Hemophagocytic Lymphohistiocytosis (HLH) – Part I

A rare, but important disease that is becoming more widely recognized and more frequently diagnosed. This disease, while uncommon, is rapidly progressive and caries a high mortality rate.

Causes are not completely understood, but involve abnormal activation of the immune response due to a failure of the typical downregulation in hyperinflammatory processes.

Two types exist:

            Congenital/Familial – genetic predisposition which usually requires a triggering event to occur

            Acquired – occurs in adults with no known predisposition (often have underlying genetic predispositions) – triggering events include infections , immunodeficiency, rheumatologic disorders, and malignancy in addition to many others.

Diagnosis is challenging due to the wide variety of symptoms and constellation of symptoms, which often mimic more common infections/sepsis presentations.  Common symptoms include the following:

• Fever – 95 percentSplenomegaly – 89 percent 
• Bicytopenia – 92 percent (most often anemia and thrombocytopenia) 
• Hypertriglyceridemia or hypofibrinogenemia – 90 percent

Symptoms can, and do, occur in any body system – rashes, conjunctivitis, DIC, LFT abnormalities,  hypotension/shock, and respiratory failure are all common concomitant findings in the presentation of HLH

More on the specific diagnosis and treatment to follow in part II...

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Urinary retention in pediatrics is defined as the inability to void for more than 12 hours in the presence of a palpable bladder or a urine volume greater than expected for age.

Maximum urine volume calculation for age:  (age in years + 2) x 30ml.

Causes of urinary retention include mechanical obstruction, infection, fecal impaction, neurological disorders, gynecological disorders and behavioral problems.

The distribution is bimodal occurring between 3 and 5 years and 10 to 13 years.

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There are few conditions that can be as dramatic or difficult to control as variceal GI bleeding in a cirrhotic patient.  It is important to be familiar with all options in these cases, from Blakemore/Minnesota tube placement to massive transfusion to when and which consultants to get involved.  In cases that are refractory or not amenable to endoscopic intervention, emergent interventional radiology consultation for Transjugular Intrahepatic Portosystemic Shunt (TIPS) may be a consideration.  In high risk cases, think about getting IR on the phone at the same time as you engage GI, in case endoscopic management fails.  Variceal bleed patients can decompensate rapidly, get your consultants involved early!

Generally accepted indications for emergent TIPS (both of the following should be true):

-GI bleeding not amenable or not controllable by endoscopy

-Cause is felt to be variceal. May also consider in portal hypertensive gastropathy

Contraindications:

-Right heart failure or pulmonary hypertension

-Severe liver failure (MELD > 22, T Bili > 3 or Child-Pugh C. In these cases TIPS may not confer a significant survival benefit)

-Hepatic encephalopathy (relative contradindication.  HE may be worsened by TIPS).

-Polycystic liver disease (makes TIPS technically challenging)

-Chronic portal vein thrombus (makes TIPS technically challenging. Acute PV thrombus is NOT considered a contraindication)

Bottom Line: In cases of variceal GI bleeding from portal hypertension, consider getting IR on the phone early to discuss emergent TIPS.

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Slipped Capital Femoral Epiphysis (SCFE)

• Progressive, posterior medial displacement (slipping) of the proximal femoral epiphysis
  • Complicated by AVN and premature physis closure

http://www.raymondliumd.com/images/SCFE%20illustrated%20and%20cropped.jpg

Early Diagnosis:

• Allows best chance for intervention and good functional outcome

• Subtle and difficult with X-ray

• Classic teaching is Klein’s line

Klein’s Line on AP view

• A line drawn from the superior aspect of the femoral neck will not intersect the femoral head epiphysis

• Modified line
  • >2mm difference in width lateral to line between each side

https://pedemmorsels.com/wp-content/uploads/2018/01/Slipped-Capital-Femoral-Epiphysis-3.png

Another virtual line may assist in diagnosis

S-sign

• The S-sign is a curvilinear line drawn on the inferior margin of the proximal femoral head neck junction along the proximal femoral physis.
•  Discontinuity or an abrupt sharp turn are abnormal

https://images.squarespace-cdn.com/content/v1/562149a6e4b0bca6fa53cb35/1530197888065-AOF0LA079Y81Q6M89RJU/ke17ZwdGBToddI8pDm48kE2XMWnCJSZ3ROkmIxQ7DdsUqsxRUqqbr1mOJYKfIPR7LoDQ9mXPOjoJoqy81S2I8N_N4V1vUb5AoIIIbLZhVYxCRW4BPu10St3TBAUQYVKcIZH9X6Fb-UKi0lvZd9RVmtFt1P_lj4JzgsdTxe78uiejbzfgXQaCWxJNArJhpf7P/Screen+Shot+2018-06-26+at+10.09.17+AM.png?format=1500w

Klein's line and S-sign

• A group of 20 orthopedic surgeons, radiologists, and pediatricians viewed 35 radiographs of SCFE using Klein's line on the AP view and the S-sign on frog-leg lateral view to make the diagnosis. 

