Quick rundown of the articles we talked about today in morning report:
ANDROMEDA-SHOCK trial, JAMA 2019: RCT of 424 patients with septic shock randomized to capillary refill vs lactate to target resuscitation efforts. Primary outcome of interest was 28 day mortality. While the difference between the two groups was not statistically significant, the study may have been underpowered. Interestingly, there were lower rates of organ dysfunction at 72 hours with the cap refill guided resuscitation than lactate. So keep doing your cap refill bedside exam!
E-cigarettes vs nicotine-replacement therapy (NRT): Multi-center RCT in the UK that randomized 886 people to e-cigarettes or NRT of their choice for 3 months. Outcome of interest was abstinence from smoking at 6 months and 1 year. They found a significantly higher rate of abstinence in the e-cigarette group than the NRT group. However, while only 9% of the abstinent NRT users were still using NRTs at 1 year, over 80% of the abstinent e-cigarette users were still using e-cigarettes at the end of the study period! Together with the alarmingly high incidence of e-cigarette use amongst adolescents, the results of this study would have to be interpreted cautiously.
EAGLES trial. Lancet. 2016: Multi-center, double-blind, RCT looking at neuropsychiatric effects of varenicline (Chantix), bupropion, or nicotine patch or placebo involving ~4k people without psych history and 4k people with psychiatric history. Study found that Chantix resulted in the highest rates of sustained abstinence across all study arms. In the psychiatric cohort, there were no differences between the treatment groups in terms of rates of psychiatric events. Bottom line: use Chantix whenever you can to help your patients trying to quit smoking!
EXTEND trial. NEJM. 2019: Multi-center, randomized, placebo-controlled trial of 225 patients who presented with ischemic stroke within 4.5-9 hours after onset of symptoms with radiologic evidence of salvageable brain tissue randomized to receive tPA vs conservative management. The primary outcome of interest was functional status at 90 days and was significantly better for the intervention group vs control arm. Caveats are that symptomatic intracranial hemorrhage was six times higher in the intervention group than the control arm. 65% of the patients in the study woke up with neurologic deficits and had an unknown time of onset.
Thyroid hormone replacement for subclinical hypothyroidism (Feller et al. JAMA. 2018): Meta-analysis of 21 RCTs with 2192 patients randomized to hormone replacement or no replacement. The study found no significant difference in qualify of life, thyroid replacement symptoms, fatigure/tiredness, depression, cognition, or SBP after 12 months of therapy. Based on this study, the new guidelines state that in patients with no symptoms of hypothyroidism or non-specific symptoms of hypothyroidism who have fT4 within normal limits and TSH <20, thyroid hormone therapy is strongly recommended against.
We see patients with ischemic strokes pretty frequently as Internists. We will use today’s journal club to go over some basics of acute ischemic stroke management, and the studies behind our management.
We went over CHANCE, POINT, SPARCL, FLAME, and FOCUS in detail, but the hyperlink to the other trials we briefly mentioned are included!
Acute Stroke Management
ABC: Airway, breathing circulation
History, physical, glucose, O2 sat, EKG, noncon head CT ASAP
Determining time last see normal to see if patient is a candidate for tPA
Mechanical thrombectomy can be considered 16-24 hours (DAWN, DEFUSE 3)
Additional studies as needed depending on pre-test probability
TTE, carotid US, etc if needed
Things to consider in the acute setting
Ensure euvolemic, hypovolemic esp in older adults can worsen cerebral blood flow.
Severe hypoglycemia can cause neuronal injury, rapidly correct any hypoglycemic state
Associated with poor outcome in stroke patients. AHA/ASA guidelines aim for BG 140-180mg/dL
SHINE trial: tight glycemic control vs standard of care, no different in outcome
Swallow: Dysphagia screen prior to giving oral meds or food, aspiration precautions.
Head and body position:
Elevated head of the bed to 30 degrees if concerned for elevated intracranial pressure like is ICH, cerebral edema from large ischemic infarction, aspiration, or cardiac/pulm disease
Do so after 24 hours after, dec risk of PNA, DVT, PE, pressure sores. Very early < 24 hours mobilization is associated with dec favorable outcome at 3 months (AVERT trial)
Rule out infectious etiology
Can be present after brain injury, fever within 24 hours is associated with 2x inc in mortality at one month.
Ischemic stroke only
Stabilize blood pressure below 180/105 for at least 24 hours if s/p tPA
If no tPA, permissive HTN, do not treat the BP unless SBP > 220 or DBP > 120, or if pt has underlying CAD, HF, aortic dissection, hypertensive emergency.
Lower BP by no more than 15% in the first 24 hours
Rate of blood pressure control will be dependent on vascular imaging, if a large artery stenosis is found, keep BP high to maintain cerebral blood flow.
