Friday, October 18, 2013

Carbon monoxide toxicity

Carbon monoxide (CO) poisoning is one of the most common sources of poisoning in North America. In a ten year period in the US, there was nearly 12,000 reported cases of death related to CO toxicity. The rates of poisoning vary throughout the year, where cold weather is risk factor, given heaters and  automobile use increases. CO is produced by the incomplete breakdown of hydrocarbons, and can be produced by many sources, a common one being smoke inhalation during house fires. Other sources include automobile, propane, methane, paint remover and other solvents.

The pathophysiology is a result of tissue hypoxia and direct toxicity at a cellular level. CO binds to hemoglobin with an affinity of over 200x that of oxygen. This binding results in a shift in the oxygen-dissociation curve to the left, meaning there is increased difficulty in extracting oxygen for tissue use. The increased affinity and tissue hypoxia cannot explain all of the effects of CO toxicity, and reactive oxygen species likely play a role. This is probably mediated through xanthine oxidase.

The clinical manifestations of CO poisoning can be subtle. Patients may be mistaken as having influenza (similar symptoms and both peak in winter months), presenting with headache, myalgias, confusion, tachypnea, tachycardia, presyncope and altered LOC. Classically, patients are described as having cherry red lips, though this is an insensitive sign. One retrospective study found the initial diagnosis to be listed as stroke, cardiac ischemia, encephalitis or seizure in multiple cases, highlighting the diagnostic challenge. Other acute symptoms include cardiac chest pain, and this has been described in 30% of cases. This is associated with increased mortality in CO poisoning. Chronic symptoms include the neuropsychiatric syndrome, which presents with personality changes, focal deficits, or cognitive impairment. This occurs with a month following poisoning and can persist for years. The mechanism is not clear, but may be related to myelin destruction from reactive oxygen species.

Because of the non-specific nature of CO poisoning a high index of suspicion is needed to make the diagnosis. The oxygen saturation on pulse oximetry is normal, given the maintained binding of hemoglobin. The diagnosis is made using co-oximetry to measure the amount of carboxyhemoglobin (venous or arterial blood). Amounts of carboxyhemoglobin can be found in several situations:

1-3% carboxyhemoglobin - Normal individuals
under 10% - smokers
Consider the patients history and presentation to determine if the levels are reasonable or as a result of poisoning.

The treatment of CO poisoning is emergency management.

1. ABC's - Many patients will have CO poisining from smoke inhalation. Security of the airway is crucial. Tachypnea, hypoventilation, stridor, facial blistering, burns and edema should prompt intubation and laryngoscopy. Patients can develop airway edema within 24 hours after the inhalation injury following thermal injury, this requires admission and monitoring for respiratory deterioration.

2. Oxygen therapy - all patients should receive high flow 100% oxygen. This results in rapid
improvement in CO levels compared to room air. The half life of CO is 300 minutes, and decreases to 90 minutes when supplimental oxygen is provided.

3. Consider hyperbaric oxygen therapy (HBOT) - Although this therapy is ubiquitous within the literature, the benefit of hyperbaric oxygen is somewhat controversial. There is no doubt that hyperbaric oxygen decreases the half life of oxygen even further than high FiO2 therapy, decreasing the half life to roughly 30 minutes. Whether this extends to improved long-term outcomes is debated. A cochrane review from 2011 found that further RCT's are required to determine whether HBOT should be offered, based on the poor quality of previous studies (see link below for details). Indications are variable, some directives suggests asymptomatic patients with a level of  over 40% CO should have HBOT, while others say 25% is a reasonable cutoff. Other reasons to initiate HBOT are:

Pregnancy and CO level over 20%
Decreased LOC or new neurologic deficits
Myocardial ischemia
Acidosis (less than pH 7.1)

4. Isocapneic hyperventilation - this is an experimental treatment that doesn't seem to be widely used in the clinical setting. One study (actually affiliated with anaesthesia at the University of Toronto), showed that in dogs, hyperventilating while providing inhaled CO2 to maintain pH balance resulted in improved removal of CO.

Cochrane review on HBOT

Wednesday, October 9, 2013


Defined as dissolved skeletal muscle content, rhabdomyolysis is exactly that. It can present in many ways, from completely asymtpomatic to life-threatening end-organ damage.  In the early 1900's the syndrome of rhabdomyolysis was recognized as a cause of acute kidney injury following crush injuries. A case series corroborated this following the bombing of London in 1940, where patients injured from falling buildings were found to develop similar symptoms. Non-traumatic causes and the overall pathophysiology of rhabdomyolysis were not well recognized until decades later.