• Overall diagnostic accuracy was better with the S-sign than Klein's line, 92% vs 79%.
  • Sensitivity of the S-sign was 89%, specificity 95%. 
  • Sensitivity of Klein's line was 68%, specificity 89%. 

• Combined S-sign + Klein's line sensitivity was 96%, specificity 85%.

Consider adding both of these virtual lines/signs to your review of the pediatric hip plain film

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Pearl: consider desmopressin (DDAVP) for patients with an intracranial hemorrhage who are taking an antiplatelet. Caution, this is not for patients with an ischemic stroke with hemorrhagic conversion and it was not specifically evaluated for patients on anticoagulation or going to the OR with neurosurgery.

How strong is this evidence? International guidelines already give cautious approval for this practice, and now there is a retrospective review to support it. Though there were only 124 patients in the trial, the rate of hemorrhage expansion was much lower in the DDAVP group (10.9% vs 36.2%, P = .002) and there was no increased risk of hyponatremia (no events reported).

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Adenosine is an atrioventricular nodal blocking agent that is commonly used in the treatment of supraventricular tachycardia.  It is dosed as 6 mg IV Push x 1, followed by dose escalation to 12 mg IV Push if the initial dose was unsuccessful.  In patients with central access or prior orthotopic heart transplantation, the initial recommended dose is 3 mg.

Due to its short half-life (< 10 seconds) it is imperative to administer in the most proximal access and follow with a 20 mL bolus of saline.  Traditionally this is done using a two-way stopcock. 

A new study compared single syringe (adenosine 6mg + 18 mL saline) vs two syringes (adenosine 6mg in one, 20 mL saline in the other) in 53 patients with SVT.  The single syringe arm converted to NSR 73.1% after one dose compared to 40.7% in the two-syringe arm (p=0.0176).  After up to three doses, the single syringe arm had 100% conversion compared to 70.4% in the two-syringe arm (p=0.0043).

Single syringe adenosine has been recommended in FOAM for several years.  Although small, this study is the first to compare the two methods.  This method simplifies administration and may improve cardioversion rates.

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After many years of national shortage and FDA’s black box warning in 2001 (QT prolongation) droperidol is slowing becoming available.

In 2015, a prospective observational study was published involving ED patients who received droperidol for agitation (acute behavioral disturbance). 

Method

• Study period: August 2009 to April 2013 in 6 EDs in Australia
• Intervention: droperidol 10 – 20 mg IM or IV (if available)
• EKG performed within 2 hours of droperidol administration.
• QT was manually measured and plotted against the heart rate on the QT nomogram – if above “at-risk line” = abnormal

Results

• Droperidol was administered in 1,403 ED patients
• EKG available in 1,009 ED patients
• Median age: 34 years (IQR: 25-44)
• Men: 59.9%

Four leading reason for ED presentation

1. Alcohol intoxication: 421
2. Deliberate or threatened self-harm: 200
3. Psychostimulant use: 130
4. Mental illness/psychosis: 142

• Median droperidol dose: 10 mg (IQR: 10 to 17.5 mg) 
• Abnormal QT interval: 13 (1.3%, 95% CI: 0.3% to 2.3%)
  • 7 patient had other potential contributing factors: methadone, escitalopram, Amiodarone or preexisting condition. 
• Median time to sedation: 20 min (IQR: 10 to 30 min)

Adverse events

• Desaturation (<90%): 22 (1.6%)
• Airway obstruction: 8 (0.6%)
• Hypotension: 28 (2.0%)
• Extrapyramidal symptoms: 7 (0.5%)
• Arrhythmia: 1 (0.1%)
• Hypoventilation (RR < 12 breaths/min): 4 (0.2%)
• Seizure: 1 (0.1%)
• No adverse events: 1,333 (95.0%)

Conclusion

• Droperidol is a safe sedating agent with no evidence of increased risk for QT prolongation with the doses used. 