Choice of meds: IV preferred, titratable, precise
2nd line: Nitroprusside, inc risk of inc ICP, inc risk of stroke in older folks
5170 Chinese patients with high risk TIA or minor ischemic stroke within 24 hours of sx onset
Combination ASA/Plavix x 21 days, then aspirin
90 day subsequent strokes
DAPT associated with 3.5% absolute reduction (8.2% vs 11.7%), NNT 29
No difference in bleeding events
Main criticism: Chinese patients have a larger proportion of undertreated modifiable stroke risk factors i.e. DM and HTN and greater burden of large vessel cerebrovascular disease. Also Chinese population might have polymorphisms in genes regulating Plavix metabolism.
Thanks to Eric and Naina for presenting the fascinating case of an elderly man who presented to the ER with acute, progressive shoulder and neck pain/stiffness that started after a visit to the dentist, found to have Crowned Dens Syndrome (???!!!) on CT imaging!
The exam maneuvers we use to determine nuchal rigidity (neck stiffness, Kernig, Brudzinski signs) are not sensitive for meningitis. Kernig and Brudzinski, when present, are highly specific. Jolt accentuation is more useful as a screening tool because it is highly sensitive (>90%) but not very specific (~60%).
Make sure to check out Beers list when prescribing new meds for our geriatric patients.
For patients presenting with traumatic neck pain, consider using NEXUS or Canadian C spine rules to help you determine whether CT imaging is necessary.
Crowned Dens Syndrome is a rare finding in patients with CPPD and refers to deposition of calcium pyrophosphate crystals in and around the atlanto-axial articulation, which resembles a crown on CT imaging (image here).
The knee accounts for 50% of all acute CPPD flares.
No indication for CT if all of the following criteria are met
Absence of posterior cervical spine tenderness
Normal level of alertness
No evidence of intoxication
No abnormal neurologic findings
No painful distracting injuries
Canadian C-spine Rule
Step 1: CT indicated if any of the following are present:
Age > 65 years
Dangerous mechanism of injury
Paresthesias in the extremities
Step 2: Assess for low risk factors that allow for safe examination of the cervical spine range of motion
Simple rear-end mechanism
Sitting position in the ED
Ambulatory at any time
Delayed onset of neck pain
Absence of midline cervical spine tenderness
If ALL of these are present proceed to step 3
Step 3: Examine range of motion
Test active range of motion
Perform radiography in patients who are not able to rotate their neck actively 45 degrees both left and right. Patients able to rotate their neck, regardless of pain, do not require imaging
Umbrella term that covers
Pseudogout: acute synovitis/flare
Chondrocalcinosis: radiographic calcification in hyaline and/or fibrocartilage
4-7% of adults
~50% of those with radiographic findings are >84 years of age
Acute CPP crystal arthritis: self limited acute or subacute attacks of arthritis involving one or several extremity joints. Knee is affected in over 50% of all acute attacks followed by wrists, shoulders, ankles, feet, and elbows.
Triggers: Trauma, surgery, severe medical illness. Abnormalities in serum calcium, magnesium, bisphosphonates, hemochromatosis.
Chronic osteoarthritis: Most prevalent form of symptomatic disease.
Severe joint degeneration
Crowned dens syndrome: rare, characterized by severe acute or recurrent axial neck pain, neck and shoulder girdle stiffness, and associated fever, elevated inflammatory markers, and CPP or calcium phosphate crystal deposition on CT in and around the atlanto-axial articulation
DDx would include PMR, Milwaukee shoulder (deposition of hydroxyapatite crystals, commonly seen in women >70 years of age) less frequently meningitis, cervical discitis, or inflammatory spondyloarthritis
Thanks Brandan for presenting an elderly lady who developed sudden onset headache, CN3 palsy, and bitemporal hemianopia. She had a CTH that was unremarkable the day before, and a repeat CT found a large pituitary “mass,” and MRI was concerning for pituitary apoplexy!
This case demonstrates a few important concepts:
Visual Field Pathology (commonly tested!)
A: Optic Nerve pathology or structural pathology leading to complete blindness in one eye, i.e. trauma, optic nerve neuropathy, optic neuritis (i.e. MS)
B: Bitemporal hemianopsia= optic chiasma pathology until proven otherwise.
Physiology: Lacteral rectus, with CN VI innervation, remains intact and not opposed by the medial rectus which is innerved by CN III. Down because the superior oblique (innerved by CN IV) is unopposed by the paralyzed superior rectus, inferior rectus, and inferior oblique
Ischemic (affects somatic fibers over parasympathetic, typically spares the pupils)
Tumors (mass effect so both somatic and parasympathetic fibers are typically affected)
Cavernous sinus thrombosis (don’t miss this!)
