Echocardiography and pulmonary embolism

Echocardiography is not recommended routinely as part of the diagnosis of pulmonary embolism (PE). However, given presenting symptoms and clinical instability associated with PE, patients may have this investigation performed during their admission.The availability and accuracy of CT protocols for PE has reduced the need for additional diagnostic testing. As stated, an echo is not the test of choice for PE, considering only up to 40% of patients with PE will have abnormalities. The value of its use may lie within its prognostication.

Signs suggestive of a PE on echo include, RV dilation and hypokinesis, pulmonary hypertension, tricuspid regurgitation and IVC distention. A decrease in LV size can be seen as a results of a dilated RV and bulging of the interventricular septum. Occasionally (~5%), of patients with PE will have an observed thrombus in the RV on echocardiography, confirming the diagnosis. In acute PE, RV dysfunction while sparing the apex (McConnell's sign) may be seen, which has a documented specificity of 94%.

Moderate to severe RV dysfunction on echo has been linked to increased mortality in acute PE. One Swedish study found a 6 fold increase in death compared to patients with normal RV function. The presence of malignancy was also a negative predictive factor in these patients. This finding was identified as one of the most important predictors of increased death at 3 months post presentation. The increase in associated mortality with RV dysfunction suggests this finding may be useful in supporting the decision for thrombolysis in acute PE. The MAPPET registry (see link), found that patients with moderate to severe RV dysfunction have reduced mortality with thrombolysis (with increased risk of severe bleeding), and those with RV dysfunction given anticoagulants alone were at risk for repeat clot. It should be noted, that these patients had normal blood pressures at the time of thrombolysis. RV dysfunction on echo has also been shown to improve post tPA.

The above information makes a case for echocardiography, by a trained specialist, in the patient presenting with symptoms suggestive of PE, adding another diagnostic piece to the initial assessment. It is also valuable in predicting patients with poor outcomes in the months post evaluation.

Acute PE: a multicentre registry

Antipsychotics in delirium and dementia

Medication therapy has become commonplace in the treatment of patients with delirium/dementia during hospitalization. Ideally, patient confusion/aggression can be controlled with non-pharmacologic therapy, however when changes in mental status become a threat to patient and health care worker safety, medications can be helpful.

Antipsychotics are generally categorized as first (typical) and second (atypical) generation drugs. As the name suggests, second generation drugs were developed later, where the term "atypical" neuroleptics was introduced in 1998. These were developed to control psychiatric illness, while minimizing side effects. Both classes of drugs antagonize dopamine (D2) receptors, improving hallucinations and delirium. Atypical antipsychotics bind the D2 receptor with less affinity and higher specificity for the mesolimbic area of the brain. This is felt to cause similar efficacy with less extrapyramidal side-effects, which include rigidity, spasticity, and tardive dyskinesia as well as negative symptoms (psychomotor retardation), attributed to blockade in the nigrostriatal and prefrontal regions respectively. 

Neuroleptic medications are amongst the most common drugs used to treat delirium and behavioral dementia. In 2005, the FDA issued a warning statement for these medications as a group, citing a small but significant association with increased mortality with their use. This increased mortality was secondary to an increase in infectious (pneumonia) and cardiovascular (sudden death/CHF/stroke) events. An increase in cerbrovascular events was seen with multiple atypical antipsychotics (ex. risperidone, olanzapine). This has led to controversy regarding the use of these drugs in clinical practice.

Psychotropic medications should be used judiciously in response to delirium, but are sometimes warranted. These drugs should not be provided prophylactically, considering they have not been shown to reduce delirium incidence, but duration following it's occurrence, which was examined in an RCT of postoperative delirium (kalisvaart et al. 2005). The efficacy between agents is similar, where comparisons of haldol (typical) and risperidone, qeutiapine, olanzapine and ziprasidone (atypicals) have been performed. To manage aggressive behavior in patients with dementia, risperidone has been investigated the most and showed mild benefits in multiple trials. The meta-analysis (2005 JAMA), examined 15 RCTs of atypical antipsychotics and placebo in delirium and found a grouped reduction in mortality in the placebo group, however amongst the specific drug subgroups, no increased mortality was identified. Long term follow up patients randomized to continue their current medication (haloperidol, risperidone, thioridiziner, chlorpromazine etc) or placebo. Results showed an associated increase in mortality in those taking antipsychotics over a 12 week period. There tends to be a dose dependent response and increased risk with haloperidol. Intramuscular haloperidol may be less arrythmogenic making oral/IM the routes of choice.

Physicians should constantly re-evaluate the need for antipsychotic use and discontinue when possible. See the link below for one of many citations. 

Mortality and antipsychotic use

Hypercalcemia

Hypercalcemia is a common problem encountered on internal medicine, with a long list of etiologies. Despite this, the large majority are related to (>;90%) malignancy and hyperparathyroidism.

The categories of causes can be broken down in multiple ways, but it may help to think of it based on the mechanism by which the calcium is increased.

1. Bone resorption
                               - primary hyperparathyroidism and tertiary hyperparathyroidism.
                               - malignancy - direct boney destruction and osteolysis with metastasis.
                                                     - PTHrP production by SCC
                                                     - osteoclasts activating factors (OAF) and RANKL production in
                                                       multiple myeloma
                               - thyrotoxicosis - with increased metabolic rate and bone resorption
                               - Pagets disease of the bone with immobility
                               - hypervitaminosis A

2. Increased calcium absorption
                               - milk alkali syndrome - secondary to over supplimentation, can be worsened in
                                 context of kidney disease
                               - hypervitaminosis D - can be endogenous or exogenous
                                               - endogenous - secondary to granulomatous disease (sarcoidosis) or
                                                                        lymphoma
3. Miscellaneous
                               - Drugs - lithium, HCTZ, theophylline toxicity
                               - Adrenal insufficiency - multiple mechanisms including volume contraction
                               - familial hypocalciuric hypercalcemia - autosomal dominant mutation in sensory
                                 receptor of parathyroid cells

Initial evaluation should consist of confirmation on accurate calcium level (corrected for albumin), followed by PTH level. Hyperparathyroidism is more common in patients with malignancy and a hence a history of cancer shouldn't negate the ordering of a PTH level.

