper by Kelby et al in CCM 2020-found that after controlling for confounding variables such as age and neurologic diagnosis, reported that both coefficient of variation of respiratory rate and decreased maximal change in airway pressure generated during airway occlusion had almost 3-fold higher risk of extubation failure. When this subset of children developed post-extubation upper airway obstruction, reintubation rates were greater than 30%.
• What about the other factors we had in our answer choices like the Pressure Support Trial?
• Children fail PS trial for variety of reasons including ETT size, sedation, to name a few. Khemani and colleagues (Intensive Care Med. 2016 Aug; 42(8):1214-22)reported that regardless of endotracheal tube size, pressure support during extubation readiness tests significantly underestimates post-extubation effort of breathing.
• Further, A 2009 paper by Newth et al (Pediatr Crit Care Med. 2009 Jan;10(1):1-11.) reported in systematic review of weaning and extubation for pediatric patients on mechanical ventilation, that extubation failure bore little relationship to the duration of MV.
• I think it is important to highlight that though we frequently perform PS trials, we should assess other factors such as primary reason for extubation being reversed, secretions, and even neuromuscular components - extubation does not just refer to lungs being ready to have less support!
• Yes Rahul, absolutely agree — I do want to mention A controversial topic has always been the utility of measuring a leak pressure around the ETT to predict upper airway obstruction. A study by Khemani et al (Am J Respir Crit care 2016 Jan 15;193(2):198-209) reported the risk factors independently associated with subglottic UAO, included low cuff leak volume or high preextubation leak pressure, poor sedation, and preexisting UAO (P < 0.04) for cuffed ETTs; and age (range, 1 mo to 5 yr) for uncuffed ETTs (P < 0.04). For uncuffed ETTs, the presence or absence of preextubation leak was not associated with subglottic UAO.
• Lets summarize - upper airway obstruction involves checking if there is flow (in the form of pressure) surrounding the ETT — key point younger patients (1 mo to 5 yr old) with uncuffed tubes have risk to develop UAO peri-extubation.
• An older study by Wratney et al (Pediatr Crit Care Med. 2008 Sep;9(5):490-6) had previously reported that an endotracheal tube air leak pressure >/=30 cm H2O measured in the non-nparalyzed patient before extubation or for the duration of mechanical ventilation was common and did not predict an increased risk for extubation failure. The authors in that study concluded that- Pediatric patients who are clinically identified as candidates for an extubation trial but do not have an endotracheal tube air leak may successfully tolerate removal of the endotracheal tube.
• This suggests that having a leak may not be necessary for a patient to successfully extubate.
• So Rahul for our listeners What are factors associated with extubation failure?
• Thats an excellent question. Factors correlated with an increased risk of extubation failure include a longer duration of sedative use, younger age, higher complexity of medical conditions, and diaphragmatic dysfunction. The most common reported cause of extubation failure in pediatric patients is upper-airway obstruction, with other causes that include respiratory insufficiency, muscular weakness, cardiac dysfunction, and neurologic impairment. Duration of MV, PRISM III score did not predict extubation in a multivariable analysis reported by Krasinkiewicz et al (Respiratory Care April 2021 Vol 66 No 4).

Pradip, What are the main barriers to extubation in pediatrics?

Thats an excellent question Rahul. One study published in Respiratory Care in` 2021 Vol 66 No 4) reported that in patients who had their passed the extubation readiness test, most common reason for holding off extubation was a planned procedure, neurologic diagnosis/status of the patient, and no leak around the ETT, other factors included high ventilator rates and over sedation, hemodynamic instability, fluid status etc.

I think it is important for us to truly consider procedures or imaging which are planned to play a factor in our timeline for extubation readiness - this mitigates the risk for re-intubation - which is especially important in children with difficult airways!

Rahul: how do majority of children's hospitals perform extubation readiness test prior to extubation?