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Interventions Shown to Reduce Mortality in RCTs

• Santacruz and colleagues recently performed a systematic review to determine which multicenter RCTs in critically ill patients have shown that an intervention was associated with a reduction in mortality.
• Approximately 13% of the 212 trials included in this review reported a statistically significant reduction in mortality.  Unfortunately, many of the interventions were not associated with reduced mortality in subsequent studies.
• Interventions consistently shown to reduce mortality in multicenter RCTs in critically ill patients were limited tidal volume in patients with ARDS, noninvasive ventilation in acute hypercapnic respiratory failure, and noninvasive ventilation following extubation in complex cases.
• Corticosteroids in septic shock, selective digestive decontamination, and prone positioning in ARDS remain controversial.

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Antibiotic stewardship has led various organizations such as the AAP, AAFP, and IDSA to introduce two different approaches to the treatment of acute otitis media (AOM):

• Immediate treatment with antibiotics versus
• initial observation for 48-72 hours without antibiotics.

Immediate treatment with antibiotics should always include the following patients:

• Children <6 months old
• Toxic appearing
• Severe signs/symptoms: otorhea, persistent pain, fever>39C, bilateral ear disease

The observation approach can be considered in the following very slect patient group:

• Otherwise healthy children >2 years of age
• Non-severe illness
• Unilateral ear disease
• Access to follow up within 48-72 hours
• Parental comfort / Shared decision making

Often the issue with pediatric AOM isn't necessarily the overprescribing of antibiotics, but the inaccurate/inappropriate over diagnosis of acute otitis media.  An erythematous tympanic membrane does not equal AOM.  Crying and fever can result in a red TM. Fluid seen behind the TM, is often just serous otitis media, which isn't AOM. 

When antibiotics are warranted, first-line treatment is with high dose amoxicillin, 90 mg/kg per day divided into two doses; unless the child has received beta-lactam antibiotics in the previous 90 days and/or also has puruent conjunctivitis mandating amoxicillin-clavulanate instead.  In the later case, prescribing the Augment ES, 600 mg/5mL formlation with a lower clavulanic concentration lessening GI upset and diarrhea is prefered.

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• Up to 1/3 of status epilepticus do not respond to benzodiazepines.
• Fosphenytoin, valproate, and levetiracetam are 3 antiepileptic medications commonly used to treat benzodiazepine-resistant status epilepticus, though it is unclear which is more effective.
• Results from the long awaited Established Status Epilepticus Treatment Trial (ESETT) has just been released.
• Fosphenytoin, valproate, and levetiracetam each achieved seizure cessation within 1 hour in approximately 50% of patients.
  • 80% of responders had seizure cessation within 20 minutes.
• Seizure recurrence was observed in 10% of each treatment group.
• It is important to note the dosages of antiepileptic medications used were:
  • Fosphenytoin 20 mg PE/kg, max 1500 mg 
  • Valproate 40 mg/kg, max 3000 mg
  • Levetiracetam 60 mg/kg, max 4500 mg

Bottom Line: Fosphenytoin, valproate, and levetiracetaim have similar efficacy in treatment of benzodiazepine-resistant status epilepticus.

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Settings

• Patients: mechanical ventilation in the ICU. Randomization of 1000 patients.
• Intervention: conservative oxygen therapy, if spO2 reached 97%, then FiO2 was lowered to 0.21
• Comparison: no specific limits for FiO2 or SpO2.
• Outcome: number of ventilator-free days at 28 days after randomization.

Study Results:

• 484 conservative-oxygen group vs  481 to the usual oxygen group
• Comparing to the conservative-oxygen group had:
• more time at FiO2 21 (29 hours vs. 28 hours),
• less time with SpO2 > 97% (27 hours vs. 49 hours)
• Similar ventilator-free days: 21 days vs. 22 days.

Discussion:

This study’s results differed from previous single center study (Girardis JAMA 2016) or meta analysis (Chu DK, Lancer 2018), which showed mortality benefit in patients with conservative oxygen (Girardis & Chu) and more ventilator-free days (Girardis).

Conclusion: Conservative oxygen did not significantly affect the ventilator free days of mechanically ventilated patients.

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Question

A ~55 year-old female with a history of ESRD and diabetes who presented to the ED with progressively worsening foot odor. An x-ray was performed. The picture below shows the right foot.