Treatment includes fluid resuscitation, bisphosphonate therapy, discontinuation of offending meds and rarely, if ever, lasix and calcitonin. Following medical management, the correction of the underlying problem needs to be addressed.

Gastorintesintal bleeding

GI bleeding is a commonly encountered diagnosis on GIM. At TWH it is the seventh most common admission diagnosis (2009-2010). Today's case was an elderly patient with microcytic anemia and + FOBT but no signs of bleeding raising the suspicion for gastric/colonic malignancy. The CT can of the abdomen made the diagnosis, but this is not always the case. Because there was no history of obvious bleeding in our patient the approach was slightly changed.

Current nomenclature describes two terms for GI blood loss without an obvious initial source:

1. Occult bleeding - presentation with + FOBT and /or IDA with no visible blood loss
2. Obscure bleeding - bleeding from the GI tract that persists or recurs despite negative endoscopy, colonoscopy and radiologic evaluation. This can be subdivided into occult and overt based on whether there is clinically visible bleeding.

Our patient had a + FOBT, and the question was raised as to false positives with this test. There are several different forms of the test, but we use a guaiac based test which identifies hgb based on a peroxidase reaction. False positives can be caused by certain foods - horseradish, red meat, turnips NOT iron pills, and false negatives caused by vitamin c.

Once a patient is FOBT+, the next question to ask is whether they're iron deficient, where patient with a iron deficiency warrant upper and lower endoscopy. Those without anemia should undergo colonoscopy only.

Options for patients who have obscure bleeding following all endoscopic testing include:

Capsule endoscopy- patient swallows a camera and images are analyzed. This is helpful in identifying the source if the patient is actively bleeding, after two weeks from the bleeding event the yield of identifying the problem is significantly reduced. Unfortunately, capsules endoscopy doesn't allow for therapeutic intervention.

Push enteroscopy- a longer scope is pushed into the small bowel for direct visualization. Angiodysplasia are the most commonly seen lesions when this is successful, which ranges from 3-70% of the time.

Double balloon enteroscopy- a scope which allows for small bowel visualization
Small bowel follow through- patient swallows barium and images examined for lesions

Small bowel enteroclysis- barium injected directly into small bowel ,can be CT/MRI evaluated. Generally felt to be worse than capsule endoscopy.

Nuclear scans- use technetium labelled RBC which looks for source of bleeding, or technetium Meckel scan which illuminates gastric mucosa in the small bowel.

Angiography- useful in acute bleeding, as it can also allow for embolization.

As it was wisely pointed out today, the direction of your investigations should be based on the patients directives, and in our case no further investigations were required.

Pancytopenia

Today we discussed a a fascinating case of newly identified pancytopenia. By definition this means that all three cell lines (RBC, WBC and platelets) are decreased, however given the fact that the clinical approach is similar to bicytopenia (only two cell lines down), the distinction is not clinically relevant.

Overall, cytopenia is a common problem encountered in medicine. Many of our patient have multiple medical illnesses which impact the blood counts in various ways. The patient we enountered today was unique in that he was previously well, suggesting a unifying diagnosis for his pancytopenia. Presenting complaints can vary, but are usually related to the impact of each impaired cell line, anemia causing weakness/fatigue/SOB, leukopenia allowing infectious illness and thrombocytopenia causing bleeding. A study by Guyathri et al. looked at >100 patients with pancytopenia and found weakness/fatigue to be the most common complaint (100%), dyspnea (40%), fever (38%), and organomegaly (30%) followed distantly by bleeding (3%).

The DDx is huge, but consists of:

Drugs: cytotoxic chemotherapy, antibiotics (chloramphenical), NSAIDS, anti-thyroid Rx (PTU/methimazole), antibiotics etc.

Infection: Viral (parvovirus, hepatitis A/B/C, HIV, EBV/CMV), bacterial (TB, sepsis, leptospirosis)

Malignancy: Infiltration (leukemia, NHL, MDS), fibrosis (Hodgkins)

Inflammatory: SLE (57% have anemia, 47% neutropenia, 25% thrombocytopenia)

Deficiencies: copper, B12, folate

Sequestration

Pregnancy

Congenital: Fanconi's anemia, Schwacmann-Diamond, HLH

A prospective study found megaloblastic anemia to be the most common cause of pancytopenia in presenting cases (~74%).

Now that you have your differential, you order your tests accordingly and await the bone marrow results. Our patients presentation is most consistent with AML given the acuity and severity of illness. things to look for on the blood film would be signs of DIC (schistocytes/thrombocytopenia), blast cells with Auer rods (suggestive of AML).

We spoke briefly about the categorization of AML which is as follows:

1. AML secondary to medications (usually chemo)
2. AML with recurrent genetic abnormalities
3. AML with myelodysplastic features
4. AML not otherwise specified

This breakdown has prognistic importance. The large majorty >80%, end up being not otherwise specified. The classification for AML not otherwise specified consists of categories M0-M7, but this is mainly for research purposes and is not based on disease prognosis.

Exercise Induced Anaphylaxis!

Anaphylaxis is a life-threatening, multi-system disorder caused by the sudden release of basophil and mast cell inflammatory mediators. Anaphylaxis can range from mild signs to overt shock. Rapid identification and treatment must be started to prevent progression to full respiratory or circulatory collapse.

