Delirium Tremens

CIWA protocol

Delirium Tremens

Last night we had, as Dr. McNeely put it, "a tsunami of alcoholics". Here are some pearls on Delirium Tremens or the "Rum Fits"

1)What is it: It is a state of severe psychomotor agitation and sympathetic overdrive in chronic alcoholics who have been abstinent for ~ greater than48-96hrs, but can occur up to 7-10 days since the last drink. It also happens to be the name of a brand of Belgian golden ale as seen above!

2) When to suspect it:

• Prolonged daily alcohol consumption
• Symptoms of withdrawal even while serum etOH levels are still elevated
• Prolonged period of abstinence
• Comorbidities
• Increasing age
• History of DTs

3) What to expect:

• Psychomotor agitation: anxiety, delirium, tremor, hallucinations, seizures,
• Autonomic dysfunction: hyperthermia, hypertension, tachycardia, tachypnea, diaphoresis, midriasis
• Seizures: Alcohol withdrawal seizures can occur within 12-48 hours of the last drink, and can occur without DTs. They are tonic clonic, and occur as a single seizure or a brief flurry of seizure activity. If seizures are prolonged or continue for >6 hr period other causes of seizures should be investigated (i.e. intracerebral hemorrhage). 

4) How to Treat:

• Benzodiazepines are the mainstay of treatment
• For patients in the acute phase of alcohol withdrawal treat with diazepam. 
• Diazepam 10-20 mg PO Q1H x 3
• If unable to tolerate PO Diazepam IV 2-5mg Q5-10 min until appropriate level of sedation is achieved.
• Rather than keeping patients sedated it is better to practice symptom based treatment with the CIWA protocol
• When to start CIWA: For any patient at risk of alcohol withdrawal who has been abstinent for <12 hrs="hrs" li="li">
• When to stop CIWA: For any patient with a CIWA of less than 10 x 3 consecutive evaluations
• Hallucinations
•  Can treat with Haloperidol (watch the QTc)
• Metabolic disturbance
• Treat electrolyte abnormalities, Mg, Phos, K+
• Treat malnutrition: Thiamine 100mg IV daily x 3 and folate
• IV rehydration
• Patients can have arrhythmias and should be on telemetry
• Refer to the following link regarding treatment of alcohol withdrawal: CIWA protocol

Hyponatremia

Hyponatremia is the most common electrolyte abnormality encountered in the hospital. It primarily signifies a problem with water, not salt.

Etiology: Net gain of electrolyte free water relative to the body's stores of Na and K. This can occur in three volume states:

1) Hypovelemic State: ADH is appropriately released resulting in the retention of water in the kidneys. There is relatively more water retention than sodium retention resulting in hyponatremia. The urine osmolality will be high and urine sodium will be low. Thiazide diuretics are also common culprits of chronic hyponatremia.

2) Euvolemic State:

• SIADH: ADH is inappropriately released by many mechanisms including pain response, nausea/vomitting, CNS disturbance, pulmonary disease, medications (anti-depressants, anti-convulsants, MDMA/ectsasy)
• Tumour producing ADH
• Endocrine abN (hypothyroidism, adrenal insufficiency)
• Low solute diet (tea and toast, beer potomania)
• Psychogenic polydipsia.

3) Hypervolemic State: Low effective circulating volume i.e. cirrhosis, heart failure.

Severity:
The degree of severity is inversely proportional to the serum Na and the time frame over which the change occurred. The risk of hyponatremia is inversely proportional to the Serum Na, with serum Na less than 120mmol/L considered severe. Symptoms are non-specific, including lethargy, headache, confusion, seizures and decreased LOC. Patients with seizures and decreased LOC, secondary to low Na, should have their serum Na corrected quickly (see treatment below). However patients with chronically low serum Na, do not need to be corrected quickly and may in fact be harmed by over correction.

Patients with chronically low serum [Na] develop shifts in the intracerebral osmoles to coompensate for the chronically low serum [Na]. Therefore, if a rapid correction of serum [Na] occurs, this can result in a sudden shift of water extracellularly, putting patients at risk of osmotic demyelinating syndrome (ODS) or cerebral pontine myelinolysis (CPM). Patients who are elderly, malnourished and hypokalemic are at the highest risk. In the case of rapid correction (8mmol/day or more), the serum Na must be decreased quickly to prevent the development of ODS/CPM. Treatment includes administering hypotonic IV fluids and giving DDAVP to increase serum ADH.

Diagnosis:
1) Start by confirming hyponatremic hyponatremia by doing a serum osmolality. Rule out hypertonic hyponatremia caused by other osmoles (hyperglycemia, mannitol)

2) Assess volume status: hypervolemic, hypovolemic, euvolemic

3) Confirm volume status with urine lytes:

• Hypovolemic: High urine osmolality greater than 300mOsm. Low excretion of urine Na less than 20. 
• Euvolemic: Normal urine Na, normal urine osmolality.
• Keep in mind if pt is on Lasix, urine Na may be high!