What is the diagnosis?

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The role of skeletal muscle relaxants in the management of lower back pain in the ED

Patients with lower back pain (LBP) presenting to the ED are often treated with NSAIDs plus skeletal muscle relaxants.

A recent study in Annals of Emergency Medicine compared functional outcomes and pain in ED patients with acute non radicular LBP with 4 different treatment regimens.

1. Ibuprofen plus placebo
2. Ibuprofen plus baclofen
3. Ibuprofen plus metaxalone
4. Ibuprofen plus tizanidine

Conclusion: Adding a muscle relaxant to ibuprofen did not improve pain or improve function at 1 week following an ED visit for LBP.

Note: Prior studies have found no benefit to adding opioids or diazepam to NSAIDs  for ED patients with acute non radicular LBP

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As of November 20, 2019:

2290 cases of e-cigarette, or vaping, product use-associated lung injury (EVALI) from 49 states (except Alaska), District of Columbia and 2 U.S. territories.

• Largest number of cases (150-199) reported from CA, TX and IL
• 47 deaths

Analysis of 29 bronchoalveolar lavage (BAL) fluid samples from EVALI patients submitted to CDC from 10 states showed:

• Vitamin E acetate in all samples 
• THC: 82%
• Nicotine: 62%
• No other chemicals of concern were identified (e.g. plant oil, mineral oil, terpenes, etc.) 

*** Vitamin E acetate appears to be associated with EVALI but the investigation is continuing.*** 

• Oral ingestion of vitamin E acetate does not cause harm.
• High dose vitamin E supplementation (>2000 IU/day [2000 mg/day]) can cause GI symptoms: nausea, vomiting, diarrhea and abdominal pain.

Some research has suggested that oral vitamin E use has potential beneficial effects (i.e. anti-inflammatory/antioxidant) in the lung (e.g. asthma and allergic lung disease), cardiovascular disease and prostate cancer (Cook-Mills JM et al. 2013; Jiang Q et al. 2001)

Common uses of vitamin E

• Topical cosmetic skin products (skin cream) for antioxidant effect.
• Essential dietary vitamin (fat soluble) found in many food items and as dietary supplement.
• In vaping products: vitamin E is used as an additive/thickening agent in THC containing e-cigarette, or vaping products.

There is limited to no data on pulmonary effect of vitamin E from inhalation in the scientific literature.

Stay tuned for additional updates from CDC.

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1. Decreased hepatic function
2. Decreased renal function
3. Multiple comorbidities and polypharmacy that can affect pharmokinetics of pain medications.

Therefore, pain medications must be dosed carefully, which runs the risk of underdosing.  Pain medications can also contribute to delerium, and decreased functional status.

Recommendations:

1. Start with non-opioid medications in most cases. Consider combination acetaminophen and ibuprofen/naproxen.
2. Consider regional nerve blocks where applicable due to the decreased risk of systemic side effects and excellent analgesic properties.
3. If using opioids, start low and reassess and use the lowest dose possible. Remember half-lifes are often prolonged so patient may not need the standard dosing interview.

Streptococcal pharyngitis is common in the pediatric population however in children younger than 3 years, group A streptococcus (GAS) is a rare cause of sore throat and sequela including acute rheumatic fever are very rare.  Inappropriate testing leads to increased healthcare and unnecessary exposure to antibiotics.

The national guidelines published by the Infectious Diseases Society of America do NOT recommend GAS testing in children less than the age of 3 years unless the patient meets clinical criteria and has a home contact with documented GAS.

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Metformin is one of the most commonly prescribed oral hypoglycemic agents. Metformin associated lactic acidosis (MALA) is uncommon but potentially life-threatening complication of metformin overdose. 

Lactic acidosis occurs due to inhibition of mitochondrial glycerophosphate dehydrogenase, resulting in decreased conversion of lactic acid to pyruvate.

A small retrospective study (using Illinois Poison Center data) attempted to characterize the development of MALA after an acute overdose.