• I think Pradip there is considerable variation in the methodology of ERT. Some common practices which I have noted as a fellow include: A daily spontaneous breathing trial performed probably early in the am (~4am) by the RTs. As long as patient didn't require any procedure (imaging or surgery), hemodynamically stable, patient spontaneously breathing, FIO2 < 50% (some use 40%), PEEP ≤ 6cm H2O, SPO2 > 92% and TV exhaled ~ 6-8cc/kg on PIP ≤25 cm H2O. These are the patients who we deem on minimal vent settings. The sedation is decreased or a propofol bridge is added followed by a switch to PS CPAP trial (PS 8-10cm H2O and CPAP of 5cm H2O) for at least 2 hours. It is also important to correlate PO status with timing of extubation especially if the patient does well with the SBT.
• After switching to PS/CPAP If patient has no hemodynamic issues, hypoxia, increased WOB and a normal blood gas, the patient's secretions are manageable, upper air reflexes are intact and neuromuscular function is sufficiently good to achieve an adequate vital capacity and maximum inspiratory pressure, GCS > 8—patient is considered a likely candidate for extubation. Most institutions will also check a leak around the ETT the night before. Some may decide to use a dose of decadron prior to extubation (although this is not supported by pediatric studies). Some extubate patient directly to room air, whereas others may use NIPPV such as CPAP or HFNC.
• Pradip, what are the signs of failure of ERT and what should be done in patients who fail their spontaneous breathing trial?
• Rahul, Signs of failure during ERT: include apnea, Exhaled TV < 5ml/kg, tachypnea for age, increased respiratory effort, desaturation below target SpO2 and unstable hemodynamics. Patients SBT can be repeated later in the day, sedation, fluid balance etc may require modification of optimization. The concept of sprinting -where the patient is subjected to SBT and allowed to remain on PS/CPAP for few hours everyday and which is subsequently increased is useful in those who are slow to wean off their ventilatory support.

In essence this may optimize their neuromuscular strength.

• Can you comment on any objective indices used in pediatrics as predictors of successful extubation?
• Rahul two indices used to objectively predict success of extubation were the rapid shallow breathing index (RSBI) and the compliance, resistance, oxygenation, and pressure index (CROP index).
• A paper by Thiagarajan et al (Am J Respir Crit Care Med. 1999 Nov; 160(5 Pt 1):1562-6.) reported on 227 mechanically ventilated children.
• Extubation failures had higher RSBIs and lower CROP index values. A RSBI value of /= 0.15 ml/kg/breaths/min had a sensitivity of 83% and specificity of 53% for extubation success. IN contrast adult studies have shown that a CROP ≥ 13.5 ml/breat/min had a specificity of 91.9% and sensitivity of 87.9% in predicting extubation success.
• OK to summarize - high rapid shallow breathing index and poor compliance, resistance, oxygenation indices indicate negative predictors for successful extubation

Thats correct — for more detail, The RSBI is a ratio of spontaneous TV to RR (adjusted for age). the CROP index is the compliance, respiratory rate, oxygenation and pressure index. The CROP index (ml/ kg/breaths/min) was calculated using the formula: Cdyn × NIF × (PaO2 /PAO2 )/RR.

• Let's break this down:
• Cdyn - is a function of plateau - peep / TV.
• NIF measures conducting zone resistance
• and the OI index involves patient gas as well as alveolar gas which brings into the FiO2 the patient is receiving.

Rahul what is the role of respiratory muscle weakness in extubation outcomes?

• Khemani et al (Crit Care Med. 2017 Aug; 45(8):e798-e805.) used respiratory measurements using esophageal manometry and respiratory inductance plethysmography to assess respiratory muscle strength and predict respiratory extubation failure.
• The authors reported in their study that 35% of children had diminished respiratory muscle strength (aPiMax ≤ 30 cm H2O) at the time of extubation, and were nearly three times more likely to be reintubated than those with preserved strength (aPiMax > 30 cm H2O; 14% vs 5.5%; p = 0.006). aPiMax = maximum airway pressure during airway occlusion (aPiMax). the authors concluded that Neuromuscular weakness at the time of extubation was common in children and was independently associated with reintubation, particularly when post-extubation effort was high.

To summarize Neuromuscular status is essential to assess peri extubation - this is especially true in patients with myopathies either stress, paralytic or steroid related or primary muscular dystrophies.