Treatment of Hyponatremia:
1) Severe Hypo Na: Treat with hypertonic saline 3% (513 mOsm). Give 100cc 3%NS over 10 minutes, this should increase serum [Na] by 2meq. This can be repeated twice every 10 minutes. Pateints should be treated until symptoms resolve (i.e. seizures). Furosemide can be given reduce volume expansion and prevent shutting off of ADH and diuresis.

2) Non-severe hypovolemic HypoNa: A safe range for improving sodium is 6-8mEq/24 hrs. Patients should be monitored for urine output, repeat serum lytes and urine lytes Q4hr as they receive IV fluids. A sign of aquaresis is the sudden production of large amounts of dilute urine. If this occurs, to prevent rapid correction of serum [Na], DDAVP can be given 2-4mcg IV. Some insititutions advocate for giving DDAVP up front, however as long as close care is taken to detect aquaresis early, giving up front DDAVP can be avoided.

3) SIADH = restrict fluid to less than 1.5L per day, and consider salt tabs.

Please refer to the following recently published article on Hyponatremia in JASN: http://jasn.asnjournals.org/content/23/7/1140.full.pdf+html?sid=c14ec703-91e2-4d5e-966e-eef3e9aa8ac5

Nephrotic Syndrome

Today we talked about a patient presenting with bilateral leg edema and proteinuria. This brought up the topic of Nephrotic syndrome:

1) Nephrotic Syndrome:

• Characterized by nephrotic range proteinuria (usually more than 3 g/day), edema and hypoalbuminemia (<3g also="also" and="and" associated="associated" g--="g--" hypercoagulable="hypercoagulable" hyperlipidemia="hyperlipidemia" state.="state." with="with">
• Hyperlipidemia: Triglyceride rich lipoproteins increased in nephrotic syndrome due to decreased catabolism. This is likely due to decreased binding of lipoprotein lipase (LPL) to endothelial cells secondary to the reduced oncotic pressure.
• Hypercoagulable state: Likely secondary to an imbalance between naturally occuring pro-coagulant/pro-thrombotic factors and anti-coagulant and anti-thrombotic factors. Likely multifactorial, related to increased urinary losses of anti-thrombin, Protein C, Protein S and increased levels of fibrinogen. See this paper for a review of hypercoagulability and nephrotic syndrome
• Increased susceptibility to infections: unclear etiology, but may be related to urinary losses of IgG.

2) Etiology

• Focal segmental glomerulosclerosis: common cause of idiopathic nephrotic syndrome in adults
• Reflux nephropathy
• Nephron loss: surgical or congenital
• Intraglomerular hypertension from primary renal vasodilation: Diabetes, sickle cell disease
• Obesity
• Interferon

• Minimal change disease: Most common cause in children, also occurs in adults.
• Drugs: NSAIDs, antimicrobials (ampicllin, rifampin), penicillamine, lithium, sulfasalazine
• Paraneoplastic phenomena: Hodgkin's lymphoma, NHL, leukemia, rarely solid tumors
• Infectons: TB, syphilis, Hep C, HIV, erlichiosis, mycoplasma, echinococcus
• Systemic diseases: Diabetes, SLE, PCKD, HIV
• Allergy
• Membranous nephropathy
• Malignancy, typically solid tumor (GI, prostate, lung) and less frequently heme malignancy
• Infections: Hepatitis B/Hepatitis C, schistosomiasis, malaria, syphilis
• Autoimmune disease: SLE (lupus nephritis type V)
• Drugs: NSAIDs, penicillamine, 

• Amyloidosis
• AL/primary amyloid: Light chain dyscrasia where fragments of monoclonal light chains form amyloid fibrils.
• AA/ Secondary amyloid: Secondary to chronic inflammation where the acute phase reactant serum amyloid A forms amyloid fibrils. Occurs for example in Rheumatoid Arthritis or osteomyelitis.
• In this case, urine dipstick will be negative and serum albumin is normal.

Today we talked about a case of acute hypoxia in an elderly gentlemen with a history of dysphagia, stroke, seizures and dementia.We covered the differential for acute hypoxia and then identified that the most likely cause in our patient was aspiration pneumonia, with pulmonary embolus on the differential.

1) Causes of Acute Hypoxia: The differential for hypoxia is extensive, but the differential for sudden onset severe hypoxia is not as long.

• Pulmonary embolus
• Pneumothorax
• Pulmonary edema (cardiogenic/non-cardiogenic)
• Pulmonary hemmorhage
• Aspiration pneumonia
• Bacterial pneumonia
• Mucous plugging

2) Aspiration: Defined as misdirection of oropharyngeal or gastric contents into the larynx and lower respiratory tract. There are two entities: Aspiration pneumonitis and pneumonia. Aspiration pneumonitis can lead to ARDS and carries a high mortality (up to 12%). It can present with fever and hypoxia. Treatment is supportive. Use of glucocorticoids is controversial and animal studies have shown variable results.

Half of healthy adults aspirate during their sleep, but are protected from developing aspiration pneumonia by the following mechanisms: low virulent bacterial load in orophargyngeal/gastric contents, active ciliary transport, normal cough reflex, cellular and humoral immune system to help clear infection.