The final common pathway in causing rhabdomyolysis is increased intracellular calcium. Whether there is direct trauma to the sarcomere from trauma, or ischemia causing depleted ATP, all patients with rhabdomyolysis develop increased intracellular calcium. These leads to a worsening of intracellular energy stores, as Na/Ca exchangers actively use ATP to maintain normal electrolytes gradients. Increase reactive oxygen species leads to direct toxicity to cell membranes, and muscle death an intracellular content release occurs.

The causes of rhabdomyolysis are many, but can be broken down into several categories. I like the way its categorized on UptoDate, as it really allows you to structure your differential diagnosis. :

1. Traumatic - crush, trauma, immobolization from fall/coma (as in our patient today), burn, compartment syndrome

2. Non-traumatic exertional - significant exercise (marathon runner), myopathies that are exposed through exercise - (McCardle syndrome, carnitine palmitoyltransferasedeficiency)
Some people might include seizure in this category as it is a direct result of muscle contraction and exertion

3. Non-traumatic non-exertional - inflammatory myopathies, endocrine causes (hypothyroidism, DKA, pheo), infectious causes (viral, bacterial and parasitic causes - malaria), drugs (statin, alcohol, colchicine, herbal products, opioids, illicit drugs - cocaine) and electrolytes abnormalities (hypokalemia, hypophosphatemia)

The diagnosis can be suspected clinically, but we rely on laboratory findings to confirm rhabdomyolysis. The triad of weakness, dark urine and myalgias is typically present. On examination, muscles can appear swollen and tender on palpation. Additional urinalysis testing can be helpful. Myoglobinuria can be identified on dipstick at a level of 150mg/L, but can not be differentiated from hemoglobin. Microscopic examination will show minimal/no red blood cells if pure myoglobinuria. The pH of urine in this setting tends to be acidic. Proteinuria can be seen in up to 50% of cases. If there is more than 300mg/L of myoglobin in the urine, there will start to be a colour change to reddish/brown.

The main concern in managing rhabdomyolysis is the development of acute kidney injury. Its estimated that 10% of all AKI are related to rhabdomyolysis. However, the CK level doesn't correspond directly with increasing chance of AKI. That being said, renal injury usually develops at levels above 15,000. Mechanisms of renal injury include direct tubular toxicity, renal vscocrinstriction and tubule blockage due to myoglobinuria, not CK. This is interesting considering we measure CK levels, and not myoglobin levels in the serum (which are actually quite insensitive for the diagnosis if rhabdomyolysis). The direct tubular toxicity (mainly proximal tubule) is thought to be related to myoglobin biproducts, including free iron and production of reactive oxygen species, which can lead to direct tubular cell injury. Renal vasoconstriction is likely multi-factorial, given these patients are oven volume deplete, ill and reduced vasodilating agents (ie. NO). Tubular blockage occurs when myoglobin accumulates in distal tubules (most common). This process is enhanced by acidic urine, and volume depletion, which can cause increased Tamm-Horsfall protein casts with myoglobin can precipitate in.

Treatment is mainly focused on volume expansion to prevent AKI and treating the underlying cause. Certain IV fluids are promoted in the treatment for several reasons:

1. Normal saline - good volume expander if hypotensive/significantly dehydrated. Issues with this include the significant chloride load, which put patient at risk for metabolic acidosis. This may worsen some the physiologic mechanisms that can lead to myoglobin induced kidney injury (vasoconstriction, precipitation and tubular injury).
2. RL - reasonable choice given lack of chloride.
3. Sodium bicarbonate - will allow alkalinization of the urine, which will theoretically prevent the above issues with myoglobin. However, no RCTs have shown this strategy to improve outcomes. It seems reasonable to include this in therapy, especially if patients is hyperkalemic secondary to muscle injury.
4. Mannitol - suggested as a volume expander as it can lead to an osmotic diuresis and improved GFR, theoretically clearing tubules of myoglobin and cast debris.

Here is an article identifying some predictors for AKI in rhabdomyolysis.

