Acute Chest Syndrome in Sickle Cell Disease

1. Sickle cell anemia is also known as sickle cell disease, but is different from sickle cell trait. It is an autosomal recessive hemoglobinopathy where amino acid 6 on beta globin gene changes from glutamic acid to valine (missense mutation). This results in hemoglobin S, which sickles and causes hemolysis under hypoxic conditions.
2. HbSS, HbSC, and HbSBeta thalassemia can all cause sickle cell disease (SCD)
3. Sickle cell disease can affect every organ, and treatment begins in childhood and is multidisciplinary. Clinical manifestations include vaso-occlusive syndromes (e.g. dactylitis, acute pain syndrome, acute chest syndrome, priapism), visceral complications such as stroke, infections due to immunosuppresion from a functional asplenia, osteomyelitis, avascular necrosis of the femoral/humeral head, renal dysfunction, retinopathy, pulmonary arterial hypertension, skin ulcers, etc. Please refer to the review article below as a reference. 
4. Acute chest syndrome (ACS) is a respiratory complication of sickle cell disease that can be life-threatening. It is caused by vaso-occlusive disease in the pulmonary vasculature or is triggered by vaso-occlusive disease elsewhere in the body (e.g. fatty embolism from infarcted bone marrow)
5. ACS is more common in children than adults but more severe when in occurs in adults. It is also more common with HbSS disease than HbSC or HbSBeta thalassemia disease. The case mortality rate is usually between 1-10%. 
6. As per the Cooperative Study in Sickle Cell Disease (CSSCD), ACS will occur in roughly 50% of SCD patients. 
7. The diagnosis of ACS requires radiologic evidence of a pulmonary infiltrate as well as a fever or respiratory symptoms (e.g.. cough, increased work of breathing, hypoxia, tachypnea, PaO2<60mmHg) so it cannot diagnostically be distinguished from pneumonia. 
8. Triggers include pulmonary fatty embolism from infarcted bone marrow (45-75% of cases; a bronchoalveolar lavage can be performed to confirm this etiology but is invasive and usually not done), infection (mostly Chlamydiae pneumonia, Mycoplasma pneumonia, RSV, Streptococcus pneumonia), asthma, pain crisis (e.g. vaso-occlusive crisis in long bones), and hypoventilation.
9. Treatment is divided into acute and preventive therapies. Acute therapies include the following 5 pillars of management:

• Pain control (opioids usually effective, but must balance analgesic effects with risk of respiratory depression; NSAIDS should be avoided as they worsen vaso-occlusive disease)
• IV hydration to keep the patient euvolemic as dehydration increases sickling of RBCs
• Antibiotics: Should cover expected organisms above so usually a 3rd generation cephalosporin + a macrolide is chosen, or a 3rd/4th generation fluoroquinolone. 
• Supplemental oxygen, bronchodilators, and incentive spirometry (e.g. 10 deep breaths every 2 hours while awake)
• Blood transfusions to keep Hb between 90-100g/L. A Hb >100g/L can lead to increased viscosity which worsens vaso-occlusion. There have not been any RCTs to compare simple versus exchange tranfusions, but generally exchange transfusions are used in "severe" cases.

    10. Preventive measures include the following:

• Hydroxyurea: Indicated with 1 or more episodes of ACS and acts by increasing the level of HbF (fetal hemoglobin, composed of 2 alpha and 2 gamma chains). Increased HbF reduces the likelihood of HbS polymerization. There is an inverse correlation between HbF levels and the incidence of ACS, and in the MSH study the incidence of ACS decreased by 50% with the use of hydroxyurea. The dose is 30mg/kg per day divided BID. 
• Chronic transfusion if 2 or more episodes of ACS in the last 12 months. NB hyperhemolytic syndrome can occur 5-7 days post transfusion in SCD patients and can lead to an acute drop in hemoglobin. 
• HSCT (hematopoietic stem cell transplant) can be a curative therapy.
• Incentive spirometry. 