• Risk factors for aspiration include

• Decreased LOC caused by drugs or toxins (i.e. EtOH)
• Stroke/neurologic injury causing dysphagia/impaired cough reflex
• Seizure disorder
• Degenerative CNS disease: dementia, Parkinson's, ALS
• Dysphagia: esophageal stricutre, diverticulum etc.
• Recent anesthetic
• ETT/Trach/NG tube
• Frequent reflux/vomitting/gastric outlet obstruction
• Risk factors for developing aspiration pneumonia:
• Poor dentition
• Treatment with PPI
• Underlying lung disease
• Immunosuppression/decreased cellular immunity
• Colonization of oropharynx with s. aureus, GNB (Klebsiella pneumonia, Escherichia coli)
• Common bacterial pathogens:
• Oral anaerobes: Fusobacterium, Bacteroids, Peptostreptococcus
• Gram negative bacilli: Klebsiella, E. coli
• S. aureus
• Management:
• Swallowing assessment: by SLP +/- Video Fluoroscopic Swallowing Study (VFSS)
• Dysphagia diet
• Antibiotics
• When anaerobic bacteria is the most likely pathogen: consider Clindamycin
• Other regimens that also cover CAP: 
• Amoxicillin-Clavulanate
• Moxifloxacin
• Flagyl plus Amoxicillin or Penicillin
• For nosocomial pneumonia and pt is unwell and coverage for both aerobic and anaerobic bacteria is important: 
• Pipericillin-tazobactam
• Carbapenems
• Management of dysphagia:
• Studies have looked at using dopamine agonists and ACEi to increase substance P, which enhances swallowing and the cough refelx.
• Percutaneous feeding/PEG tube has not been shown to increase survival, quality of life or decreased aspiration events

The following is a systematic review of the evaluation and management of dysphagia due to dementia in the elderly: 

http://bf4dv7zn3u.search.serialssolutions.com.myaccess.library.utoronto.ca/OpenURL_local?sid=Entrez:PubMed&id=pmid:22608838

Today Dr. Okrainec took us through a very interesting case of an unstable patient with an UGIB.
The medical students, R1s and R2s did a great job of stabilizing the patient and eventually saving his life! Here are some key points that came out of this morning's session.

1) Approach to the unstable patient:

• Always remember your ABC's
• Be cognisant of changes from a patient's baseline, a drop of more than 20mmHg from the baseline BP is significant, even if the absolute value is not in and of itself alarming.
• Does the patient look sick? Sweating, clammy, cold extremities
• Always reassess vitals when there is a change in pt's status and Q2-5 minutes
• Call for help: when needed you can call a code blue to get a 1) monitor 2) ICU nurse 3) RT/anesthesia 4) crash cart
• Gather as much information as possible: delegate a member on your team to collect information such as: meds, last blood work, past medical history, major things to look at are last creatinine, INR, hgb, wbc
• Do a focused physical exam
• Always plan ahead: Check that you have adequate IV access, inform the ICU of a sick patient, will you likely need blood (do you have an up to date group&screen in the lab?)

2) Approach to UGIB

• ABCs
• Start with getting 2 large bore (16-18G) IVs 
• Start with fluid resuscitation
• Get blood: Uncross matched if pt is hemodynamically unstable and low likelihood of having alloantibodies.
• Initial Management:
• Start Pantoloc 80mg IV bolus followed by 8mg/hr infusion
• If hx or risk factors for liver disease and varices start octreotide
• Consider NG tube, but careful if pt has known esophageal varices
• Optimize clot formation:
• Reverse INR: Octreotide + Vit K
• Platelets: should be above 50
• Uremia: can give DDAVP to help platelet function
• Definitive management:
• Call GI: for early endoscopic treatment
• Call ICU: for possible intubation
• If pt has liver disease and ascites consider prophylaxis for subacute bacterial peritonitis (SBP)

Today we had a great discussion on bread and butter Internal Medicine cases from the night before. Here is a tasting menu of the issues that came up in this morning's "Grand Morning Report"

1) Proton Pump Inhibitors - potential side effects

• Proton pump inhibitors have revolutionized the treatment of UGIB. An acidic environment inhibits   platelet aggregation and promotes fibrinolysis of formed clot by the enzyme pepsin. Bringing the gastric pH to above 6 is thought to promote clot formation. Studies have shown that treatment with a PPI signficantly reduces recurrent bleeding secondary to PUD. 
• PPIs are often started for various reasons, i.e. to promote healing of peptic and duodenal ulcers, symptom relief from GERD etc. They are very effective, however many forget to reassess the need to continue on PPI therapy and patients may continue them indefinitely. This has led to long term complications of PPI use.
• Nutritional:
• Protein bound dietary Vitamin B12 requires acid and pepsin for its initial absorption. Vitamin B12 then binds to haptocorrin, found in the saliva. It is then liberated in the higher pH environment of the duodenum, where it binds to intrinsic factor and is absorbed in the terminal ileum.This may be more important for people who have low Vit B12 intake (i.e. Vegans) or the elderly. Therefore it may be reasonable to measure Vit B12 levels in these populations of people who are on PPIs.
• There is a theoretical possibility of iron deficiency, as gastric acid is needed to reduce non heme iron (Ferric iron) to the more soluble Ferrous iron.
• Osteoporosis: Gastric acid secretion is important for dietary calcium absorption.
• Infections:
• Pneumonia: By changing the gastric flora and seeding of the lungs from the upper alimentary tract.
• C. difficile and other enteric infections: Also due to changes in the gastric flora 
• Cancer:
• Theoretically the hypergastrinemia resulting from chronic acid suppression can lead to hyperplasia of the gastric enterochromaffin-like cells and lead to gastric carcinoid tumours. Gastrin is also trophic for colonic mucosa, and may also lead to colorectal carcinoma.