Predictors of AKI and Rhabdo

Saturday, October 5, 2013


Cryoglobulins are antibodies that precipitate at temperatures below 37 degrees Celsius. Its important to recognize that cryoglobulinemia is by definition the presence of precipitating proteins at low temperatures, however, clinicians tend to use this label to mean the clinical syndrome it is associated with. Cryoglbulins are classified into several categories, with each having its own clinical features and associations. :

Type 1 cryoglobulinemia - is monoclonal antibodies of one type, ie IgG or IgM. Associated with hematologic malignancies (Waldenstroms macroglobulinemia or myeloma). The primary clinical concern here is hyperviscosity syndrome where patients presents with infarcted digits, TIA/stroke like symptoms or thrombosis.

Type 2 cryoglobulinemia aka essential mixed cryoglobulinemia - results from monoclonal and polyclonal antibodies, including rheumatoid factor. The large majority of these patients have hepatitis C (30-100%), although connective tissue disease (Sjogren's syndrome) and lymphomas can also lead to this condition. Other less common infectious causes include HIV, streptococcal infections and brucellosis.

Type 3 cryoglobulinemia - is another form of mixed cryoglobulinemia, where all antibodies are polyclonal.

The classic triad was described by Meltzer in 1966, as purpura, arthritis and myalgia. These symptoms suggest cryoglobulinemic vasculitis. Palpable purpura is the most common manifestation, present in up to approximately 80% of patients. Purpura refers to bleeding under the skin that is larger than 3mm, when less than 3mm its termed petechiae. Other dermatologic findings include ulceration, levido reticularis and digital necrosis. Renal involvement is present in 30% of patients, where proteinuria, hematuria and active sediment production can occur. Nephrotic and nephritic syndrome occur in 21% and 14% of cases respectively. Neuropathy is also common, with up to 60% of patients describing symptoms burning and parasthesias. Mononeuritis multiplex (neuropathy involving a nerve with a name) is also seen, where patients can develop wrist or foot drop.

Testing for cryoglobulinemia is problematic, where samples need to be obtained in warmed syringes and kept at 37 degrees. Once serum is isolated it can be stored in a refrigerator at 4 degrees. It takes days for mixed immunoglobulin to precipitate, but type 1 proteins can be identified within hours. The quantity of cryoprecipitate can also be determined, using a test called the cryocrit. This is important because disease severity is proportional to amount of protein. Additional tests include complements, where low C4 is common, and elevated rheumatoid factor. Looking for an underlying disease association is also important if not already recognized.

Treatment is targeted towards the underlying cause and removing the monoclonal immunoglobulin. Considering HCV is so common in mixed cryoglobulinemia, ribavirin and interferon therapy should be considered with consultation by hepatology. Plasma exchange is helpful in life threatening disease with hyperviscosity. There is some growing evidence for the use of rituximab (monoclonal antibody targeting B-cells). A RCT from 2010 showed expedited rates of remission, improved renal involvement and higher rates of protein clearance compared to antiviral therapy in those with HCV. See a NEJM review on treatment in HCV associated cryoglobulinemia for more details (courtesy of the admitting physician).

HCV cryo treatment

Thursday, October 3, 2013

Heart block

Abnormal conduction between the atria and ventricles, termed AV conduction blocks, are common conditions in internal medicine. They range from mild asymptomatic findings to emergent, life threatening conditions. In 1964, Lev published the anatomic basis for atrioventricular blocks in the American Journal of Medicine, and still today, the disease that carries his name is responsible for nearly 50% of cases. The common nomenclature of AV block is documented as:

1st degree - slowed conduction between atria and ventricles with maintained synchrony
2nd degree - impaire conduction with intermittent loss of synchrony (separated into type I and II)
3rd degree - complete loss of synchrony between atria and ventricles. 

For the most part, conduction block are a disease of ageing or ischemia. Lev's disease, is used to describe the gradual fibrotic changes that occur with ageing to the cardiac conduction system, which lead to impaired functioning. Myocardial ischemia is the next most common cause, and can be acute or chronic. One study (Circulation, 1978) examined the natural history of heart block in patients following acute MI, and found that AV block is common. Twenty-two percent of patients developed second degree heart block type II. The most common type of blocks were LBBB and RBBB with anterior fascicular block. Patients who developed high grade AV block post MI had a significantly increased mortality (47% vs 23%), which was often directly related to the arrhythmia development and hemodynamic compromise. Other less common causes for AV block include:

Infection - endocarditis (aortic root abscess leading to AV pathway dysfunction), diptheria, scarlet fever, tuberculosis (with pericardial invovlement) mumps, lyme, toxoplasmosis
Inflammatory conditions - rheumatoid arthritis, lupus
Miscellaneous - sarcoidosis and amyloidosis (from infiltration)
Cardiomyopathy - hypertrophic cardiomyopathy, myocarditis'
Genetic - inherited forms of AV block exist, but are uncommon
Medications - remember to take a detailed history to identify agents that will impact the conduction system. 