Reference Articles:

1. Management of sickle cell disease in the community by Valentine Brousse, Julie Makani, and David Rees

• BMJ 2014;348:g1765  

2. Acute chest syndrome: sickle cell disease by Rabindra Paul, Oswaldo Castro, Anita Aggarwal, and Patricia Oneal

• European Journal of Haematology 87 (191-207)

3. How I treat acute chest syndrome in children with sickle cell disease by Scott Miller

• Blood, 19 May 2011. Volume 117, Number 20

Metabolic Acidosis

1. Metabolic Acidosis (MA) is defined by a decreased serum bicarbonate and an arterial blood gas (ABG) indicating acidemia.
2. Metabolic acidoses are separated into those with a wide anion gap (WAGMA) and normal anion gap (NAGMA, aka hyperchloremic metabolic acidosis)
3. The anion gap (AG) is artificial in the sense that it is a lab artifact. In theory all the positive charges in the serum should equal the negative charges to achieve electrical neutrality. The serum anion gap is calculated as AG= Na - (Cl + HCO3). In other words, it is the measured cations minus the measured anions. Another way to think of it is the unmeasured anions minus the unmeasured cations. 
4. Albumin is the major unmeasured anion in the serum. One must correct for the albumin level. Generally, for every 10g/L below the normal value of 40g/L, one should add a correction factor of 2.5 for the corrected anion gap. 
5. The normal anion gap range depends on whether K (potassium) is used in the equation to calculate it. Generally, it is not. It also depends on the lab's way of measuring chloride. At LHSC a normal AG is 12-14. 
6. Causes of a low anion gap include anything that causes a high level of unmeasured cations (e.g. paraproteinemias, hypermagnesemia, hypercalcemia) or low level of unmeasured anions (e.g. hypoalbuminemia)
7. WAGMA is usually due to unmeasured organic acids. It is usually due to ketoacidosis, lactic acidosis, acute kidney injury/chronic kidney disease, or ingestions.

• Ketoacidosis: The ketoacids are beta-hydroxybutyrate and acetoacetic acid. Acetone is a ketone body but not a ketoacid. Ketoacidosis can result from diabetic ketoacidosis, starvation, or alcohol consumption. 
• Lactic Acidosis: Type A is due to impairment in tissue oxygenation (e.g. circulatory or respiratory failure, sepsis, ischemic bowel). Type B is due to impaired lactate clearance (e.g. liver disease), metastatic disease, or certain drugs (e.g. metformin when renal function is impaired, salicylates, NRTIs). D-Lactate (NB L-Lactate is measured routinely in the serum) can be due to short-gut syndrome in which bacteria in the colon metabolize glucose to D-Lactate. 
• AKI or CKD: Impaired clearance of organic acids, phosphates, sulfates, and urates. 
• Ingestions
• Salicylates (e.g. acetylsalicylic acid, methyl salicylate from oil of wintergreen, bismuth subsalicylate): Lactic acidosis can result from impaired oxidative phosphorylation since salicylate overdose can poison the mitochondria involved in the Kreb's cycle. 
• Acetaminophen: 5-oxoproline (aka pyroglutamic acid) can result from chronic acetaminophen use, usually in older, typically malnourished females. 
• Ethylene glycol: Metabolized into oxalic/glycolic acid. Used in antifreeze solution. 
• Propylene glycol: Can result in lactic acidosis. Used as diluent in IV lorazepam/diazepam infusions as well as IV nitroglycerin. 
• Methanol: Metabolized into formic acid. Used in engine coolants. 
• Iron: Can result in a lactic acidosis since excess iron can be toxic to mitochondria.
• Toluene: Can result in hippuric acidosis. Used as solvent for dyes, paints, rubbers. 

   8. NAGMA (hyperchloremic metabolic acidosis) are usually a result of a loss of bicarbonate, gain of chloride, or impaired excretion of acids. Causes include:

• Loss of HCO3 (e.g. for the GI tract from diarrhea, from the kidneys in type 2 RTA (renal tubule acidosis when HCO3 reabsorption in the proximal tubules is impaired)
• Impaired acid excretion (e.g. type 1 or type 4 RTA)
• Infusing HCO3-free fluid (e.g. IV normal saline infusions)
• Total parenteral nutrition (amino acids are broken into ammonium chloride which is an acid)
• Ureteral-ileal/colonic conduits or diversions. Urine makes contact with the GI tract and HCO3/Chloride exchange can occur, resulting in hyperchloremia. 
• Pancreatic fistulas
• Drugs (e.g. acetazolamide, cholestyramine, toluene)

   9. Remember that acid base disturbances are often mixed. For example, a WAGMA can coexist with a NAGMA or a metabolic acidosis can be combined with a respiratory acidosis. It is diagnostically convenient when a single acid-base imbalance occurs, but this is seldom the case. 