2) Treatment of bacteriuria in the Elderly

• There is no evidence for treatment of asymptomatic bacteriuria in the elderly. The only cases where asymptomatic bacteriuria should be treated is in pregnant patients and prior to urologic procedures.
• Bottom line, a positive urinalysis in an obtunded elderly patient does not mean the patient has urosepsis! Look for other signs of infection: Fever, white blood cell count, imaging findings of pyelonephritis, lower urinary tract symptoms.

3) When to suspect Legionella?

• Fever >39C
• Neurologic findings, confusion
• Gastrointestinal findings: Nausea/Vomiting/Diarrhea
• Transaminitis
• Leukocytosis, thrombocytopenia
• Hematuria
• Hyponatremia
• Failure to respond to beta-lactams or aminoglycocide
• CXR: can show anything from lobar consolidation to interstitial pulmonary inflitrates

Paroxysmal Nocturnal Hemoglobinuria

Today we talked about Paroxysmal Nocturnal Hemoglobinuria, an interesting cause of intravascular hemolysis and thrombosis.

1) Pathogenesis:

• Defect in the PIG-A gene that encodes the cell membrane anchor glycophosphatidylinositol (GPI). Glycophosphatidylinositol is necessary for binding proteins to the RBC membrane.
• Defect in the GPI anchor leads to the absence of GPI linked proteins. Two important proteins that are missing include CD55 and CD59, which are involved in the down regulation of the complement system.
• The complement system is part of our innate immunity and is composed of a cascade of enzymatic reactions that culminate in the creation of a membrane attack complex (MAC) that results in cell lysis and destruction. There are two forms of the complement system, the classical pathway that is initiated by IgG/IgM antibodies and the surveillance system that does not require antibodies to become activated. It is this latter system that affects RBCs. 
• CD55 and CD59 act to accelerate decay of the complement system and protect against lysis, respectively, thereby preventing the formation of the deadly MAC. Patients with PNH who lack CD55/CD59 suffer from episodic intravascular hemolysis, the severity of which depends on the degree of absence of GPI linked proteins.
• PNH III: complete absence
• PNH II: partial absence
• PNH I: normal

2) Symptoms

• Hemolysis: Episodic hemolysis, the severity of which depends on the degree of expression of CD55/59. The hemolysis is intravascular and therefore characterized by hemoglobinuria, hemoglobinemia and hemosiderin in the urine. Hemolysis in PNH can happen at any time, not necessary at night as the name implies. However, it is thought that hemolysis increases at night due to intestinal absorption of lipopolysaccharides that enhance the complement system. 
• Nitric Oxide sequestration: Free hemoglobin is a NO scavenger. Nitric Oxide is important in relaxing smooth muscle, therefore depletion of NO as a result of hemolysis results in smooth muscle dysfunction. This manifests as esophageal dysmotility with dysphagia and abdominal cramping.
• Renal dysfunction: Acute hemolysis results in hemoglobinuria that can cause acute kidney injury. Also over time, chronic renal dysfunction occurs due to hemosiderin deposition.
• Prothrombotic state: Patient with PNH have a higher propensity for both venous and, to a lesser extent, arterial thrombosis. The etiology is not well known but thought to be secondary to an abnormal  line of platelets. Patients present with thrombosis of hepatic veins, intra-abdominal veins and even cerebral veins.
• Diminished hematopoiesis: May progress to aplastic anemia
• Hematologic malignancies: May lead to myelodysplastic syndrome and acute leukemia.

3) Treatment

• The treatment of PNH has been revolutionized by the introduction of eculizumab, a humanized monoclonal antibody against C5. This stops terminal complement activation. See this link to the TRIUMPH study a double blind randomized multicenter control study looking at use of eculizumab compared to placebo for PNH. TRIUMPH
• Supportive therapy includes intermittent transfusions as needed and iron/folate supplementation. Be careful of patients developing iron overload due to repeated blood transfusions!
• Anticoagulation is initiated for those with a history of thrombosis. Prophylactic anticoagulation may also be used in those with a large percentage of abnormal granulocyte clones.