Pituitary apoplexy: A Medical Emergency!
Hemorrhage or infarction of the pituitary gland usually involving a pituitary adenoma, and occasionally it may be the first manifestation of a pituitary adenoma.
HTN, surgeries, coagulopathies, certain meds (i.e. VKA, DOACs, antiplatelets)
Sudden onset headache, vomiting, encephalopathy, visual field defect, hemodynamic instability (esp with ACTH defects).
DI is very common in the immediate setting, but as axons in the pituitary die, ADH is released which can lead to SIADH (but only transient until stores of ADH are used up), followed by recovery but it depends on the extent of the damage.
Management: IVF, hydrocortisone (get labs first)
Acute secondary adrenal insufficiency is seen in 2/3 of pts, important cause of mortality.
Acute hypocortisolemia leads to hemodynamic instability
Inc vasopressin release from posterior pit can lead to fluid and lyte disturbances.
Any signs of hemodynamic instability: Can do 50-100mg hydrocortisone Q6H or continuous infusion 2-4mg/hr
Role of surgical management:
Decision to operate based on whether there is deteriorating level of consciousness, severely reduced visual acuity, or presence of visual field defects.
Otherwise, medical management with corticosteroids, monitoring, re-evaluation is recommended.
Vision outcomes: Conflicting data on medical vs surgical management.
Pituitary function outcomes: No difference b/w surgical vs medical management
Please refer to this paper for a detailed read on pituitary apoplexy!
Credit goes to Dr. Jon Reitzenstein from Michigan State!
Today we went over a case featured on the Human Diagnosis Project.
A 28yo F with no medical history presents with 1 day history of unsteady gait, with associated “indifference” per her husband and intermittent diplopia. She also has been having significant N/V for the past 3-4 weeks, barely able to keep anything down. She was dehydrated on exam with elevated spec grav and ketones on the UA. Her pregnancy test returned positive (estimated 6 week old fetus). Ultimately she was given thiamine with rapid symptomatic improvement.
The final diagnosis is Wernicke’s Encephalopathy in setting of poor nutritional intake and increased metabolic demands secondary to unexpected/unknown pregnancy.
Most cases are associated with chronic EtOH use but not all the time!
Extreme poverty, war zones, refugees
More common in men
Up to 12.5% of pts with chronic EtOH
Chronic inadequate intake of thiamine (vitamin B1) leading to degeneration of the peripheral nerves, thalamus, mammillary bodies, and cerebellum.
Credit goes to Eric for informing us about this case!
A 48yo M presents with acute onset encephalopathy. He has a distant history of alcohol abuse, and during the day of presentation he had complained about not being able to see. On presentation, his labs were notable for an anion gap of 35 with bicarb of 4, lactic acid of 11.9, ABG of 6.56/52/336, and osm gap of 65. Volatile screen ultimately came back positive for methanol level of 145.56 mg/dL (yes this is very high). He was given bicarb pushes, fomepizole, and urgent dialyzed.
It turns out that he might have ingested Klean Strip denatured alcohol, which is 40-60% methanol!
Toxic metabolite of methanol poisoning is formic acid, which is formed from formic acid after methanol is metabolized in the liver by alcohol dehydrogenase and aldehyde dehydrogenase
Leads to retinal injury and eventual blindness (permanent)
Formic acid can also cause ischemic or hemorrhagic injury to the basal ganglia, hence in methanol poisoning you might see changes around the area (putamen is part of the basal ganglia).
Ingestion of 1g/kg is fatal, and toxicity has been reported in as little as one teaspoon
Ethylene glycol, on the other hand, mainly causes renal damage. (Flank pain, hematuria, oliguria). Buzz words = calcium oxalate crystals in urine.
Visual blurring, central scotomata (black spot in center of vision), and blindness are suggestive of methanol poisoning.
Eye exam might reveal: mydriasis, retinal edema, hyperemia of the optic disk
Co-ingestion of ethanol can delay presentation of toxicity.
Osmo gap takes Into account the quantity of uncharged molecules, hence it will only be elevated in presence of the parent alcohols.
In late presentation: most alcohols have been metabolized already into charged active metabolic, hence osmo gap is not very sensitive in late presentation.
ABC comes first.
Sodium bicarb administration
Corrects systemic acidosis, which limits penetration of formic acid by converting it into negatively charged formate, which cannot cross cell membrane to cause damage.
Formic Acid <- -> H+ & Formate-, adding bicarb dec H+, hence driving the equilibrium equation to the right. See? College O-chem is still helpful.
