Methanol and Ethylene Glycol

Today we discussed a patient who presented in a Hyperosmolar Non-Ketotic state secondary to hyperglycemia. You can read more about the precipitants and management of DKA and HONK here.

We also discussed poisoning with methanol and ethylene glycol - either by intentional or unintentional ingestion.

These get metabolized in the liver first by Alcohol Dehydrogenase, then Aldehyde Dehydrogenase. They have toxic byproducts - Formic Acid in methanol poisoning, and Calcium Oxalate in ethylene glycol. Formic acid causes renital edema and destruction and can also lead to ischemia in the basal ganglia. Calcium oxalate can cause irreparable renal damage.

What to do? Firstly, "intoxications" have to be on your differential diagnosis - if you don't think about it, you will never diagnose it. Also consider other co-ingestions with prescribed or non-prescribed drugs/toxins.

Clinical Hints: Patients may have a decreased level of consciousness and those with methanol intoxication may complain of blurry vision. Look for evidence of renal failure, a raised anion gap, and an elevated osmolar gap. Note that it is possible to have methanol/ethylene glycol poisoning with a normal osmolar gap. Also note that if patients co-ingest alcohol, this will delay the presentation of methanol/ethylene poisoning. Send off blood levels for these alcohols.

Plan: Basically we want to get rid of the methanol or ethylene glycol - and dialysis is the fastest and most effective mechanism to do this. We also want to prevent the formation of our toxic byproducts (formic acid and/or calcium oxalate). How do we do this?

• Ethanol: best given intravenously. The alcohol dehydrogenase will work on ethanol rather than methanol/ethylene glycol - preventing the formation of toxic byproducts. It is cheap, but difficult to dose.
  
• Fomepizole: this will directly inhibit alcohol dehydrogenase. Easy to use, very effective, very expensive.
  

Links:

• A great paper assessing the utility of Fomepizole in methanol intoxication.
• Pictures of calcium oxalate stones in the urine of a patient with ethylene glycol poisoning.
  

Dion Phaneuf of the Calgary Flames (smoking the Ottawa Senators) pictured left.

HoPingKong-isms and "seppie"

(if you type 'seppie' into google, this comes up. I think it is Italian for cuttlefish)

1. ....."Hi...how are you? Grow up!" ..... This was in the context of a patient presenting with a decreased level of consciousness. kind of a tough one. He is referring to a Hygroma - namely, a pocket of cerebrospinal fluid (CSF) in the subdural space. Large hygromas can cause focal neurologic deficits and mental status changes. They can result from head trauma. CT showing a subdural hygroma below.

2. ....."The result of any mass on the cortex...What do soldiers and scouts do? They march."....He is referring to a Jacksonian March - where seizure activity spreads through the primary motor cortex, resulting in the clonic activity of the corresponding area of the homunculus. This often starts on the hands and moves more proximally.

3. ...."Flappy hands...you're going to flap again"....This was mentioned in the context of Hepatitis C infection. He is referring to Asterixis, commonly seen in hepatic encephalopathy, uremic encephalopathy, and hypercarbia.

4. ...."Does our patient have respiratory distress?....did you bring your purse?".....Referring to pursed lip breathing - one of the physical signs of respiratory distress. Other signs to look for include positioning (sitting up, leaning forward, 'tripoding'), nasal flaring, use of accessory muscles (intercostal retraction, use of trapezius and sternocleidomastoids), and paradoxical breathing - the inward movement of the diaphragm on inspiration.

5. ...."He has hypotension and tachycardia, and he sounds sick. What is going on? Think of something...ummmmm....seppie."..... Okay, this is not the hardest one, but I thought it was funny. He is referring to sepsis. I just liked the use of the word "seppie".

Some helpful links to the case we discussed:

1. An approach to decreased level of consciousness can be found here.
2. An approach to Acid-Base issues can be found here.
3. Stigmata of chronic liver disease can be found here.

(subdural hygroma - and how to get one)

Diagnosis of Systemic Lupus Erythematosis

(Discoid rash on the left, and malar rash on the right)

The American College of Rheumatology have criteria for diagnosing Systemic Lupus Erythematosis. You need 4 of the following to have a diagnosis, or 3 to have a 'probable' diagnosis.