Today we discussed an interesting case of a 21 year old male with a non-healing ulcer on his shin. Interestingly he had been recently diagnosed with ulcerative colitis. While, the diagnosis of pyoderma gangrenosum seemed most obvious, the biopsy in fact showed evidence of leukocytoclastic vasculitis and the patient was found to have high peripheral eosinophils and was P-ANCA positive. Talk about a curve ball!

Here are some interesting questions that arose from our discussion:

1) Differential Diagnosis of ulcerative lesion:
Refer to the following NEJM article for an interesting discussion of skin ulcers misdiagnosed as pyoderma gangrenosum. This article gives a great differential diagnosis for ulcerative skin lesions. The key is to have a broad differential and to do a biopsy! The treatment for pyoderma gangrenosum is not benign (steroids and other immunosuppressants) so be sure of the diagnosis before you treat.

2) Leukocytoclastic vasculitis is not a diagnosis in and of itself but a pathologic term describing neutrophilic small vessel vasculitis. It is an indication of small-vessel vasculitis. This can occur in the following settings:

• ANCA associated small vessel vasculitis:  
• Granulomatosis with polyangiitis (formerly known as Wegener's vasculitis)
• Churg-Strauss vasculitis
• Microscopic Polyangiitis
• Immune Complex associated small vessel vasculitis:
• Hepatitis C with cryoglobulinemia
• Henoch-Schonlein pupura (HSP)
• Connective tissue disease-associated vasculitis:
• RA
• SLE
• Sjogren's Syndrome
• Endocarditis
• Hypersensitivy vasculitis:
• Penicillin, ASA, amphetamines, thiazides
• Viral infections:
• Strep throat
• bacterial endocarditis
• TB
• hepatitis
• Staphylococcal infections
• Foreign proteins (serum sickness)

3) Differential for non-vasculitic P-ANCA positivity:

• Infectious: HIV, mycobacterial infections, severe pneumonia, bacterial endocarditis
• Chronic: Rheumaotid arthritis, IBD, Sweet's syndrome, eosinophilia-myalgia syndrome, Goodpasture's syndrome
• Neoplasms: Atrial myxoma, small cell lung cancer, NHL, myelodysplasia, colon carcinoma

See ANCA in diseases other than systemic vasculitis

4) Differential for Eosinophillia:

• Infectious: Parasitic infection, fungal infection (aspergillosis)
• Hematologic/neoplastic: Hypereosinophilic syndromes, leukemia, lymphoma
• Allergic disorders: atopic dermatitis, asthma, rhinitis, medications
• Rheumatic disease: Churg Strauss
• Miscellaneous: Adrenal insufficiency, cholesterol embolization

This morning we discussed an interesting case of an 84 year old male who presented with falls and change in mental status. Dr Nadjafi took us through an approach to delirium (see blog from July 5th for approach to delirium). After thorough investigations it was discovered that the patient's Calcium was 3.98mmol/L! Here is a quick approach to hypercalcemia:

1) Diagnosis:
- Serum Calcium: 40-50% of calcium in serum is bound to protein (mainly albumin). It is the ionized (or "free") calcium that is physiologically important. Therefore, hypo- or hyper-albuminemia can affect the serum ionized calcium. The following calculation helps you determine ionized calcium from measured calcium.

Ionized Calcium = measured Ca + 0.2(40-measured albumin)

- Degree of hypercalcemia: Mild hypercalcemia (<2.75mmol/L) usually seen in hyperparathyroidism. Severe hypercalcemia (>3.25mmol/L) usually indicates malignancy associated hypercalcemia.

2) Symptoms:
 

Neuropsychiatric	Anxiety, depression, cognitive dysfunction In severe cases lethargy and confusion
Gastrointestinal	Abdominal pain, nausea, anorexia and constipation
Renal	- Diabetes insipidis: Inability to concentrate urine, polyuria/polydipsia - Nephrolithiasis: RTA type I: Rare - Nephrocalcinosis from long standing hyperCa: Necrosis of tubular cells and interstitial fibrosis
MSK	- Bony pain (from primary cause ie. Cancer or hyperparathyroidism

"Moans, groans, stones, and psychic overtones"

3) Etiology:

a) PTH Mediated:

• Primary: Sporadic
• Secondary: Renal disease and decreased production of 1,25-dihydroxyvitamin D. Adynamic bone disease results in reduced bone turnover. The reduced uptake of calcium into bones after a calcium load leads to hypercalcemia.
• Tertiary: Prolonged hyperphosphatemia and hypocalcemia leads to hypertrophy of the parathyroid glands and unregulated release of PTH. Occurs in patients post renal transplant.
• Familial: MENI and IIa, familial hypercalciuric hypercalcemia

b) Non-PTH mediated

• Malignancy:
• Osteolytic: Bone mets resulting in induction of local osteolysis by tumor cells and release of osteoclast activating factors in multiple myeloma
• PTHrp: some tumors produce PTH related peptide that mimics PTH. These include squamous cell carcinomas (lung and H+N), breast, bladder, ovarian
• Ectopic PTH secreting tumor
• Granulomatous disease
•  Activation of extra-renal 1-aOH leading in macrophages and/or lymphocytes. Leading to PTH-independent production of 1,25-dihydroxy Vitamin D
• Drugs:
• Lithium
• Thiazides
• Increased Vitamin D intake
• Miscellaneous:
• Immobility
• Hyperthyroidism
• Pheochromocytoma
• Adrenal insufficiency
• Milk alkali syndrome: excessive ingestion of Calcium supplements
• Paget's disease