A consensus criteria was created in 2006, outlining three criteria for anaphylaxis, of which only one is needed to make the diagnosis highly likely:

• Acute onset of illness involving skin/mucosa (hives, pruritis, angioedema) and either respiratory or hemodynamic compromise (SBP less than 90mmHg)
• At least 2 signs and sx occurring following exposure to a likely allergen or trigger
• Systolic BP less than 90 or symptomatic hypotension following a likely allergen or trigger

Allergic Anaphylaxis:

• Immunologically mediated involving IgE and IgG or immune complex-complement interactions. 
• Common triggers: food, insect stings, medications
• Food allergies are more common in children, while insect stings and medication allergy is more common in adults.

Non-allergic anaphylaxis:

• Previously referred to as "Anaphylactoid" reactions. These are non-immunologic and non-IgE-mediated reaction.
• Common triggers: anesthetics, latex, seminal fluid, exercise

Exercise induced Anaphylaxis:

• Typically presents during or shortly after exercising
• Signs and symptoms include: fatigue, warmth, pruritis, flushing and urticaria. In extreme cases, it may progress to angioedema, bronchospasm, airway compromise and full circulatory collapse.
• Many patients do not consistently have symptoms with regular exercise and may experience symptoms monthly or years apart.
• Patients are instructed to carry an epinepherine autoinjector when exercising, exercise with a partner trained in symptoms recognition and epinepherine injection and to avoid all food, alcohol, NSAIDs at least 4 hours prior to exercise.

Food-Dependent Exercise Induced Anaphylaxis:

• Known triggers include: NSAIDs, alcohol, and cereals containing wheat gliadin (barley, rye, oats and wheat)
• Patients may be unaware of a food allergy, as symptoms only occur in association with post-prandial exercise. Patients can be tested with skin prick testing using NaCl wheat suspensions.
• Patients with allergy to wheat gliadin directed to eat a gluten free diet may continue physical activities with no symptoms

For more information refer to the following interesting articles:
Exercise induced Anaphylaxis and association with allergy to Gliadin
Case report of exercise induced anaphylaxis
Review on Exercise induced Anaphylaxis

Thinking Fast on Hyperkalemia

Hi all.  This Dr. C filling in for Natalie today.  We had great discussions at Rapid Fire Morning Report today.

On the topic of heuristic thinking and biases here is the reference to the book Dr. Abrams brought up by Daniel Kahneman.  It's a fascinating read.

We also discussed bronchiectasis and the choice of antibiotic treatment in an exacerbattion. As Dr Sibbald mentioned, the British Society Guidelines recommend Amoxicillin as first line (often in high doses), with the caveat that previous cultures should guide therapy.  This is especially true for coverage of Pseudomonas. We did not delve into treatment of non tuberculous mycobacteria, but here is a BTS reference  as well as a more recent ATS guideline for further reading.

Lastly we had a great discussion on managing hyperkalemia.  Here is a link to an interesting article that highlights an important point that came up in our discussion:
- Up to 50% of patients with K>6.5 may have no ECG changes!! Often this is related to chronicity, with slower rises in potassium causing less ECG changes, however that level of hyperkalemia requires prompt treatment.

Finally take a look at the CMAJ article on treatment of hyperkalemia from 2010.

Cheers

Painless Jaundice!

This morning we discussed an interesting case of a patient with painless jaundice after receiving multiple courses of antibiotics, including septra, for a presumed cellulitis.

Here is an approach to painless jaundice (not an exhaustive list):

1) Prehepatic causes:

• Hemolysis: i.e. AIHA, G6PD with offending drug
• Impaired hepatic bilirubin conjugation: Gilbert's, Crigler Najjar

2) Intra-hepatic causes:

• Inflammatory: Primary biliary cirrhosis, primary sclerosing cholangitis
• Malignant: Cholangiocarcinoma, hepatocellular carcinoma
• Infectious: Chlonorcus senensis (Chinese liver fluke), Ascaris lumbricoides, Viral: HBV, HCV, EBV, CMV (but usually produces more hepatocellular picture rather than a cholestatic picture), alcoholic hepatitis
• Drug induced liver injury
• Other: NASH, liver infiltration (amyloid, sarcoid, lymphoma)

3) Post-hepatic causes:

• Cholelithiasis: common bile duct obstruction, Mirizzi syndrome where distended gallbladder causes obstruction of extrahepatic bile duct
• Pancreatic neoplasm
• Stricture post instrumentation

A little more on Drug Induced Liver Injury (DILI)

1) Types of DILI:

• Can mimic all patterns observed in primary liver disease
• Acute hepatocellular injury: increased ALT/ALP ratio
• Cholestatic injury: Isolated increase in ALP, with decrease in ALT/ALP ratio
• Granulomatous hepatitis
• Steatohepatitis
• Can present as acute or chronic liver injury
• Acute hepatocellulary injury and fulminant liver failure:
• Examples of drugs that cause acute fulminant hepatitis include: acetaminophen, isoniazid, sulfonamides, cotrimoxazole, ketoconazole, anticonvulsants
• Acute Cholestatic injury:
• Presents clinically with jaundice, pruritis, dark urine and pale stools
• Liver enzymes reveal elevated ALP, GGT and Bili.
• Common culprit drugs include: anabolic steroids, oral contraceptives, prochlorperazine, and antibiotics (septra and erythromycin)
• See the following articles for more information:
• NEJM article on DILI
• Case report of Septra induced prolonged cholestasis: http://www.ncbi.nlm.nih.gov/pubmed/1587437

Use of Fluoroquinolones

Today in morning report we had a quick discussion on the use of fluoroquinolones. Here are some pearls to consider prior to prescribing a fluoroquinolone:

• Sensitivity to UV: wear sun protection!
• Prolongation of QT interval: Check baseline ECG and repeat ECG while on medication if baseline QTc is prolonged
• Tendonopathy and tendon rupture: worse in elderly >60yrs, mainly Achilles tendon
• Rash: Immediate IgE mediated reactions and delayed type hypersensitivity reactions (maculopapular rash)
• Hepatic toxicity: may cause transaminitis and rarely acute liver injury
• Hypoglycemia: mainly seen with gatifloxacin
• Exacerbation of myasthenia gravis