Correct, also, More recently Glau et al (Pediatr Crit Care Med. 2020 Sep;21(9):e672-e678) reported Diaphragm atrophy is associated with prolonged post extubation noninvasive positive pressure ventilation in children with acute respiratory failure.Serial bedside diaphragm ultrasound may identify children at risk for prolonged noninvasive positive pressure ventilation use after extubation. However There was no difference in diaphragmatic parameters (atrophy rate, and peri-extubation diaphragmatic thickness in expiration and inspiration) in extubation success versus failure (Mistri S. et al. Pediatr Pulmonol. 2020 Dec;55(12):3457-3464).

So Rahul to look at our case again, what about her metabolic alkalosis prior to extubation ?

• I generally correct metabolic alkalosis (when Sr HCO3 ≥30) using acetazolamide or chloride in form of K chloride. I also optimize Mag, Phos and Ca in any patient prior to extubation. I also optimize the nurtitional status with help of our PICU dietician as soon as a patient is intubated.
• To wrap up, Rahul, why should we extubate patients early?

Great question: There is increased morbidity from prolonged mechanical ventilation: To name a few— VAP, pneumothorax, muscle weakness, atrophy of diaphragm, pressure sores, subglottic stenosis (can happen in less than a week of MV), unplanned extubation with cardiac arrest, and prolonged ICU length of stay. Additionally delirium and need for abstinence medications and rehabilitation.

The SCCM's ICU liberation ABCDEF bundle recommends use of spontaneous breathing trials and spontaneous awakening trials to improve patients outcomes. PCCM providers should strive for early mobility, minimal sedation, focus on analgesia as well as push to liberate patient from MV as soon as safely possible.

To highlight a key concept from today - extubation readiness is a coordinated effort in the PICU - it involves asessments from RTs nurses and as well as physicians and advanced care providers. Understand the primary etiology why the patient was intubated and whether or not that cause was reversed. Plan to complete imaging Or procedures within reason prior to activating the patient. Understand components such as sedation, neuromuscular weakness, and secretions to provide a holistic assessment on extubation readiness!

• Pradip - Are there any recent publications related to extubation success?
• Furhman and Zimmermans latest edition of the textbook of Pediatric Critical Care chapter 54 page 642
• A recent article by Krasinkiewicz et al in respiratory Care April 2021 Vol 66 no 4 has done a great job on extubation readiness practices and barriers to extubation in pediatric patients.

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

and my name is Rahul Damania and we come to you from Children's Healthcare of Atlanta Emory University School of Medicine. Today's episode is dedicated to optimizing your Pediatric Critical Care Knowledge and study skills by utilizing your medical librarian.

We are delighted to be joined by Ms. Carrie Price a health Professions librarian. Carrie was formerly at the Welch Medical Library, serving the faculty, students and staff of Johns Hopkins Medical Institutions. Ms Price is currently at the Albert S. Cook Library of Towson University in Towson, Maryland.

Ms Price is an expert searcher with a strong interest in user-centered and instructional design, evidence-based medicine, and inter-professional education.

Ms Price also maintains and updates a YouTube Channel with videos about citation management, searching, and evidence-based medicine. Carrie is on twitter @carrieprice78

Q1. Carrie welcome to PICU DOC on Call Podcast. Our topic today— Value of the librarian in PedsICU education and it is one of the first in our series of how learners can organize their study habits while rotating in the PEDS ICU.

Carrie: Thanks Rahul and Pradip for having me on PICU DOC on Call podcast. I have no conflicts of interest or financial disclosures.

Q2. Carrie tell us your story and how you came to be an expert medical librarian ?

Carrie: I came into librarianship as a second career, after a first career in nonprofit development. I was fortunate to start my work in libraries at Johns Hopkins University, where I worked as a library assistant in access services while getting my masters degree in library science. During this time my mom was diagnosed with appendix cancer, a rare cancer, (she's okay now), and through the time we spent together in the hospital, I noticed there was a medical library in the building. I had this epiphany that librarians weren't limited by traditional career paths. From then I started focusing on health and consumer health classes. Later, at a work all-staff meeting, I literally bumped into the former director of the Welch Medical Library, and the rest is history! I applied for an open position, was hired, and started working at the Welch Medical Library in 2012. It has been an incredible experience. I am fortunate to work extensively with a number of departments and divisions at Johns Hopkins and now at Towson University, so my experiences have been really multidisciplinary. In the past I worked as a physical therapy technician, which was awesome and helped inform the knowledge I brought to the profession. I've taken a lot of professional development in the field. I just never stop learning, and I love sharing information on Twitter, YouTube, and on my website, which is carrieprice78.github.io.