   10. Because of the above, the delta/delta gap, or the ratio of the extent of the anion gap divided by the extent of the metabolic acidosis (i.e. anion gap -12/24-HCO3, where 12 is considered a "normal" anion gap and 24 a "normal" HCO3 level), can be used to help evaluate a mixed versus pure NAGMA/WAGMA or the presence of a concurrent metabolic alkalosis. 

Reference Article:

Kraut, J.A. and Madias, N.E. Metabolic acidosis: pathophysiology, diagnosis and management. Nat. Rev. Nephrol. 6, 274-285 (2010). 

Hypercalcemia

physiology:

 

·        Adult body has 1 kg of Ca (99 % in bones as hydroxyapatite)

·        Circulating calcium in tight range of 2.25 -2.5 mmol /L

·        50-60 % protein bound (albumin), or complexed with phosphate/citrate

·        40-50 % free or ionized; proportion that is regulated and responsible for symptoms

·        so for every drop in albumin by 10, Calcium drops by .2 mmol /L

 

PTH à from parathyroid glands

·        glands sense [calcium] with calcium sensing receptor

·        low Ca increases secretion and vice versa

actions

·        Kidneys: increases Ca reabsorption + phosphate excretion / stimulates 1-alpha-hydroxylase so more 1, 25 Vit D

·        Bone: activates osteoclasts liberating calcium from skeleton

 

1, 25 Vitamin D: 

·        cholesterol in skin, light converts it to cholecalciferol ? or get from diet, liver converts it to 25- hidroxycholecalciferol, kidney converts it to 1,25-dihydroxycholecalciferol

actions

·        Gut: increases calcium / phosphate absorption

·        Bone: increases bone turnover as well

 

Calcitonin

·        parafollicular cells in thyroid gland secrete it/tries to lower calcium level

 

Signs + Symptoms (moans /bones /stones /psychic overtones)

·        related to degree or rise and absolute value

·        polyuria / polydipsia (due to nephrogenic DI)

·        GI discomfort: anorexia, constipation

·        mental status changes: apathy, fatigue, coma

·        pancreatitis, renal stones, band keratopathy (calcium deposits on cornea), ECG: shortened qt

 

W/U: Do PTH/lytes/extended lytes/cre/ maybe 24 hr urine Ca

 

a. PTH mediated (high / inappropriately normal)

b. non PTH mediated (if suppressed)

 

PTH mediated

·        Hyperparathyroidism (most common cause in outpts): primary when parathyroid out of whack due to adenoma or hyperplasia; secondary when CKD causes low calcium as vit D production impaired, PTH increases; tertiary when autonomous nodule develops in CKD

-        Generally get osteoporosis, in past presented with osteitis fibrosa cystica (skull demineralization/resorption of finger periosteum), kidney stones as more filtered calcium, can lead to nephrocalcinosis

-        Multiparathyroid adenomas generally seen in MEN 1 (pituitary, pancreas) or 2a (med. Thyroid, pheo)

·        FHH (familial hypocalciuric hypocalcemia): autosomal dominant deactivating mutation in Calcium sensing receptor in parathyroids and kidney

Dx with fractional excretion of calcium: (24 hr U Ca / serum Ca) / (24 hr U cre / serum cre)

24 hr U ca < 100 mg / FE_Ca < .01

·        Lithium : increases set point for PTH suppression by calcium

 

Non-PTH mediated

 

·        Malignancy (most common for inpatients), due to local osteolytic activity, PTHrP (humoral), calcitriol..

a.      Osteolytic tumors: myeloma, breast Ca, lymphoma

b.      PTHrP (PTH related peptide): protein produced by malignant cells, generally SCC of head + neck, AdenoCa of breast+ovary, RCC, myeloma. Cells produce small amounts of PTHrP so need a lot of tumor to be the cause.