4) Treatment:

• The cornerstone of treatment is: FLUIDS, FLUIDS, FLUIDS
• Patients are often quitet hypovolemic secondary to their inability to concentrate urine and nephrogenic diabetes insipidus
• The kidneys should be able to excrete the majority of excess calcium
• Also consider:
• 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.
• Steroids: Prednisone 20-40mg/day. Decreases conversion of 25 hydroxyvitamin D to 1,25-dihydroxyvitamin D
• Lasix: Caution as this can cause worsening hypercalcemia. Only used of pt is showing signs of volume overload from fluid resuscitation. see article from Annals of Internal Medicine: Furosemide fro Hypercalcemia: An unproven yet common practice

On Friday we spoke about a case of fever of unknown origin or FUO.
The original definition of FUO as proposed by Petersdorf and Beeson in 1961 required the following criteria:
(1) Fever of >38.3 on more than one occasion
(2) Fever for more than or equal to 3 weeks
(3) No etiology discovered after at least 1 week of inpatient investigations

However, the definition has evolved with the increasing population of patients with HIV and neutropenia and the ability to perform investigations in an outpatient setting. The following is a new definition proposed in 1991 by Durack and Street:

Hayakawa et al. Am J Med Sci. April 3. 2012 Epub ahead of date

A thorough history, including onset, duration and nature of the fever, is crucial. While the pattern of fever has not been found to correlate significantly to the etiology, two patterns have been described: (1)Pel-Ebstein (fever for 3-10 days on, then 3-10 days off, typical of Hodgkin's lymphoma) (2) Typhus inversus: reversal of normal diurnal pattern seen in TB.

In many cases the etiology can be narrowed down based on the patient's social history. Including the patient's country of origin, vaccination status, recent travel history (where exactly), animal or insect exposure, recreational activities (gardening or swimming in fresh water), sexual activity, use of recreational drugs. The most at risk population for acquiring an travel related infectious disease, are those who immigrated long ago and return to their country of origin to "visit friends and relatives" (VFR), as these people tend to be the population who take the least precautions.

The following is a table of common causes of FUO:

Hayakawa et al. Am J Med Sci. April 3. 2012 Epub ahead of date

For a comprehensive approach to FUO refer to the following interesting articles:
http://archinte.jamanetwork.com/article.aspx?articleid=215227

This morning we discussed a case of a 60 year old male with end stage liver disease secondary to Hepatitis C who presented with confusion. Dr Panisko guided us through the process of building a differential diagnosis using the patient's past medical history as a starting point. This is a useful method of organizing your approach, especially when faced with a non-specific presentation such as confusion. Another useful acronym for an approach to delirium is DIMS:

D - Drugs, drugs, drugs
I - Infection
M - Metabolic derangement (endocrine, electrolyte)
S - Structural (intra-cranial process, liver/renal/heart failure)

 Inouye SK. Delirium in older persons. N Engl J Med. 2006;354: 1157-1165

Our patient had multiple possible causes for his confusion:

1) Drugs: Drugs are the most common causes of delirium. Common culprits are psychotropic meds (anxiolytics, antipsychotics, dopamine agonists), anticholinergics, analgesics (opioids), corticosteroids, anticonvulsants etc. Our patient was on seroquel, paroxetine and bupropion, all of which may have contributed to his delirium. One must think of serotonin syndrom given this patient's use of an SSRI. The patient however did not fulfill the Hunter criteria for serotonin syndrome, which includes history of ingesting a seritonergic agent and one of:

• Spontaneous clonus
• Inducible clonus PLUS agitation or diaphoresis
• Ocular clonus PLUS agitation or diaphoresis
• Tremor PLUS hyperreflexia
• Hypertonia PLUS temperature above 38ºC PLUS ocular clonus or inducible clonus

2) Hepatic encephalopathy: Our patient had allegedly stopped his lactulose which puts him at risk for developing hepatic encephalopathy. The pathophysiology of this involves increased blood to brain transport of neurotoxins (such as amonia, amino acids) and biochemical alterations in the uptake and function of neurotransmitters. Up to Date has a good review on the pathophysiology of HE.

3) Infection: Patients with cirrhosis have altered immune defenses and are considered immunocompromised individuals. Changes in gut motility and increased translocation of bacteria can result in increased risk of developing SBP and other infections. Early treatment of infection is important in end stage liver disease (Management of bacterial infections in cirrhosis, J Hepatol. 2012;56 Suppl 1:S1-12)

4) Hyponatremia: Patients with cirrhosis are at risk for developing hyponatremia. This is largely secondary to the systemic vasodilation resulting in the activation of the renin-angiotensin system and ADH, thereby decreaseing the kidney's ability to excrete free water. Treatment for hyponatremia in cirrhosis involves fluid restriction and vasopressin receptor antagonists.