This is such an amazing story!

Q3: Carrie the practice of critical care medicine requires that learners in the Peds ICU remain current in their knowledge of the literature. Given an overwhelming amount of information out there how should these learners drink from that fire hydrant without being blown away?

Carrie: I think that's an excellent question. Prior to the arrival of internet, most additional knowledge was acquired from physically going to a library and perusing through peer reviewed journals and textbooks. Now, things are digital and even "born-digital" — and there is so much information available online and on your phone.... I understand that given how much information is out there, a learner can feel overwhelmed and have difficulty trusting the information they see. That's why critical appraisal is a key part of evidence-based practice. Studies have shown the value of readily-available information in patient care and have highlighted the role of the library and librarian in support of clinical practice.

In 1996 Sackett et al (BMJ 1996). defined evidence based medicine (EBM) as “the conscientious, explicit and judicious use of current best evidence in making decisions about the care of the individual patient." It's come to be seen as a combination of sound research evidence, clinical expertise, and patient preference. While the Accreditation Council for Graduate Medical Education (ACGME) requires peds residents to have formal training in EBM, there is considerable variation in what constitutes EBM training. This is where learners can pull from the expertise of medical librarians, who are experts in searching and evaluating literature. I suggest reaching out to your medical librarian right away. They can help you set up search alerts for topics of interest and journal tables of contents from PubMed and other resources. There are also apps, there is an app called QxMD that can help you be more aware of current literature in fields you follow. There's another app called Browzine, which you may have access to through your institution, where you can subscribe to journal table of contents. You can also find clinical, evidence-based, frequently-updated summaries with tools like UpToDate and DynaMed, depending on what you have through your institution.

Having comprehensive resources such as UpToDate and Dynamed can help you curtail individual studies into a concise review!

Q4. Carrie: now that you brought out the concept of Evidence-Based Medicine, what are some of the appropriate venues for teaching evidence based prospects in the Peds ICU environment?

Almost all pediatric critical care medicine fellowships have a fellow conferences where learners have "protected time" for their education. Fellows conferences can have journal clubs, lectures, chapter reviews and case reports. Fellows conference could be one of the best venues for teaching EBM, where faculty and learners can interact. I think EBM practices should be a part of the peer-peer sign out after a call or service, or morning report. Programs can invite librarians to attend meetings, or seek help of a librarian while preparing for presentations. I also want to emphasize that with daily patient care rounds in the PICU — most fellows should question practices on rounds, which are handed down from previous trainees but don't always have sound evidence behind the practice, or some new research may have changed practice or knowledge. You can reach out to your librarian with these kinds of queries. Librarians can also help with PICO question formulation, searching for and appraising the evidence, and translating evidence into practice—all critical aspects of EBM.

As trainees we are always wanting to optimize our clinical skills and understanding by asking the Why, the How, and the Why Not behind certain clinical scenarios in children! Asking these PICO questions, which stands for isolating the Population, Intervention, Comparison, and Outcome can help us ascertain key clinical questions which come up in our training!

Q5. Carrie: How are librarians utilized by the pediatric residency programs ?

There is an excellent study by Boykan and Jacobson (2017) which evaluated this exact question by surveying ~ 91 Program Directors of Pediatric Residency Programs in the US.

In their study, Boykan and Jacobson reported that 80% of programs utilized medical librarians. Most of these librarians assisted with scholarly or research projects (74%), addressed clinical questions (62%), and taught on any topic — not necessarily EBM (58%) — it might be something like citation management or workflow tools. Only 17% of program directors stated that librarians were involved in teaching EBM on a regular basis. Size of the program mattered the most when it came to the use of librarians. Smaller programs (≤29 residents) were more likely to utilize librarians (100%) than were medium (30-59 residents) (71%) or large programs (>60 residents) (75%). The authors concluded that while most pediatric residency programs have an EBM curriculum and engage medical librarians in various ways, librarians’ expertise in teaching EBM is underutilized. It is important to stress that regardless of the program size, the cost of utilizing librarians did not appear to be a barrier.