c.      Increased calcitriol production: B cell lymphoma

 

·        Granulomatous disease (due to increased calcitriol production by autonomous production of 1alpha-hydroxylase): sarcoidosis, tuberculosis, leprosy, wegener’s (GPA)

·        Thyrotoxicosis, prolonged immobilization, paget’s disease: increased turnover

·        Vitamin D intoxication

·        Milk-alkali syndrome: when large amounts of calcium and consumed (> 4 g/day), get polyuria, leads to contraction alkalosis

·        Meds: Thiazides (increase Ca absorption)

 

Management

·        lytes/extended lytes/cre/ maybe 24 hr urine Ca/ calcidiol (25-vit D)/ calcitriol

·        w/u appropriate for underlying cause

·        IV fluids (dry secondary to polyuria)

·        Diuresis? Only if patient is euvolemic to hypervolemic

·        Bisphosphonates: Pamidronate (60-90 mg IV) or zoledronic acid 4 mg IV; calcium begins to decrease at 48-72 hrs; effect lasts for weeks

·        Calcitonin: 4 IU/kg sc q12h; acts quick; tachiphylaxis

·        Glucocorticoids: in Vit D mediated hypercalcemia like lymphoma and granulomatous disease; decrease intestinal absorption, and decrease activity of 1alpha hydroxylase

·        Gallium nitrate, plicamycin

·        Dialysis may be indicated in nothing works

·        Primary hyperparathyroidism:

Indications for surgery: symptoms!, age < 50, Creatinine Cl reduced by > 30 %, Ca > 2.75, high 24hr urine calcium, T score < -2.5

May localize with nuclear scan +- ultrasound; remove adenoma; remove 3.5 glands if hyperplasia (may be guided by intraop PTH levels)

Bisphosphonate increases BMD, but doesn’t lower Ca /PTH

cinacalcet (activates CaSR), lowers PTH, lowers Ca, doesn’t change BMD

pneumonia

Hey all,

Here are some notes from a recent morning report on pneumonia. Enjoy!
 

Diagnosis:

·       Hallmark symptoms are cough, fever, sputum production, pleuritic chest pain

·       Physical exam described by Laennec (1819, inventor of stethoscope, died of TB which was diagnosed by nephew with Laennec’s stethoscope)

·       Findings: cachexia (LR 4), vital signs normal (LR .3), asymmetrical chest expansion (LR 44), dullness (LR 3), bronchial sounds (LR 3.3), egophany (LR 4.1)

·       CXR imaging required; pulse oximetry helpful

·       Remember classic lobar, typical bug vs. interstitial, atypical bug is not really useful

·       Can search for microbe with following tests if it will change abx coverage or will likely be positive: blood cultures (+ 10%), sputum culture (14 % useful in all comers, a good sample has < 10 squamous cells / LPF), legionella urine antigen (serogroup 1), pneumococcus urine antigen (70 % sens, > 90 % spec), np swab (60 % sen, 100 % spec), bronchoscopy: consider if immunosuppressed, critically ill, non-responders

Who needs admission/ CURB-65:

·       CURB 65 from Lim W et al, thorax, 2003 (excluded NH residents)

·       Confusion (disorientation to person, place, time), uremia > 7, RR greater or equal to 30, BP < 90 / <=60, age 65 or older.

·       30 day mortality: 0 = .7 %, 1 = 2.1%, 2 = 9.2 %, 3 = 14.5 %, 4 = 40%, 5 = 57%

·       Generally 0,1 for outpt rx; 2s to ward; 3 + to ICU

·       Pneumonia severity index (PSI) stratifies into 5 mortality levels, 3-5s need admission, maybe a bit better at ruling in low risk patients but need !20! variables

·       Remember scores are only a guide, need to consider comorbidities, ability to take meds, hypoxia

Bugs:

·       Strep pneumonia, Haemophilus influenza, Moraxella catarrhalis, staph aureus

·       Atypicals (not on stain): Mycoplasma pneumonia, Chlamydophila pneumonia, legionella species

·       Viruses: A/B influenza, adenovirus, parainfluenza, RSV

·       Anaerobes: only if frank aspiration +- patients with gingival disease

Fun scenarios:

·       Bat/bird droppings: histoplasmosis

·       Exposure to rabbits: F. tularensis

·       HIV/ AIDS: PCP, MAC, histoplasmosis, Cryptococcus and all else

·       Bronchiectasis: pseudomonas, staph, burkholderia cepacia

·       Cough > 2 weeks with whoop or post-tussive vomiting: bordetella pertussis; children or adults with waning immunity

·       Hotel + cruise ship: legionella (from central AC,water towers), first outbreak at legionnaires conference, Philadelphia, 1976

·       Bioterrorism: bacillus anthracis, Yersinia pestis (plague), francisella tularensis (tularemia)

Empirical therapy

·       Outpt / healthy / no abx last 3 months : Macrolide, doxycycline

·       R.Fs for macrolide resistant pneumococcus: old age, recent abx in 3 mos, medical comorbidities, alcoholic, immunosuppressed

·       Outpt / comorbidities / abx in last 3 months (use diff class): resp. FQ or B-lactam + macrolide

·       Inpt/ non-icu: resp FQ or B lactam + macrolide (better survival v. only macrolide)

·       Inpt/ icu: B lactam (3^rd gen cephalosporin) + [macrolide or resp FQ), better survival with double pneumococcus coverage in some studies in really sick pts

·       If worried about pseudomonas i.e alcoholic, frequent abx: use B lactam (that covers pseudomonas and pneumococcus = tazocin, carbapenems, cefipime) + FQ

·       If MRSA: add vanco or linezolid

·       If viral pneumonia: early treatment (within 48 hrs) with oseltamivir, zanamivir recommended by both IDSA + Canadian guidelines, may reduce shedding after 48 hr. N.B remember you can check Ontario respiratory virus bulletin for information about was occurring.

Controversy

·       Cochrane review conducted on antivirals for influenza found lots of problems with data

·       Over 60% of data from phase 3 trials never published, much of it withheld by drug makers

·       42 of 67 studies not used because of discrepancies in data like not including serious adverse events

·       Found antivirals shortened symptom duration by 21 hrs

Management considerations:

·       May not be improving because insufficient time, insufficient dose, resistant bug, wrong diagnosis, metastatic infection (endocarditis, meningitis)

·       Switch to oral therapy when improving, able to tolerate PO, and stable

·       Treat for minimum of 5 days, as long as afebrile for 48-72 hrs + stable

·       Halm E et al Arch Intern Med assessed stability for d/c by using 7 RFs: Temp, HR, RR, sBP, oxygenation, PO intake, mental status. If 2 or more markers at d/c, higher rate of mortality, readmission, any adverse event (OR 7.4)

Hospital acquired pneumonia / healthcare associated pneumonia:

·       Who: Hospitalization within 90 days, NH, home wound care or infusions, dialysis etc.

·       Bugs: gram negative bacilli

·       Drugs: (antipseudomonal drug, PCN, cephalosporin, carbapenem) + FQ + MRSA drug

Ischemic Stroke

Hey all,  today I've posted some notes on ischemic strokes. Enjoy!

Causes of stroke:

·       Embolic (75%): arterial, cardiac, paradoxical, cryptogenic (25 % may be paroxysmal a. fib)

·       Thrombotic (25%): large vessel and small vessel (lacunar)

·       Other causes: dissection, vasculitis, vasospasm

·       DDx: Seizure with todd’s paresis, hypoglycemia

Stroke Syndromes:

·       Opthalmic artery: amaurosis fugax

·       Anterior cerebral artery: hemiplegia (leg > arm), sensory deficits, primitive reflexes

·       MCA: hemiplegia (arm/face > leg), aphasia if dominant hemisphere, neglect if nondominant, gaze towards side of lesion

·       PCA: visual deficits, i.e contralateral homonymous hemianopsia

·       Cerebellar: vertigo, Nx+ Vx, diplopia, dysarthria, ataxia

·       Lacunar: pure sensory or motor loss

·       PICA (posterior inferior cerebellar artery): lateral medulla infarcted, loss of pain +temp contralateral body and ipsilateral face (spinothalamic tract)

Workup:

·       History + physical exam : NIHSS (Nat. institute of health stroke scale)

a.     LOC objective score - alert, response to stimuli

       LOC questions-- how old, what month

       LOC commands-- open then close eyes, grip and release hand

b.     Best gaze (follow my finger)