Physical Exam




We reviewed the physical exam for ascites. The following is a table from the JAMA Rational Clinical Exam series for ascites:

JAMA. 1992. 267 (19): 2645-2649

Bottom line:
1. Sensitive tests for Ruling OUT ascites:

• Negative history for ankle swelling/increased abdo girth

• Lack of bulging flanks, flank dullness or shifting dullness

2. Specific tests for Ruling IN ascites:

• Positive shifting dullness and fluid wave

Thiamine Deficiency

 This morning we discussed a case of thiamine deficiency. Thiamine, or Vitamin B1, is a water soluble vitamin, found largely yeast, legumes, pork, rice, and cereals.

Two major thiamine deficiency disorders have been described in adults.

1. Beriberi: hallmark of adult beriberi is symmetrical peripheral neuropathy. Wet beriberi also involved cardiomyopathy and CHF.
2. Wernicke-Korsakoff syndrome: Wernicke is an acute presentation of nystagmus, opthamoplegia, ataxia and confusion. Korsakoff syndrome is the chronic condition that involves impaired short-term memory and confabulation with otherwise grossly normal cognition.

 Uptodate have a good review article on Water soluble vitamin deficiencies.

I like to point you toward a really good review about determinant of healthy eating among low-income Canadians. As we care for our patients, it is very important that we appreciate the socio-economic context of their illness.

Diabetic Foot Ulcers

We discussed diabetic foot ulcers this morning. The best way to prevent these ulcers is early detection of diabetic neuropathy, which is best done with a brief history and screening with Semmes-Weinstein monofilament.

Use the monofilament in 8-10 anatomic sites recommended (see above picture). However, even testing 4 plantar sites on the forefoot identifies 90% of the patients with an insensate site. Monofilament testing is fairly sensitive (66-91% ) and has a very good NPV 94-95%.

Here is review article on preventing diabetic foot ulcers. 

Extended Light's Criteria

This morning we discussed an approach to pleural effusion.

 

One concept we discussed was the possibility of transforming transudative pleural fluid in patients receiving diuretic therapy to an exudate.

In such cases we can use the “extended Light’s criteria”, which is to calculate the total protein gradient (serum minus pleural fluid). The fluid is a transudate if the total protein gradient is greater than 31g/L.

Here is a previous post about the Light’s criteria with a review article by Dr. Light himself!

Bacterial Meningitis

This morning we talked about a case of bacterial meningitis.  This is a disease that is rare but has significant mortality and morbidity, so it is important to be familiar with how to diagnose and treat it. Here are a few key point we discussed this morning.

1. Do not delay antibiotics for procedures such as CT head or LP
2. Antibiotic doses of meningitis are different (and much higher) 
3. Even if the CSFcultures are sterilized by prior antibiotics, other clues such as degree of neutrophillia, CSF glucose level, or the gram stain can point toward bacterial meningitis
4. No everyone needs a CT head
5. IDSA recommendation for CT prior to lumbar puncture is below:
1. Immunocompromised state
2. History of CNS disease Mass lesion, stroke, or focal infection
3. New onset seizure Within 1 week of presentation;
4. Papilledema
5. Abnormal level of consciousness …
6. Focal neurologic deficit
7. fields, gaze palsy, arm or leg drift

 Here is a review from Lance on management of bacterial meningitis. 

**Gram stain CSF: GPC in pairs and short chains suggestive of Streptococcus pneumoniae

KEEP COOL

Given the extreme heat in Toronto recently, I want to bring your attention to a post I did about a year ago about heat stroke, when we were hit with a heat wave and increased admissions. This extreme weather causes no only heat stokes, but also exacerbations of many chronic cardiopulmonary disease.

ABCDE rule

Early recognition of melanoma is an important prognostic factor. To distinguish early melanoma from other forms of benign pigmented lesions, we can use the ABCDE rule.

• Asymmetry (if a lesion is bisected, one half is not identical to the other half)
• Border irregularities
• Color variegation (brown, red, black or blue/gray, and white)
• Diameter ≥6 mm
• Evolving: a lesion that is changing in size, shape, or color, or a new lesion

The diagnostic accuracy of the ABCD vary in different studies. In a retrospective study of 1140 lesions including 460 melanomas, the sensitivity in identifying a lesion as a melanoma was 97 percent when using a single criterion and 43 percent when using all five criteria jointly. By contrast, specificity was 36 percent for a single criterion and 100 percent for all five criteria.

CAM

This morning we discussed a case of delirium.  Although a common diagnosis, it is sometimes challenging to diagnose delirium, especially in patients with underlying dementia or depression. The Confusion Assessment Method (CAM) is a validated tool to help you identify delirium. 

The diagnosis of delirium by CAM requires the presence of features 1 AND 2 plus either 3 OR 4.

1. Acute onset and fluctuating course

2. Inattention

3. Disorganized thinking

4. Altered level of consciousness 

For admitted medical and surgical patients, the CAM has a sensitivity of 94-100% and a specificity of 90-95% for diagnosing delirium.