Today, our patient was taking donepezil (an acetylcholinesterase inhibitor), which may have contributed to the development of bradycardia and heart block. There are multiple case reports of high grade AV block and even torsades des pointes with this class of medications. Donepezil is thought to be more associated with SA node dysfunction, causing sinus bradycardia more than high grade AV block, but both have been documented.  

After treating possible underlying conditions and removing offending medications, the next step is to consider pacing and pacemaker insertion.Determining treatment for the large majority of patients, which have ischemic or age related conduction disease, is based on symptoms and risk of worsening conduction delay.  
Generally accepted reasons for pacemaker insertion in AV block include:

1. Complete heart block, 
2. Symptomatic second degree heart block
3. Second degree block type II with consecutive dropped atrial contractions
4. Second degree block with previous wide complex on ECG
5. Exercise induced high grade blocks

Patients with bifascicular and trifascicular block may also require a pacemaker in the setting of syncope, given it may be due to the development of transient third degree heart block. More detailed instructions can be found in the AHA guidelines for pacemaker insertion linked below.

Wednesday, October 2, 2013

Enterococcus and endocarditis

Infective endocarditis (IE) is a huge topic. The IDSA guidelines are very comprehensive and cover the treatment of IE based on microbiology and valve involved (mechanical vs bioprosthetic). These are linked below.

Enterococcus fecaelis and fecium were given their name to emphasize their presence in the human gastrointestinal tract. There are multiple species of enterococcus, but these two tend to be the most clinically relevant bugs. In the 1930's, the Lancefield classification placed enterococcus in group D, along with strep gallolyticum. Enterococcus was identified as a cause for IE as ealy as 1906, and over the following decades found to cause urinary tract infections, biliary infections, peurperal sepsis, and wound infections during WWI. 

Infective endocarditis is caused by enterococcus in 5-15% of cases. The virulence of this organism is much lower compared to other organisms (ie. S. aureus). Two studies from the 1980's found that bacteremia from enterococcus had a relatively low likelihood of developing endocarditis, where only 2.5% of those with positive blood cultures met criteria. E. fecaelis is more common than E. fecium, which often requires vancomycin therapy given penicillin resistance. Even less frequent than this is vancomycin resistant enterococcus as a cause for endocarditis.  Enterococcal endocarditis is more common in men and older patients, where the average age in one study was 65.  One study from the archives on internal medicine showed that 50% of cases in men followed urinary tract instrumentation, an important risk factor that was present in our case discussion. Other associations include a history of malignancy and nosocomial acquisition. Below is a relatively recent retroprospective database from the American Jounral of Medicine.

Anecdotally, enterococcal endocarditis is less commonly associated with peripheral stigmata, which were absent in our patient. The disease course tends to be subacute with aortic valve involvement being most common.  

Unfortunately, enterococci are less susceptible to beta-lactam antibiotics and synergy with aminoglycosides are often employed. The purpose of dual therapy is to have cell wall breakdown from the penicillin antibiotic allow for improved penetration of the aminoglycosides, which act intra-cellularly on ribosomal activity. Different strains can have varying susceptibility to these antibiotics, which may influence dosing and antibiotics choice. Gentamicin/streptomycin have toxic effects, including ototoxicity and nephrotoxocity and the minimum six weeks of antibiotics required for this diagnosis can lead to significant morbidity. Prosthetic valve endocarditis may fail to be effectively treated with antimicrobials alone, and often requires surgical opinion. I would also advocate for the involvement of the ID service to help with antibiotic choice, dose, interval and duration of therapy.

Tuesday, October 1, 2013

Chronic myeloid disorders

Chronic myeloid disorders can be a confusing group of diseases to understand. There is overlap between conditions, making diagnosis challenging at times and many conditions have multiple names. Today we discussed a case of myelodysplastic syndrome, which is very likely a case of myelofibrosis. Here, we describe a general approach to these conditions and some of the clinical features.