1. Malar Rash: erythema over the malar eminences that spares the nasolabial folds.
2. Discoid Rash: raised patches with scaling. This may scar.
3. Photosensitivity: a rash on skin exposed to sunlight.
4. Oral Ulcerations: usually painless. See image below.
   
5. Arthritis: this is nonerosive and involves 2 or more peripheral joints.
6. Serositis: like pericarditis or pleuritis. You may hear a 'rub' on physical exam.
7. Renal Disease: >0.5 grams of protein per day, or casts (red or heme granular).
8. Neurologic Disease: seizures or psychosis, with other causes ruled out.
9. Hematologic Disease: hemolytic anemia, thromocyotopenia, leukopenia, or lymphopenia.
10. Antinuclear Antibody: positive titre in the absence of drugs known to cause a high titre (eg. procainamide, hydralazine).
11. Immunologic Disorders: Antiphospholipid antibodies, or Anti ds-DNA antibodies, or anti Smith antibodies, or a false positive VDRL.

(oral ulcerations)

Fever in the Returning Traveler

Fever in the Returning Traveler....a very common situation.

There are some very pertinent questions that must be asked: above and beyond your medical history and physical exam, it is important to ask the following questions...

1. Where did you go? (exactly)


2. How long were you there?


3. What did you do?


4. What is the date you left, date you returned home, and date of every stop along the way?


5. Exposures: Water, animals (eg mosquito's, tics, farms), sexual?


6. Did you get pre-travel advice? What was the advice? Did you take the advice?
   

An approach: Think about what causes fever...

• Infection related to where patient was traveling.


• Infection not-related to travel.


• Non-infectious causes of fever.
  

What are the 4 "biggies" for infection in the returning traveler?

• Malaria


• Dengue fever


• Viral hepatitis (A)


• Typhoid fever

Some good review papers:

1. Here is the sentinel article from NEJM (written by local talent) looking at the spectrum of diseases in ill returning travelers.
   
2. Here is a great review on malaria prophylaxis from NEJM.

Getting Back to (or, at?) Spontaneous Bacterial Peritonitis

Today we discussed many complications of portal hypertension, including:

1. Ascites
2. Gastroesophageal Varices
3. Hepatic Encephalopathy
4. Hepato-renal syndrome
5. Hepato-pulmonary syndrome

The issue of Spontaneous Bacterial Peritonitis came up.

The diagnosis is relatively straight forward - a diagnostic paracentesis is performed and sent for cell count and differential, culture and sensitivity, albumin (make sure you have a serum albumin), and total protein. You can also send off for glucose, LDH, and amylase. Remember - the pathogenesis of this conditions is from translocation of gut bacteria into the ascitic fluid....patients with low protein (eg immunoglobulins) are at a significantly higher risk for developing bacterial peritonitis. You can read more about the Serum-Ascites Albumin gradient here. If the cultures are positive, or if there are >250 polymorphonuclear leukocytes per mm3, you have a diagnosis. Hooray.

Treatment revolves around covering organisms that have translocated - the vast majority being E. coli and Klebsiella, but other G- and sometimes G + organisms are the culprit. Ceftriaxone is a good agent, but there are certainly others that will work just fine. Intravenous albumin has also been shown to reduce renal failure and death when given with antibiotics on days 1 and 3 of treatment. Here is the original article on the benefits of IV Albumin in the treatment of SBP.

Prophylaxis: Okay, now you're entering a world of hurt. This is an area fraught (yes, "fraught") with controversy. Let's start with a few reasonable words - patients who have a history of SBP and have high risk factors (read: low ascites protein) are at significant risk of developing SBP again - with associated morbidity and mortality. So it would seem reasonable to use prophylactic therapy to prevent this from happening. There are many issues with this, such as developing bacterial resistance, cost, dangers of being on prolonged antibiotics, efficacy, which drug to use, and how often to use it. Currently, there are a couple of well described patterns of prophylaxis:

• Q weekly: Cipro given once per week at 750mg. Here is a link to the original trial. (Note: other Abx have been used q weekly as well).

• Q daily: Cipro given daily at 500 mg. Here is a recent trial showing benefit. (other drugs have been used successfully q daily as well).

Read the articles, critique them, ask around, digest the information, and come up with your own opinion on what you think is the appropriate prophylaxis.