Here is a detailed explanation of Confusion Assessment Method (CAM).

RS3PE SYNDROME

RS3PE syndrome stands for remitting seronegative symmetrical synovitis with pitting edema.

This syndrome has many similar features to PMR. Patienst are often over the age of 50 and are seronegative. However, unlike PMR, many patients with RS3PE have sudden onset of polyarthritis, usually more prominent distally.

Patients with this disorder respond to low-dose glucocorticoids.

RS3PE also has been described as a paraneoplastic disorder that is associated with solid tumors and hematologic disorders.

Here is a good review article on PMR.

* Areas of pain in PMR

Doctor, my legs are so puffy!

This morning we discussed a case of new onset bilateral leg edema. 

Approach to is to think about one or more of the following etiologies: 1. increased capillary hydrostatic pressure (e.g. CHF) 2. decreased capillary oncotic pressure (e.g. nephrotic syndrome) 3. increased capillary permeability (e.g. inflammation)

As we discussed, focus your history on cardiac, hepatic, or renal disease, or drugs that affect any of those systems.

 Physical examination should focus on the pattern of edema. Is the JVP elevated? Is there pulmonary edema? Is there ascites? Is the edema localized or generalized? Is it pitting or non-pitting? Is it acute or chronic? Pattern of edema will help you narrow down your differential diagnosis.

  Here is a reference on the topic.

Romberg Test

This morning we talked about the Romberg test.

The ability to maintain a steady posture depends on input from 2 of the 3:
o vestibular apparatus
o eyes
o propioception from feet
The cerebellum coordinates the input from all three.

ROMBERG test tells you about problems in propioception or the vestibular apparatus.
The test start with the patient standing with heels together and eyes OPEN. If there is unsteadiness, then there is cerebellar ataxia. If the patient is steady, then ask the patient to stand with eyes CLOSED. Inability to stand for 60 seconds with eyes CLOSED is a positive Romberg sign, and reflects vestibular disease or sensory ataxia.

*The test was named after the German neurologist Moritz Romberg (1795-1873).

Ref: Evidence-Based Physical Diagnosis, McGee. 2007.

"what about my water pill, doctor?"

This morning we briefly talked about the mechanism of action of furosemide (lasix). This drug is a loop diuretics that inhibits the Na-K-2Cl channel in the thick ascending limb of the loop of Henle on the luminal side.

The efficacy of Furosemide is dose-dependent, but a plateau is reached in which even higher doses produce no further diuresis (when all the channels are saturated). The bioavailability of furosemide is only about 50%, so IV is twice as potent as oral. The drug is renally cleared.

IV therapy is preferred in patients with decompensated heart failure initially because drug absorption may be slowed by decreased intestinal perfusion and mucosal edema.

Furosemide is a sulfonamide drug so can cause hypersensitivity reactions, but patients with a history of allergy to sulfonamide antibiotics usually tolerate furosemide with little cross-reactivity.

Another side effect furosemide to be aware of is ototoxicity.

Here is a review article on diuretic therapy.

Pleural Effusion and Ultrasound

At Gel Rounds today, we discussed pleural effusion. The image above is the ultrasound image of a small right sided effusion. The top of the image represents the probe resting on the chest wall, the dark area (e) is the effusion. The Bright band between (e) and the liver is the diaphragm (d). The lung is seen superior and deep to the effusion.

Now that you know how to identify pleural effusion with the ultrasound, use it in addition to your physical exam when doing a bedside thoracentesis.

Prothrombin-Complex Concentrates (PCC )

This morning we discussed the use of PCCs in reversing the INR. PCC is the combinations of vitamin K-dependent coagulation factors (ie, factors II, VII, IX, and X). It is used to normalize the INR and acts more rapidly than FFP or vitamin K alone.

PCC available in Canada is Octaplex (there are more in the market). This is a human blood product derivative (not a recombinant).

Advantage of using PCC is the much lower volume load compared to FFP. Thrombotic complications (such as DIC or MI) have been reported with PCC, but this risk is difficult to quantify.

Vitamin K should be given if you need to completely reveres INR even when using PCC to avoid delayed secondary rise in the INR as the coagulation factors are metabolized (remember factor VII has a half-life of four to six hours in vivo).

The cost of INR reversal with PCC is between $1000-$3000 USD.

Here is a review on reversal of vitamin K agonist therapy.

The Perfect Storm

This morning we discussed a case of thyroid storm. This is a life-threatening condition, characterized by exaggerated symptoms of hyperthyroidism.

Thyroid storm can present as first time presentation of thyroid disease, but more commonly seen in those with long standing history of hyperthyroidism triggered by infection, trauma, surgery, post-partum, or an iodine load.

Patients are often tachycardic with hemodynamic instability, and can have hyperpyrexia, altered LOC, and GI symptoms. Given the high mortality associated with thyroid storm (20-30%), a high index of suspicion should be kept in patients with history of thyroid disease.

Here is a review on thyroid emergencies.