Q6. Carrie: How can librarians help the Peds ICU fellow and other learners in the PICU with respect to clinical practice?

In the clinical practice arena with the PICU: As librarians, understand the Peds ICU fellow and other learners, especially in their first year of training, will be very busy from the get go. The peds ICU fellow and other learners, such as the advance practice nurses, serve the role of team leaders within the picu: managing residents, medical students, and the clinical care team, and report to their PICU attending. Some programs are very busy and leave very little time to adequately prepare for gathering the evidence necessary for making informed clinical decisions. Research has shown that when clinical librarians are involved in providing information in the patient care setting, answers to clinical questions can be obtained more quickly and efficiently. (McGowan et al Plos One 2008; Oliver et al. J Med Libr Ass 2011). The Value Study by Marshall et al. noted that clinicians who had used their librarian had changed patient care based on the information they received. This was spread across patient education, diagnosis and differential diagnosis, choice of medication, and... overall they felt that they had made more informed clinical decisions because they were able to receive timely, high-quality information. Your librarian can efficiently and effectively search for evidence, which can be quickly appraised and put to use by busy Peds ICU fellows or others. Librarians can provide information for fellows/faculty during morning reports, grand rounds, committees, morbidity and mortality conferences, and more. One case controlled study has (Banks DE, Shi R, Timm DF, et al. J Med Libr Assoc. 2007;95(4):381-387) demonstrated that librarian support was associated with saved resources and reduced costs beyond a health practitioner’s time savings; a librarian’s presence at morning report correlated positively with shorter length of stays and lower hospital charges in 55 cases with 136 matched comparisons.

This is such a key point, leveraging your instutitions libarian can serve to be a bimodal learning process! As both trainee and librarian collaborate learning can be optimized and this can ultimately affect patient outcome!

Q7. Carrie: How can librarians help the Peds ICU fellow and other learners in the PICU with respect to research and their scholarly activities?

At most institutions, Librarians and library professionals choose what resources and databases to buy: they negotiate prices; ensure that electronic resource vendors have the information they need to provide access; ensure remote access through proxy servers; organize the information on digital portals and guides; build interfaces and education to facilitate searching; and collect and analyze usage data to validate use of institutional resources.

Most PedsICU fellows require some scholarly activity (research/publication) during their fellowship. Besides talking early on with the statistician, Peds ICU fellows and learners could really benefit talking to a librarian about their research question prior to initiation of the research project. Medical librarians are your research partner! A 2015 publication by Rethlefsen et al. showed that librarian involvement on systematic reviews in general internal medicine correlated with higher quality reported searches. Additionally,y our librarian can update you with new references from your literature search, and over time, help you understand your research impact. And like I said, they can help you set up alerts and understand what's out there and how the literature is trending in your areas of interest. The librarians can help with organizing references needed for the project. If a full text article is not available, the librarians can help you obtain it through inter-library loan. Librarians are invaluable to decreasing the stress of fellow/learner embarding on a research project.

Q8. Carrie: Do you see a role for the healthcare librarian in patient safety and quality initiatives?

Yes! Many institutions will also have fellows on a committee or two within the PICU based on their interests such as the airway safety committee, vascular access committee etc. Librarians have an increasing role in providing patient- and family-centered information and can help the fellows acquire the latest information and evidence, which may be necessary to update protocol or guidelines commonly used in the PICU. Fellows and learners should approach librarians when faced with the task of updating a previous protocol, guidelines, standard of care, algorithm or best practice documents used in their PICUs to get the best and the latest available evidence.

Q9 Ms Price: whats your advice to the fellows with respect to online databases use to access medical information:

I think fellowship programs should invite their librarian to speak to the fellows and the PICU team to inform the learners of what resources their institutional library provides. Most libraries, especially in the healthcare setting, have a number of resources free and easily accessible, with access to content that you wouldn't have otherwise. The most commonly utilized is the free resource PubMed, from the U.S. National Library of Medicine. It's considered one of the premier databases for health and biomedical literature, containing over 32 million records. It does not include full text journal articles; however, links to the full text are often present when available from other sources, either through your university or institution, or through the publisher's website or PubMed Central. Your institutional library will have its own collections of journals and databases provided to you free of charge. Even Google Scholar can be helpful for finding hard-to-locate articles and interfacing with citation management tools. I should also mention that good collection of the latest articles from the Peds ICU literature is provided by Dr. Hari Krishnan at picujournalwatch.com.