Surviving Sepsis Campaign

The Surviving Sepsis Campaign came out with updated guidelines for the management of severe sepsis and Septic shock in 2012. Here is a summary. Please refer to this link to access the entire article: Surviving Sepsis Campaign

A. Initial Resuscitation:

• Recognize septic shock: defined as documented hypotension despite adequate fluid challenge and evidence of end organ hypoperfusion (lactate >4g, AKI, change in LOC, cardiac ischemia)
• Goals for the first 6 hrs:
• CVP 8-12mmHg
• MAP 65mmHg or greater
• Urine output goal 0.5mL/kg/hr
• Central venous saturation 70% or mixed venous O2 sat of 65%
• Target resuscitation to the normalization of lactate

B. Diagnosis:

• Septic w/u: cultures should be drawn prior to antibiotic administration anaerobic/aerobic at least one peripherally and one from all central lines
• If fungal infection/candidiases is suspected: use 1,3 beta-D-glucan assay, mannan and anti-mannan antibody assays
• Imagine as needed to investigate source

C. Empiric Therapy

• Administer IV abx within first hour of recogntition of shock.
• Think about potential bugs and penetration of IV abx
• Combination therapy for severe sepsis/neutropenic patients is recommended for up to 3-5 days but should be narrowed thereafter. Consider combo therapy for pseudomonas, acinetobacter and other multi-drug resistant organisms (i.e. an extended spectrum beta lactamase and gentamycin or flouroquinolone)

D. Get Source Control

• Every effort should be made to get source control within 12 hrs of identification, this may involve getting the surgeons or interventional radiology involved. Abx treatment should be limitted to 7-10 days, unless there was slow response to abx
• For example, infected peripancreatic abscess or infected necrotizing pancreatitis should be drained percutaneously or surgically once viable and non-viable tissue is demarcated.
• If percutaneous devices are a possible source infection, they should be removed promptly!

E. Infection Prevention:

• Selective oral and or digestive decontamination should be used i.e. oral chlorhexidine

Wolfram's Syndrome and secondary causes of diabetes

Today we had an interesting discussion of a patient with Wolfram's Syndrome or DIDMOAD, this generated an interesting discussion on secondary causes of insulin resistance:

1) What the heck is DIDMOAD?

• Wolfram syndrome has three genetic forms one of them being DIDMOAD
• It is an autosomal recessive disorder with incomplete penetrance, affecting 1/770 000
• DI - Diabetes insipidis: due to loss of vasopressin secreting cells, anterior pituitary dysfunction has also been described
• DM - Diabetes Mellitus: Patient typically develop diabetes in childhood requiring insulin (due to an inability to convert pro-insulin to insulin)
• OA - Optic atrophy occurs early in childhood 
• D - Deafness: sensorineural deafness

2) What are other causes of insulin resistance?

• Primary pancreatic: Infiltrative (hemochromatosis, amyloidosis), cystic fibrosis, pancreatic cancer, chronic pancreatitis, surgical removal/trauma
• Endocrine: Cushings (secondary to elevated cortisol), acromegaly, pheochromocytoma (secondary to adrenergic stimulation), Conn's (secondary to hypokalemia)
• Drugs: Steroids (increases gluconeogenesis and decreases peripheral glucose transporter), thiazide diuretics, atypical anti-psychotics, nicotinic acid, HAART therapy, ocreotide infusion, inotropes
• Unusual causes: muscular dystrophy, friedrich's ataxia, Wolfram's syndrome etc.

3) Work up and Management of hyperglycemia:

• Confirm: Repeat the accucheck
• Look for causes: 
• Known diabetes? HHS/DKA (look for precipitating factors: infarction, infection, insulin non-compliance, new diagnosis of diabetes) 
• Secondary causes of insulin resistance: i.e. medications
• Look for perpetuating factors:
• Severe hypovolemia results in both hemoconcentration and decreased GFR leading to decreased filtration of glucose
• Increased adrenergic/stress state drives gluconeogensis and insulin resistence
• Investigations:
• Physical exam to look for precipitating factors and degree of volume depletion
• Laboratory work to look for DKA/HHS and precipitating factors:
• ABG, anion gap, serum ketones, serum osmolarity, electrolytes (esp. K+), creatinine
• Septic w/u, ecg, troponin/ck, amylase/lipase
• Treatment:
• Fluids for the hyperglycemia
• IV Insulin to close the anion gap and decrease fat metabolism and the generation of ketones. Continue until the anion gap is closed
• potassium replacement
• Treat the underlying cause
• Transition to SC insulin once patient's B.G. is stable and insulin requirements have been minimal and stable and patient is eating... and in the daytime! Ensure at least 1-2 hrs of overlap.
• Please see the following article for treatment of Diabetic ketoacidosis: CMAJ 2003 Treatment of DKA/HHS

Asthma

Today we had an interesting discussion on Asthma and it's potential mimicers, here is a synopsis:

• Diagnosis:
• FEV1/FVC less than0.75-0.8 with 12%+ improvement with beta-agonist
• More than 20% variation in peak expiratory flow (PEF)
• Methacholine challenge: PC20 (Concentration required for a drop in FEV1 of 20%) less than 4mg/ml
• Measures of poor control:
• Daytime symptoms more than 4/wk and night time symptoms more than 1/wk
• Missing days of work/school
• Decreased physical activity
• Frequent exacerbations
• FEV1 or PEF less than 90% of personal best
• Need for fast-acting beta2 agonist more than 4 doses/wk
• Sputum eosinophils more than 2-3%
• Treatment of Asthma exacerbation:
• Markers of severe disease/impending respiratory collapse:
• Work of breathing: use of accessory muscles
• Hypoxia (asthma is really a problem with ventilation, when oxygenation starts to decrease that's a worrisome sign)
• Pulsus paradoxus greater than10mmHg
• Silent chest!
• Inhaled beta agonists: short acting beta 2-agonists (salbutamol, albuterol) and short acting anti-cholinergics (iptratropium) MDI with aerochamber
• Prednisone: 40-60mg Prednisone daily or if unable to take PO consider IV solumedrol for 10-14 days.
• Adjuncts: MgSO4 2mg IV, Leukotriene receptor antagonists
• Intubation if needed
• Abx if evidence of pneumonia 
• Complications of asthma that may present as worsening/non-responding asthma:
• Churg-Strauss: Medium-small vessel vasculitis that presents with worsening asthma, eosinophilia and ANCA positive in 40-60%. Other signs of vasculitis include: leukocytoclastic vasculitis (palpable purpura), mononeuritis mulitplex and less commonly RPGN.
• ABPA: Allergic bronchopulmonary aspergillosis. Major diagnostic criteria:
• Hx of asthma
• New pulmonary infiltrate
• Immediate skin sensitivity to aspergillus precipitins
• Precipitating serum antibodies to A. fumigatus
• Peripheral eosinophilia (500/mm3)
• IgE (1000ng/ml)
• Increased serum antibodies IgG, IgA, IgE
• Central bronchiectasis
• Cryptogenic Organizing pneumonia (previously called BOOP):
• A non-specific pulmonary inflammatory process manifesting as inflammation of the distal bronchioles, alveolar ducts/walls. Characterized by fever, malaise, chronic cough, areas of infiltration in CXR
• Terminology: Organizing pneumonia of determined cause and if it is "idiopathic" it is referred to as organizing pneumonia of undetermined cause or COP
• Causes of organizing pneumonia: infections (including: mycoplasma, PJP, HIV, cryptococcus), drugs (amiodarone, cocaine, bleomycine), malignancy.
• Can also occur in the context of CTD: SLE, sjogren's, dermatomyositis, etc.
• Mimicers of Asthma:
• Paradoxical vocal cord motion: the vocal cords move in during inspiration. Can be triggered by stress, exercise, airway manipulation, irritant inhalations. Presents with upper airway stridor, throat tightness, hoarseness cough. Treat with reassurance and asking the patient to "pant"
• Laryngospasm: Can be induced by URTI, presents with aphonia and choking sensation. Use of continuous positive airway pressure and heliox may help.
• "Cardiogenc wheeze": Don't miss the patient who presents with wheeze secondary to pulmonary edema (cardiogenic or non-cardiogenic)!

C. Difficile Colitis

1) Risk factors:

• Age >65yrs
• Recent antibiotic use (all and any abx use will put patients at risk for C. diff but increased risk if multiple abx and prolonged use)
• Recent hospitalization or residence in a nursing home/health care facility
• Treatment with PPI
• Comorbidities (DM, liver disease, CKD, cancer on treatment, solid organ transplant)

2) C. Diff treatment from the IDSA guidelines:

• Initial episode, mild/moderate
• WBC less than 15, Creat less than 1.5 x baseline
• Treat with metronidazole 500mg PO TID x 10-14 days
• Initial episode, severe 
• WBC greater than 15, Creat greater than 1.5 x baseline
• Treat with Vancomycin 125mg PO QID x 10-14 days
• Initial episode, severe + complicated
• WBC greater than 15, Creatinine greater than 1.5 x baseline
• PLUS toxic megacolon, ileus, shock
• Vanco 500mg PO QID and consider rectal instillation if ileus
• IV Metronidazole 500mg Q8H
• Surgical consult
• Initial recurrence
• Classify as mild/moderate/severe/complicated and treat appropriately
• Ok to treat with metronidazole if mild disease, however avoid prolonged metronidazole to avoid neurotoxicity
• Second recurrence
• Treat according to severity, otherwise treat with Vancomycin 125mg PO QID with a tapered regimen
• See the IDSA guidelines for more details: IDSA Clinical Treatment guidelines for C. diff 2010

2) Diagnosis of Toxic Megacolon:

• Etiology: IBD, infectious (c. diff, CMV, shigella, salmonella, e.coli, etamoeba histiolytica etc.)
• Diagnosis: 
• Radiographic findings (greater than 10cm) 
• At least three of: fever, elevated WBC, tachycardia, anemia, dehydration, altered sensorium, electrolyte abN, hypotension.
• Treatment: 
• Surgical consult!
• Medical Mx: ICU admission, NG tube for decompression, restart eteral feeding as soon as symptoms improve, consider IV steroids in IBD associated toxic megacolon

See this link for further information: Clostridium dificille infection Mayo Clinic Proceedings 2012

Hypercalcemia

Hypercalcemia:

Causes of hypercalcemia:
1) PTH mediated: 

• Primary- sporadic
• Secondary - Chronic renal failure
• Teritary - post renal transplant - autonomous production from hypertrophied parathyroid glands

2) Non-PTH mediated

• Malignancy mediated:

1. PTH rP - SCC (lung, H+N), solid tumours (renal, breast, bladder, ovarian)
2. Lymphoma - from activation of extra-renal 1-alpha OH and production of calcitriol
3. Bony mets: Osteoblastic (prostate, carcinoid, SCLC, hodgkins), osteolytic (myeloma, RCC, nonSCLC, NHL, melanoma)

• Non-malignancy related

1. Granulomas: Sarcoid, TB (activation of extra-renal 1-alpha OH and production of calcitriol)
2. Paget's disease: Regional areas of accelerated rate of bone remodelling resulting in abnormal bone architecture, bony pain, fractures and hypercalcemia.
3. Immobilization (often concomitant with another cause of hypercalcemia)
4. Medications: Thiazide, lithium
5. Endocrine: Hyperthyroidism, adrenal insufficiency
6. Milk alkali

Symptoms:

• Moans: Abdominal pain/constipation, nausea, anorexia
• Bones: Bony pain
• Groans: Calcium kidney stones (CaPhos or Caoxalate)
• Psychic overtones: Change in LOC, delirium