MALA was defined as 

• Lactate: > 5 mmol/L
• Acidemia: (HCO₃< 20 mmol/L or pH < 7.35)

Results

40 cases of MALA identified between Jan. 2001 to Dec. 2014

• Meadian age: 41 year
• Female: 55%
• Acute on chronic ingestion: 62.5%
• Hypoglycemia: 3 (7.5%)

Time to development of MALA (n=30)

• <=6 hours: 18 (60%)
• 6-12 hours: 9 (30%)
• >12 hours: 3 (10%)
• Unknown: 10

Death: 1 (2.5%)

Conclusion

1. The majority of MALA developed within 6 hours. However, delayed onset of MALA can occur, up to 12 hours post ingestion.
2. Minimum of 12 hour of observation is recommended after an acute metformin overdose.

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When managing cardiac arrest, it is important to differentiate PEA, the presence of organized electrical activity without a pulse, from "pseudo-PEA,"where there is no pulse but there IS cardiac activity visualized on ultrasound. 

Why: 

• Pseudo-PEA is essentially a profound, low-flow shock state that often has reversible causes, such as hypovolemia, massive PE, tension pneumothorax, etcetera.
• Compared to PEA, with appropriate care patients with pseudo-PEA have a higher rate of ROSC as well as overall survival.

How: 

• POCUS during rhythm check in cardiac arrest. Be careful not to prolong the pause in compressions; acquire the US, if needed, for review once hands are back on the chest. 

What:

• In addition to searching for & addressing reversible causes of the pseudo-PEA, manage the profound shock state with pressors and/or inotropic support.
• In EDs where TEE is utilized during cardiac arrest resuscitations, strongly consider synchronization of external compressions with intrinsic cardiac activity to potentially improve ventricular filling and therefore coronary perfusion pressure.

Bottom Line: Pseudo-PEA is different from PEA. Utilize POCUS during your cardiac arrests to identify it and to help diagnose reversible causes, and treat it as a profound shock state with the appropriate supportive measures, i.e. pressors or inotropy. 

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Lateral hip pain is a common presentation of hip pain.

Typically seen in runners and women over the age of 40 who start unaccustomed exercise.

Pain from OA of the hip which is typically medial (groin pain)

Lateral hip pain has traditionally been diagnosed at trochanteric bursitis.

Research suggests that lateral hip pain may be multifactorial and better termed Greater trochanteric pain syndrome.

Pain from the gluteal medius and/or minimus due to non-inflammatory tendonopathy is likely causative. This may cause a secondary bursitis.

Pain is insidious, gradual worsens and is variable based on activity type.

Also, can be seen after a fall resulting in tearing.

Pain is described as a deep ache or bruise. It can stay localized or radiate down lateral thigh towards knee.

Patients report night/early morning pain and when rolling over onto the outer hip on affected side.

Fatigue from prolonged sitting, walking and single leg loading activities such as walking up stairs.

Provoking activities and postures cause compressive forces on the involved tendons.

            These generally occur when the hip is adducted across midline such as with

Side sleeping,

            Place pillow between legs to align pelvis and keep knee and hip in line

Crossed leg sitting

            Sit w/ knees at hip distance and feet on floor

Selfie poses - Standing w a hitched hip (pushing hip to the side).

Attempt to correct biomechanical issues before progressing directly to bursal steroid injection

            May only be a temporary fix if underlying issue not addressed.

A helpful clinical guide

https://bjgp.org/content/bjgp/67/663/479/F1.large.jpg?download=true

Droperidol has recently become available again in select U.S. institutions. It has been used as an antiemetic and to treat agitation prior to the FDA’s black box warning (for QT prolongation) and national shortage. 

Recently, a retrospective study was conducted (Melbourne, Australia) in the use of droperidol in the management of cannabinoid hyperemesis syndrome (CHS).

Results

689 medical records were identified from January 2006 to December 2016.

76 cases met diagnostic criteria of CHS (below)

• Long-term cannabis use
• Symptoms of recurrent vomiting
• Absence of illness that could otherwise explain symptoms.

Droperidol group (DG) = 37; no droperidol group (NDG)= 39 

Median length of stay: 

• DG: 6.7 hr vs. NDG: 13.9 hours (p=0.014)

Median time to discharge after final drug administration: 

• DG: 137 min (IQR: 65, 203) vs. NDG: 185 min (IQR: 149, 403)

Frequency of droperidol (dose) used: 

1. 0.625 mg (n=25)
2. 1.25 mg (n=20)
3. 2.5 mg (n=17)

Metoclopramide and Ondansetron use in non-droperidol group was twice that of droperidol group

Conclusion

• Droperidol use to treat CHS associated nausea/vomiting resulted in decreased length of stay and lower use of antiemetics.