Check out the stigmata of chronic liver disease here.

Febrile Neutropenia

(Aspergillus fumigatus pictured left)

Today we discussed issues related to Febrile Neutropenia. In adults with underlying malignancies, we define febrile neutropenia as:

• Fever: single measurement >38.3 Celsius, or sustained temperature >38 Celsius for more than 1 hour.
• Neutropenia: absolute neutrophil count less than 500 cells/microL. Remember that this is often a dynamic process and your patients ANC may be above 500, but the expected nadir is below.

Think about the immune deficits of your patient: Think about their underlying malignancy, chemotherapy, and other past medical history. With low levels of functioning neutrophils, there is already an impairment in Phagocyte function - these patients will be at risk for Gram + and Gram - bacterial infections, and also Fungal infections like Candida and Aspergillus. Is there an associated deficit in Humoral Immunity (eg CLL, Multiple Myeloma), or Cellular Immunity (eg HIV, immunosuppressive agents)?

Look for potential localizing sources of Infection: A careful history and physical exam to assess for an underlying etiology. In particular, pay close attention to lines and indwelling venous catheters - making your patient more prone to G+ infections. Also look for evidence of Mucositis. Remember that in the absence of neutrophils, the signs of inflammation may be severely blunted. Your investigations will reflect potential sources of infection - blood cultures from peripheral veins and lines, urine cultures, chest x-ray, possibly a CT scan of the chest or abdomen if clinically indicated.

Treatment: This is a potential emergency. Patients will need broad coverage for Gram + and G- (including Pseudomonas) upfront. Antifungal agents should be added if the neutropenia is persisting for more than 5(ish) days. Many hospitals have their own protocols that reflect coverage for particular organisms unique or more prevalent in their environment. Some patients have febrile neutropenia but do not appear to be unwell. Based on certain clinical criteria, they may be considered "Low Risk" and have treatment as an outpatient on oral therapy (eg Cipro + Amoxicillin/Clavulanate). These patients must be very carefully selected, and the hospital must be able to closely follow up with them should their condition deteriorate.

1. Here is a trial from NEJM describing an outpatient management plan for Febrile Neutropenia in "low risk" patients.
   
2. Here are the Infectious Diseases Society of America's 2002 Guidelines for Febrile Neutropenia. There are 2009 guidelines that should be out shortly, so stay posted.

(Ecthyma Gangrenosum pictured left - this is a cutaneous manifestataion of Pseudomonas common in patients with febrile neutropenia)

Wernicke-Korsakoff syndrome

Wernicke's and Korsakoff's syndromes are the result of Thiamine deficiency - usually related to chronic alcohol consumption, but can be seen in other disorders of malnutrition (eg. anorexia nervosa, gastrointestinal surgery).

Wernike's Encephalopathy presents as a classic triad of

1. Oculomotor dysfunction: in particular lateral rectus palsies - uni or bilateral, but nystagmus and oculomotor nerve deficits are also seen.
2. Gait ataxia
3. Encephalopathy

MRI may show lesions around the cerebral aqueduct. Mamillary body atrophy is quite a specific sign from Werneke's encephalopathy.

Korsakoff's Syndrome represents permanent neurological damage from thiamine deficiency. Patients have anterograde and retrograde amnesia, but a preserved sensorium and often have preservation of long term memory and other cognitive skills. Confabulation is classic feature in this disorder.

When patients present to hospital and chronic alcoholism is suspected, we always give Thiamine upfront - before glucose - to prevent Wernicke's and Korsakoff's syndromes.

You can read more about alcohol withdrawal here.
Here is a good review article from NEJM about Alcohol and Drug withdrawal.

Diabetic Ketoacidosis

Today we discussed a case of Diabetic Ketoacidosis.

• You can read more about precipitants to DKA here.


• Check out the management of DKA/HONK here.

Preeclampsia

Preeclamsia

What is it? Hypertension that develops after 20 weeks gestational age which is associated with proteinuria.

Breifly, what is the pathophysiology? The release of placental/fetal factors that alter maternal endothelial function. Ultimately there may be less vascular endothelial growth factor (VEGF) - possible from VEGF antagonists released by the placenta.

What are the diagnostic criteria?