Treatment:

• The cornerstone of treatment is: FLUIDS, FLUIDS, FLUIDS. Patients are often quite hypovolemic secondary to their inability to concentrate urine and nephrogenic diabetes insipidus. The kidneys should be able to excrete the majority of excess calcium  
• Calcitonin:  4u/kg IM/SC rapid reduction in serum Ca by 1-2mmol/L. Works in 4-6 hrs.  
• Bisphosphonates:  Pamidronate 30mg, 60mg, 90mg IV. More sustained reduction in Ca, takes 1-2 days to start working.  
• Lasix:  Caution as this can cause worsening hypercalcemia from hypovolemia. Only used of pt is showing signs of volume overload from fluid resuscitation. see article from Annals of Internal Medicine: Furosemide from Hypercalcemia: An unproven yet common practice

Thanks to our palliative care physicians, we had a great palliative care MR on pain control at the end of life:
1) Opioid Equivalence:

• Codeine: 100mg PO
• Morphine: 10mg PO (5mg IV/SC)
• Oxycodone: 5mg PO
• Hydromorphone: 2mg (1mg IV/SC)

2) Opioid Side Effects:

• N/V: may resolve after a period of time
• Constipation: does not resolve over time
• Somnolence/drowsiness
• pruritis
• urinary retention

3) Opioid Toxicity:

• Myoclonus is an early sign of toxicity
• Nausea/vomitting
• myosis
• Somnolence
• Respiratory depression

4) Treatment of opioid toxicity:

• Dose reduction 25-50%
• Change type of opioid

5) Incomplete Cross Tolerance:

• Results in increased response to an equivalent dose of a different type of opioid
• Therefore, when changing to a different opioid dose should be reduced by 25-50%

Post Call Morning Report

This morning we had an interesting discussion on all patients admitted to GIM over night. Here are some interesting topics that were discussed:

1) Treatment arrhythmias associated with cocaine-associated catecholamine excess

• We discussed a complicated case of an agitated patient with recent cocaine ingestion and atrial fibrillation and signs of heart failure.
• All types of arrhythmias have been described in cocaine toxicity from wide complex-tachycardia to supraventricular tachycardia
• Arrhythmias associated with catecholamine excess include SVT, Sinus Tachy, Afib
• Supportive therapy is the mainstay: cooling, IV fluid rehydration and benzodiazepines
• Other therapies for SVT/Afib may include IV CCBs 
• For treatment of HTN may use IV phentolamine/nitroglycerine for HTN (beware of reflex tachycardia)
• It is important to avoid beta blockers in pts with possible cocaine intoxication as this results in un-opposed alpha and worsening hypertension and coronary vasoconstriction
• See the following article for more information: Cocaine toxicity and arrhythmias

2) Causes of elevated Lactate

• Type A lactic acidosis: From marked tissue hypoperfusion: Cardiogenic, septic shock, local decreased perfusion (compartment syndrome, necrotizing fasciitis), ischemic bowel, seizures (from increased O2 use)
• Type B lactic acidosis: Features of hypoperfusion are not apparent. Causes include toxin-induced impairment of cellular metabolism. causes include: liver failure (from impaired lactic acid utilization in gluconeogenesis in the liver), metformin use in renal failure (theoretical), malignancy (from direct production by malignant cells), cyanide, alcoholism, diabetes.

3) Causes of low BP not responding to fluids

• In the absence of cardiogenic or septic shock think of more unusual causes of low BP:
• Anaphylaxis
• Adrenal insufficiency - mets to adrenals, infarction of adrenals secondary to severe infection (Waterhouse-Friederichsen), hemorrhage/adrenal vein thrombosis, 
• Hidden bleeding: retroperitoneal

Palliative Care Resources

Palliative Care Articles:

This week is palliative care week. Check out the following resources for further reading (Courtesy of Dr. Goche):

• Withholding Nutrition at the End of Life - Cleveland Clinic
• This is a great article on the ethics and legality of withholding nutrition at the end of life and the evidence behind why it may be beneficial at the end of life to withhold nutrition.
• Delirium in Advanced Cancer Patients - Palliative Medicine 2004
• This article discusses the precipitants, preventative approaches and treatment options for delirium in advanced cancer patients.
• Do Opioids Precipitate Death? Canadian Family Physician 2010
• This is a thought provoking article on how to kill symptoms without killing the patient.
• Discussing Do Not Resuscitate - Journal of Clinical Oncology 2001
• This article is an excellent article on how to approach a DNR discussion
• A request for non-disclosure: Don't tell mother
• This is an excellent article discussing the ethical dilemma's around non-disclosure, when families ask that their loved one not be told that they have a terminal illness. This article talks about how to approach these situations practically as physicians.

Hypertensive Emergency

Today we discussed a patient with a hypertensive emergency. Here are some key points:
1) Classification of HTN:

• HTNsive urgency: SBP>180 or DBP>120 without end-organ damage 
• HTNsive emergency: Acute severe hypertension with end organ damage
• Malignant HTN: Hypertension with papilledema, renal involvement or microangiopathic hemolytic anemia.

2) End organ damage in HTN (head to toe)

• CNS: Encephalopathy (confusion), seizures, intracranial hemorrhage, SAH, and lacunar infarcts. Radiographic finding called PRES (posterior reversible encephalopathy syndrome) characterized by posterior symmetric white matter edema seen on CT
• Optic: retinal hemorrhages, exudates, papilledema and vision loss
• Cardiac: acute MI, aortic dissection, acute heart failure with pulmonary edema
• Renal: AKI, hypertensive nephrosclerosis (over time)
• Hematologic: microangiopathic hemolytic anemia

3) HTNsive retinopathy:

• Mild — Retinal arteriolar narrowing related to vasospasm, arteriolar wall thickening or opacification, and arteriovenous nicking, referred to as nipping
• Moderate — Hemorrhages, either flame or dot-shaped, cotton-wool spots, hard exudates, and microaneurysms
• Severe — Some or all of the above, plus optic disc edema. The presence of papilledema mandates rapid lowering of the blood pressure.