Q10. Carrie what are some good resources to store articles, citations for future use? (Carrie please add/delete stuff as you want)..

There are a lot of good resources for storing references collectively called reference or citation management software: there are Zotero, Mendeley, EndNote, and actually a lot more. They all kind of compete with each other so they're all pretty good, and the ones I just mentioned are either completely free or have free versions. Most reference management software programs have the same functions: importing references, organizing, storing, and creating citations and bibliographies in a manuscript. These can be a huge time saver for the busy pedsICU fellow — and your librarian can help you get set up and get started with the tool you select. Personal preferences, type of operating software used, and pricing may factor in choice of reference management software. I cant stress enough to save your work, hopefully to the cloud, for ready access anywhere, but also in case there is a malfunction or loss of your device. Another great tool — not a citation management tool, but one that everyone who has published or hopes to publish should sign up for is ORCID. ORCID is open researcher and contributor ID. It's a free researcher profile system that is increasingly being used and even required for grant applications and article submissions. This researcher profile system can help you save all your research products in one place, update your CV, speed up the process of creating your Biosketch or applying for grants, and help disambiguate you from other researchers. You can check it out at orcid.org.

OK to summarize, have a reference manager which can quickly capture and organize key articles — as you delve into your research project utilize this reference manager and their respective integrations to streamline your manuscript process!

Q11 Carrie we appreciate your insights on today's podcasts, as we wrap up, would you mind highlighting your personal clinical pearls?

I think I would say that the medical librarian is your friend. Set up a meeting with them early on in your fellowship. Make use of this invaluable resource for not only to improve on your clinical work, patient outcomes, and decreasing costs but also for research, systematic and scoping reviews, quality and safety initiatives within the PICU. We can save you time doing literature searches, getting you the latest and best evidence, helping you organize citations, requesting the reference/article you need for that case report or lecture presentation, even finding Creative Commons medical images for use in posters and presentations. We can be there at the point of need, at morning report, journal clubs, department meetings, and we can help faculty with creation of medical education and EBM instructional materials. Librarians should be included in development of educational curriculums, written into grants, considered co-authors as a part of an author research team, and included in-class teaching for PICU fellow conferences. Faculty can and should coordinate with medical librarians for optimal training of the peds ICU fellows and other learners.

To summarize today's episode...

We learnt today the immense value, which the medical librarians bring to the learning environment of the Peds ICU. Medical librarian Carrie Prices would like to see more involvement of medical librarians in the development and maintenance of PedsICU learning curriculum. A collaborative approach between the librarians, faculty, fellows and other allied health personnel my be a win win for all including the patients and their families.

This concludes our episode today on Value of the Librarian in PedsICU Education. We hope you found value in this short podcast. We welcome you to share your feedback & place a review on our podcast. PICU Doc on Call is co-hosted by me Pradip Kamat and my cohost Dr. Rahul Damania. Please visit our website picudoconcall.org

Stay tuned for our next episode! Thank you

References:

Quesenberry, A. C., Oelschlegel, S., Earl, M., Leonard, K., & Vaughn, C. J. (2016). The impact of library resources and services on the scholarly activity of medical faculty and residents. Medical Reference Services Quarterly, 35(3), 259-265.

Rethlefsen, M. L., Farrell, A. M., Osterhaus Trzasko, L. C., & Brigham, T. J. (2015). Librarian co-authors correlated with higher quality reported search strategies in general internal medicine systematic reviews. Journal of clinical epidemiology, 68(6), 617–626. https://doi.org/10.1016/j.jclinepi.2014.11.025

Sollenberger, J. F., & Holloway, R. G. (2013). The evolving role and value of libraries and librarians in health care. JAMA, 310(12), 1231-1232.

Boykan, R., & Jacobson, R. M. (2017). The role of librarians in teaching evidence-based medicine to pediatric residents: a survey of pediatric residency program directors. Journal of the Medical Library Association : JMLA, 105(4), 355–360. https://doi.org/10.5195/jmla.2017.178

Ullah, M., & Ameen, K. (2019). Teaching information literacy skills to medical...