• systolic BP >140 mmHg, or
• diastolic BP >90 mmHg, and
• proteinuria >0.3 grams in 24-hours, and
• gestational age >20 weeks

What are some of the other clinical manifestations of preeclampsia? this will relate to complications of endothelial damage and severe hypertension. Think about headaches, blurred vision, peripheral edema which may include the hands and face, pulmonary edema, and fetal compromise. Also think about end-organ damage from hypertension - you can read more at this link.

Are there risk factors? Yes, some of these include nulliparity, previous or family history of preeclampsia, preexisting hypertension, APLA syndrome or other connective tissue disease, multiple gestation, or 'extremes' of age (>40, <20). style="font-weight: bold;">Dreaded complications? Yep. Eclampsia (aka seizure), and the HELLP syndrome. HELLP stands for Hemolysis, Elevated Liver enzymes, and Low Platelets.

Okay, so what do I do? well, it's kind of complicated. First, remember that the only 'cure' is delivery. Also remember that cases can still present in the early post partum period. Get the obstetrical service involved early and ensure that the unborn child is well with a biophysical profile. Sometimes this is severe and an urgent delivery is necessary - so predelivery sterioids may be necessary to decrease fetal pulmonary complications. Otherwise, hypertension can be managed with a few drugs that are safe in pregnancy. Women with this condition should be watched very closely and there should be a very low threshold for admission to hospital.

Drugs commonly used in preeclampsia include labetolol, hydralazine, methyldopa, and nifedipine. The target blood pressure is debated, but many would agree on 130 to 150 mmHg systolic and 80 to 100 mmHg diastolic.

In severe preeclampsia, where eclampsia is a very real risk, Magnesium Sulfate is administered to reduce the seizure threshold. It is generally administered during labour and delivery, and is continued for 24-48 hours afterwards.

Here is a link on the utility of Magnesium in preventing eclampsia.
Here is a cool case of preeclampsia with a twist.

HoPingKong-isms

(a helicopter?)

1. "....my favorite topic in obstetrics...the men are 'he' and the women are 'she'..." Huh? What? He is referring to Sheehan's syndrome - pituitary infarction as a result of hypotension from postpartum hemorrhage.

2. "...you've got abdominal pain, and did you hear that buzz...it sounded like a helicopter...." Okay, this one isn't too tough. helicopter = Helicobacter, as in Helicobacter pylori infection as a common cause of peptic ulcer disease.

3. "....you've got abdominal pain and I'm pointing my finger at you..." Referring to Inglefinger's sign in pancreatitis, where patients are more comfortable sitting up and leaning forward.


4. "...this patient has pancreatitis...are you from Trinidad? Are there scorpions there?..." referring to scorpion bites as an unusual cause of pancreatitis. More common etiologies include

• Gallstones,
• Alcohol use
• Hypertriglyceridemia

Other causes include hypercalcemia, viral infections (eg. mumps, vzv, HIV), bacterial infections (mycoplasma, legionella, salmonella), parasitic infections (toxoplasma, cryptosporidium, Ascaris), traumatic (like post ERCP), congenital, and yes, scorpion bites too.

5. "....hmmm....you know, in pancreatitis, no man is an island..." referring to the pancreatic Islets of Langerhans. Here, the alpha cells produce glucagon, beta cells produce insulin, and delta cells produce somatostatin.

You can read more on pancreatitis here.

Who is Chad anyways?

Atrial Fibrillation. And the CHADS2 score. What's the deal?

Well, essentially this is a very simple scoring system to determine your patients risk of thromboembolism with atrial fibrillation.

• Congestive heart failure (any history): 1 point
• Hypertension (including prior history): 1 point
  
• Age > 75: 1 point
• Diabetes mellitus: 1 point
• Stroke: 2 points

Simple as that. Add up the points. A higher number of points means that the risk of thromboembolism is more likely. Low risk patients have a score of 0 - 1, where the annual incidence of stroke is less than 2.5%. A score of 2 carries a Moderate risk (4% per year) of stroke, and anything greater than 2 is High risk.

Essentially, Aspirin can be used to treat low risk patients, Aspirin or Warfarin in moderate risk patients, and Warfarin in high risk patients. Warfarin will reduce the risk of embolic stroke by about 2/3.

Here is a link to the original article published in JAMA in 2001