4) Secondary causes of HTN: 

• Endocrine: Cushing's syndrome, pheochromocytoma, aldosterone producing tumour (Conn's syndrome), acromegaly, hyper/hypothyroidism (these do not typically present as emergency/urgency)
• Anatomic: Coarctation of the aorta
• Renal: Renal artery stenosis (atherosclerosis, fibromuscular dysplasia), renal parenchymal disease, polycystic kidney disease
• Drugs: Cocaine, MAOI and tyramine containing foods, rapid withdrawal of clonidine/propanolol
• Pregnancy: Pre-eclampsia and HELLP syndrome

5) Treatment goals:

• Hypertensive emergency: Lower the BP by 25% of the MAP in the first 24 hrs or until symptoms resolve (i.e. patient stops seizing)
• Hypertensive urgency: Safer to lower the BP over days to weeks

6) Practical treatment and specific situations:

• If HTN emergency consider admission to ICU for arterial line and monitored lowering of BP
• Labetalol 10mg IV bolus followed by infusion (can repeat bolus if necessary)
• Nitroprosuside 0.25-0.5mcg/kg/min (beware of cyanide toxicity if prolonged treatment >48hrs)
• Hydralazine (can cause reflex tachycardia, so better if pt beta blocked prior to starting)
• Catecholamine driven HTN (Cocaine, MAOI, Pheo): use an alpha blocker (phentolamine 5-10mg IV Q5-15 min). Beware of giving beta-blockers as this can result in unopposed alpha and worsening HTN
• Pre-eclampsia: labetalol IV and MgSO4
• Alcohol withdrawal: Benzodiazepines
• Aortic dissection: Avoid using vasodilators initially (i.e. nitroprusside) as this can cause a reflex tachycardia and sheer stress on the aorta. Start with beta blocker and add nitroprusside if BP still not well controlled.

Today Dr. Okrainec led us through an interesting case of an unstable patient. The following are some Clinical Pearls about the management of an acutely ill patient:

1) CAB's & MOIF +/- DONT

• Circulation: start by assessing the patient's circulation (pulse, BP and HR), feel the extremities to assess for perfusion (cold vs warm). A cool mottled patient is a sign of peripheral vasoconstriction which occurs with hypovolemia or cardiogenic shock. Warm extremities indicate a distributive picture (sepsis or anaphylaxis). If BP low, consider bolusing IV fluids using a pressurized bag, crystalloids have been shown to be equivalent to colloids.
• Airway/Breathing: Signs of resp distress: tri-poding, paradoxical abdominal breathing (Belly in with inspiration, out with expiration), quiet chest are all indicative of impending resp failure. Also assess GCS for ability to protect the airway. 
• MOIF: Monitor, Oxygen, IV x 2 and Foley. It is important to ensure the patient is being monitored (i.e. cardiac monitor or nurse at bedside to do frequent vitals). The foley catheter is useful for assessing renal perfusion

2) Primary Survey

• Once you have assessed the CAB's and initiated initial management (i.e. IV fluids, CPR and ACLS protocol if pulseless) you can do a primary survey
• The primary survey consists of a quick physical assessment to rule out/in causes of shock:
• GCS: Pupils (look for a toxidrome), focal neuro deficits, meningismus
• CVS: JVP (signs of tamponade, HF, PE), new murmurs (acute valvular rupture, aortic dissection)
• Resp: equal air entry? (signs of pneumothorax)
• Abdo: signs of perforated viscus, intra-abdo or retroperitoneal bleed (ecchymosis), check the diaper for melena/blood
• Extrem: signs of DVT
• Assess around the patient: PCA pump (opiod toxicity)? Heparin drip (bleeding risk)?

3) Initial management:

• DONT: the universal antitodes for decreased LOC (Dextrose, Oxygen, Naloxone, Thiamine)
• IV fluids: wide open and on a pressure bag (or use a BP cuff)
• STAT labs: ABG, CBC, lytes, creat, INR/PTT, lactate, blood C&S, liver enzymes, glucose, troponin/CK. The ABG can tell you roughly the lytes and hgb. Don't forget to look at pt's recent labs
• STAT investigations based on presentation: ECG, portable CXR, bedside ECHO
• Low BP resistant to IV fluids: consider giving empiric Abx (early goal directed therapy), consider stress dose of steroids if risk of adrenal insufficiency
• Low BP resistant to IV fluids: consider giving peripheral inotropic support (phenylephrine 100-200mcg IV bolus, dopamine 10-20mcg/kg/min) can give through peripheral IV for a short period
• Signs of bleeding: give blood.

4) Definitive management:

• Call ICU and arrange for transfer once CAB's are relatively stable

Today we spoke about some interesting cases that were admitted over night, here is a synopsis of the different cases we discussed:

1) Does this patient have septic arthritis?

• Identifiable risk factors and arthrocentesis are most useful for predicting septic arthritis. Physical examination and clinical history are less helpful due to non-specific symptoms and signs. 
• Age 80+y (LR 3.5)
• Hx rheumatoid arthritis (LR 2.5)
• Hx DMII (LR 2.7)
• Recent join Sx (LR 6.9)
• Prosthetic hip/knee (LR 3.1)
• Overlying skin infection and prosthetic joint (LR 15)
• WBC in synovial fluid: >25, 000 (LR 2.9), >50, 000 (LR7.7), >100,000 (LR28)
• Percentage PMN in synovial fluid >90% (LR 3.4)
• Not helpful: presence/absence of fever, ESR/CRP, peripheral WBC
• Imaging
• Ultrasound can be used to identify an effusion
• MRI best for looking for: fractures not seen on radiograph, signs of osteomyelitis, early signs of AVN and for effusions.
• Management issues:
• Joint destruction can occur within 48 hrs of septic arthritis. Therefore, should get orthopedics involved early as drainage of purulent synovial fluid is important to prevent joint destruction.