       Visual fields (confrontation)

       Facial palsy (show me your teeth, raise eyebrows)

c.     Arm motor (extended + palms down, score both)

       Leg motor (raise 30 degrees, score both)

       Limb ataxia (finger to nose, heal to shin);

d.     Sensory (use pinprick)

e.     Best language (describe, name, read)

       Dysarthria (read these words)

       Extinction/inattention (look for neglect)

·       15 items, each scored 0-3/4, > 25 = very severe

·       ABCs, IV, O₂, monitor, neurovitals

·       Screening bloodwork, CXR + ECG

·       Neuroimaging: CT/CTA or MR/MRA. If cannot get vascular imaging then get non-contrast CT

·       Neuroimaging findings: parenchymal hypodensity, swelling causing sulcal effacement + loss of grey/white matter differentiation, hyperdense MCA sign

tPA (tissue plasminogen activator)

·       For acute ischemic stroke within 4.5 hrs of symptom onset, NIHSS > 3 or aphasia

·       .9 mg/kg, to a maximum of 90 mg/kg, 10% bolus then the rest over an hour

·       ASPECTS score for CT scan (if less than 7, usually avoid tPA because of risk of hemorrhage)

·       Endovascular therapy may be an option for patients who do not qualify for tPA because of window, bleeding risk etc.

·       Many contraindications: ICH 6 mos, CVA 3 mos, major Sx, confounding dx, HTN (> 185/110), plts < 100, INR > 1.7

·       tPA can reduce disability in CVA

·       NINDS (1995): tPA within 3 hrs led to better outcome

·       ECAS III (2008): tPA between 3 and 4.5 hrs led to less disability (mRS, NIHSS), NNT 10

·       IST3 (2012): tPA up to 6 hrs- no difference in mortality/morbidity, but perhaps improvement in some risk groups such as older patients (>80), higher NIHSS scores, early Rx

Management:

·       Swallowing screen

·       Remember to think of seizures in periCVA period (10 %); Rx with benzos IV; if one off no other meds, if ongoing then load with anti Sz med

·       Blood pressure: If using tPA then target 185 / 110 to avoid risk of bleed; otherwise target < 220 /120 in order to allow perfusion of penumbra but avoid bleed. Drop by 25 % / 24 hrs, use labetolol or NTG

·       Anti-platelet: ASA 160 mg then daily 82 mg (if tPA wait 24 hrs), if already on ASA switch to Plavix leads to reduced CVA recurrence; can always start ASA, Plavix, or Aggrenox (ASA + dipyridamole)

·       Hemicraniectomy for ICP should be considered in massive MCA strokes where infarct size > 50% territory, GCS less than 8 at 24 hours, worsening imaging etc. to prevent death within 48 hrs

·       Remember for increased ICP: elevate HOB, hyperventilation, hypertonic solution

·       CVA cause workup:

a.     Vascular stenosis (i.e carotid): dopplers/CTA/MRA; endarterectomy if > 50 stenosis, NNT 6 if > 70 %

b.     Arrhythmia: telemetry

c.     ASD/PFO/thrombus: echo

d.     Coagulopathy: coag screen for ALPAs, ATIII, Protein C/S, prothrombin, homocysteine, PNH

e.     Vaculitis: esr, crp, ana, ancas, c3/c4

Long-term management (similar to all secondary CVD mgmt.):

Lifestyle-

·       Healthy diet low in sat. fats, cholesterol, and salt; fruit more than five servings / day

·       Exercise regularly, avoid obesity

·       Stick to safe drinking guidelines; stop smoking

·       Avoid HRTs or OCP in those with CVA

Risk Factors-

·       HTN: aim for less than 140/90; most important risk factor; ACE inhibitor/diuretic combo

·       Hypercholesterolemia: All CVA patients should be on statin, SPARCL study: atorvastatin 80 mg led to NNT 50 to prevent CVA; can target LDL of <2 or 50% reduction

·       Screen for DM, HBA1C > 6.5

·       Screen for OSA, as RF for CVA and consequence of CVA, severe if AHI (episodes/hr) >=30