HCO3 (mEq) required = 0.5 x weight (kg) x [24 – serum HCO3 (mEq/L)], and in general up front give 1-2 mEq/kg via IV bolus for any patients with pH < 7.3 followed by a sodium bicarb D5 gtt, at least 150-250cc/hr to correct acidosis
Goal of infusion is to keep pH above 7.35
Bicarb can be found in:
Most common: 8.4%, 1mEq/mL, 1Amp = 50mEq, you will see these in the crash cart, very helpful to familiarize yourself with setting the syringe up for injection in a code blue situation!
Gtt: 100-150 mEq/1000 mL in D5
Concentrated gtt: 1mEq/mL, might need pharmacy’s help in formulating this. You can only use this in the ICU!
PO tabs: Useful for CKD patients
Inhibition of alcohol dehydrogenase in the liver
Loading: 15mg/kg, followed by 10mg/kg Q12hr, continue until blood pH is normalized and serum methanol is less than 20mg/dL
Ethanol: ADH has better affinity for ethanol, leading to competitive inhibition.
Difficult to dose, sedating effect, cannot be used in cirrhosis patients, pregnant patients.
HD indicated if:
Severe acid-base derangements, or even high AGMA regardless of drug level
Severe levels of methanol
End organ damage
Interacts with fomepizole, hence if concurrent therapy, fomepizole should be dosed Q4H
All methanol patients treated with ADH inhibition should also receive:
Leucovorin 50mg IV (folinic acid) or folic acid Q6H
Thiamine also commonly administered due to unclear nutritional status.
Today, we talked about the case of a middle-aged man from the Philippines who presented with a one year progressive pruritic rash involving the face, arms, and legs as well as a distal symmetric peripheral neuropathy, found to have lepromatous leprosy on skin biopsy!
Mycobacterium leprae and lepromatosis like to grow in cooler areas, so infection often manifests in the skin and the peripheral nerves.
Transmission is likely via respiratory route, through broken skin, and by touching armadillos!
Early recognition and treatment is important to prevent injury to peripheral nerves.
DDx for rash + neuropathy
Lyme (usually cranial nerves, radiculopathy)
Zoster (tends to be painful rather than pruritic and localized to a dermatome)
WNV (flaccid paralysis)
Our patient presented with a pruritic rash and largely a distal symmetric peripheral neuropathy. We generated the following Venn diagram in report to help us with the diagnosis:
AKA Hansen’s disease
Infection caused by mycobacterium leprae and mycobacterium lepromatosis, separate species that cause similar clinical disease. They are both obligate intracellular parasites.
Involves the skin and peripheral nerves
Early treatment is important to prevent involvement of the eyes, hands, and feet due to neuropathy. The neuropathy is often non-reversible.
205 new cases detected in the US in 2010. 75% among immigrants (most commonly India, Brazil, Indonesia, Bangladesh, and Nigeria)
Unknown but probably respiratory route especially in lepromatous leprosy. Sometimes can transmit through broken skin. Also from armadillos.
Most people do NOT develop disease after exposure. Risk factor for disease development include older age, genetic influences, and immunosuppression.
Grows in cooler areas
Described in categories pertaining to how much bacillary burden of disease is present with tuberculoid being the least amount and lepromatous having the highest disease burden.
Hypopigmented or reddish patches on the skin
Typically involve the earlobes with nodular thickening and distributed symmetrically on the body in lepromatous leprosy.
Diminished sensation or loss of sensation within skin patches
Paresthesias of hands/feet
Neuropathy occurs early in disease course
Painless wounds or burns on the hands or feet
Lumps or swelling on the earlobes or face
Tender, enlarged peripheral nerves
Late findings in disease course:
Weakness of the hands with claw fingers, foot drop, facial paralysis, lagophthalmos (can’t close eyes completely due to CN7 palsy), lack of eyebrows/eyelashes, collapsed nose, perforated nasal septum.
Intermittent bacteremia can lead to focal lesions in various organs (liver, bone marrow, testicles and larynx)
Consider it in patients with skin lesions and/or enlarged nerve(s) accompanied by sensory loss.
No reliable blood or skin tests available.
Usually clinical and skin biopsy
Goal: Prevent and/or minimize injury to peripheral nerves!
Often times it’s loss of sensation but later can progress to painful neuropathy
Dapsone plus rifampin for tuberculoid leprosy. Clofazimine is added for lepromatous leprosy.
Duration can be up to 24 months
Treat neuritis with steroids for a prolonged course
Make sure to screen for G6PD deficiency before prescribing dapsone
Monitor liver function with rifampin
Clofazimine (causes phototoxicity) is not available in US pharmacies and must be obtained from the NHDP.
May take a few years for skin lesions to resolve completely with treatment
Very curable, low relapse rates, typically no drug resistance