Does this patient have septic arthritis - JAMA

2) What is minute ventilation?

• Tidal volume: Quantity of air moved into and out of lungs during a normal breath (normal is 500cc)
• Minute ventilation: Quantity of air moved into and out of lungs during 1 minute (normal is 5-6L)
• Therefore, the maximal L/min of O2 that can be delivered by NP is 6L/min, beyond that, you are not giving any more O2 to the patient, this is approximately equal to FiO2 of 40%
• Delivery of oxygen is limitted by the entrainment of ambient room air (FiO2 of 21%). To increase the amount of O2 delivered you must control to amount of entrained air
• Non-rebreather masks draw oxygen from a reservoir with a one way valve that directs exhaled air out of the mask, thereby limiting the amount of entrained air. These can deliver up to 100% FiO2.

3) Pulmonary Aspergillosis

• Aspergillus is a fungus that is basically ubiquitous, found in both outdoor and indoor environments
• There are 4 classic presentations:
• Allergic bronchopulmonary aspergillosis (ABPA) - common in ashtmatics and CF patients
• Chronic necrotizing pulmonary aspergillosis (CNPA) - common in immunocompromised patients or patients with underlying lung disease
• Aspergilloma: a fungus ball that can grow in pre-existing cavities ie. from previous TB, emphysema, PCP
• Invasive pulmonary aspergillosis (IPA) - occurs in severely immunocompromised hosts with neutropenia or post HSCT

Invasive Pulmonary Aspergillosis

• Diagnosis:
• Aspergillus can be a colonizer, so diagnosis is not made solely on the basis of sputum cultures
• The diagnosis of IPA is based on histopathologic evidence of aspergillus invading lung tissue
• Diagnostic criteria for ABPA:
• Hx of asthma, immediate skin sensitivity to aspergillus Ag, aspergillus precipitins, Elevated specific IgG, E, A to aspergillus, central bronchiectasis, serum IgE >1000ng/ml, elevated eosinophils >500/mm, lung infiltrates on CXR
• Treatment
• For IPA, tx should be initiated as soon as there is a clinical suspicion and while confirmatory testing is done.
• Tx depends on the degree of infection. For IPA/CNPA, voriconazole/itraconazole is first line, can use IV liposomal amphotericin b or IV voriconazole for severe infections
• First line treatment of ABPA is corticosteroids, can use itra or vori as steroid sparing agent

Review of Pulmonary aspergillosis

Pituitary Macroadenoma

Approach to Pituitary Macroadenoma

• Pituitary adenomas are classified based on size and function:
• Macroadenoma vs Microadenoma
• Functioning vs non-functioning
• Causes problems by:
• Hypersecretion: Most common are gonadotroph secreting adenomas, but they are hardest to recognize as they secrete inefficiently and the effects are not easily noticed; prolactin (PRL), responsible for amenorrhea-galactorrhea in women and decreased libido in men; growth hormone (GH), responsible for acromegaly; adrenocorticotropic hormone (ACTH), responsible for Cushing's disease; thyroid-stinulating hormone (TSH), responsible for hyperthyroidism. 
• Depressed secretion of hormones: Hypopituitarism, in the order of: GH, LH/FSH, TSH, ACTH, PRL (aka Go Look For The Adenoma Please)
• Mechanical compression
• Expansion of dura causes headaches
• Superior invasion: affects optic chiasm and causes bitemporal hemianopsia
• Inferior invasion: Through cribriform plate into sphenoid sinus causing CSF rhinorrea and risk of meningitis
• Lateral invasion: Cavernous sinus/internal carotid artery and cranial nerves 3, 4, 6, 5 (V1/V2)

• Investigation:
• Mechanical compression/extension: 
• Assessed by MRI
• Also can do visual field testing
• Hormone secretion:
• GH: is normally secreted in a diurnal pattern and is suppressed by glucose load. Tested by doing an oral glucose tolerance test. Also can test IGF-1 which does not change hour by hour and reflects integrated GH secretion during the previous 24hrs. Also can test response to OGTT, as patients have insulin resistance.
• TSH/T3/T4
• Cortisol: Screening tests: 24 UFC, late night salivary cortisol, 1mg Dex suppression test
• Prolactin: Prolactin level
• Hormone suppression:
• GH, LH/FSH/Testosterone, TSH, AM cortisol, prolactin
• Comorbidities:
• If patient found to have GH secreting adenoma should look for visceral organ effects:
• Colonoscopy to look for polyps/colon ca
• ECHO to look for cardiomyopathy
• BP to look for HTN
• Fasting BG, OGTT to screen for diabetes
• Screen for obstructive sleep apnea

• Management:
• Surgical indications:
• A visual field deficit due to the lesion or other visual abN
• Adenoma abutting the optic chiasm on MRI
• Pituitary apoplexy with visual disturbance
• Hypersecreting tumour other than prolactinoma
• Specific situations
• GH secreting adenoma: First line is surgery. Medical therapies include somatostatin analogues (octreotide/lanreotide) and dopamine agonist (cabergoline) and GH receptor antagonists (Pegvisomant). Can also use radiation (fractionated or by Gamma knife).
• ACTH secreting tumour: primary therapy is surgery
• Prolactinoma: Can use medical therapy with DA agonist.
• Micro-incidentalomas
• Follow-up MRI in 1 yr and then Q1-2 y thereafter
• If grows significantly (in proportion to original size) then consider surgery
• Macro-incidentalomas
• Follow up MRI in 6 months then Q1yr
• Evaluate for hypopituitarism and evaluate the visual fields
• If there is tumour growth, VF abN or hypopit consider surgery

See the Endocrine Society Practice Guidelines for an Approach to Pituitary Incidentaloma