Chronic myeloid disorders is an umbrella term encompassing multiple conditions: chronic myeloid leukemia (CML), myelodysplastic syndrome (MDS), chronic myeloproliferative disease and atypical chronic myeloid disorders. Chronic myeloproliferative disorders can be broken into polycythemia vera (PRV), essential thrombocytosis (ET) and idiopathic myelofibrosis (IMF). I think that confusion arises as a result of the multiple subgroups within each category of disease. You need to read about each entity separately to gain a better understanding of its differences.

MDS is as a result of ineffective and disordered hematopoeisis in one or more cell lines. Despite low peripheral counts, bone marrow evaluation reveals normal or hypercellularity. This is generally a disease of the elderly, where the majority of patients are over 65. It can be seen earlier, increasingly if caused by an external chemical exposure (ex. benzene). Clinical features are those associated with low blood counts; infection, bruising, fatigue etc. Some additional hints towards a diagnosis include an increased number of band neutrophils on the smear, the so called "pseudo-Pelger-Huet" anomaly, a result of premature cells being pushed into the blood.

The classification of myelodysplastic syndromes (MDS) changed in 2001. The World Health Organization changed the previous French-American-British (FAB) definition to improve the diagnosis of AML. MDS are a group of myeloid neoplasms, that impact on the proliferation of hematopoietic cells. Patients can present in a myriad of ways, and are generally classified into multiple categories:

1. Refractory cytopenia with unilineage dyslpasia- low RBCs or low platelets or low neutrophils
2. Refractory cytopenia with multilineage dysplasia- multiple low cell lines
3. Anemia with ringed sideroblasts- sideroblasts are abnormal mitochondria that are visibly different as a result of increased iron content
4. Refractory anemia with excess blasts - two stages based on percentage blasts (5-10%, 10-20%)
5. MDS from 5q deletion- a specific genetic variant
6. MDS otherwise unclassified

Prognosis varies depending on the subtype of MDS. Twenty percent of patients with MDS will die from AML, however those with 5q deletion are less likely to convert, and have a more indolent course.

Myelofibrosis (IMF), aka agnogenic myeloid metaplasia, is a different disease. This is a clonal stem cell disorder with progressive bone marrow fibrosis. An abnormal precursor is thought to produce factors that result in fibroblast proliferation and collagen deposition. Premature fibrosis pushes precursor cells into the periphery resulting in deposition of these cells in distant tissues. This leads to hematopoeisis outside the marrow. Cells can deposit in many different organs, including the lungs, pericardium, spleen, bowel, liver etc. IMF is less common than MDS, present in only 0.5 people per 100,000. The clinical presentation includes fatigue, splenomegaly, constitutional symptoms, and complications of bone marrow failure. Counts are often increased initially because of compensatory extramedullary hematopoeisis. Blood smear will often show premature WBCs, teardrop cells, giant platelets, termed a leukoerythroblastic pattern. Up to 60% of these patients will have a testable mutation in a gene called JAK-2. Occasionally,  can be difficult to distinguish IMF, from burnt out ET or PRV.

The prognosis in IMF is poor, with 10% of patients transforming to AML, having an average survival of 2-5 years. Unfortunately there are few successful treatments for this condition. In young individuals, allogeneic stem cell transplant can be considered, but in the elderly there is little that can be done. Blood counts can be controlled with various chemotherapy, and low counts managed with transfusion.

Two reviews for each of these conditions are listed below.

MDS review - NEJM
Myelofibrosis and NEJM

Thursday, September 26, 2013


Hepatocellular carcinoma (HCC) is a growing concern. Currently, it is listed in the top ten most common cancers worldwide amongst both men and women, and is continuing to increase. The majority of cases are in the setting of viral hepatitis, where hepatitis B makes up nearly 50%  of cases. Any causes of cirrhosis can theoretically lead to HCC, and rarely, HCC can develop in the absence of cirrhosis (10%). The burden of hepatitis C has been driving HCV in North America, where HCV related liver cancer is the fastest growing cause of cancer related death in the US.

Patients with HCC tend to present with symptoms of cirrhosis. Jaundice, ascites, GI bleeding and so forth. HCC should be considered in those presenting with acutely decompensated cirrhosis, as it can precipitate worsening liver disease through tumor extension. As an internist, it's also interesting to recognize the various paraneoplastic symptoms of HCC; erythrocytosis, hypoglycemia, sign of leser trelat, hypercalcemia, and diarrhea are recognized phenomenon. 

The diagnosis is based on imaging and possible need for biopsy. MRI or CT can be very helpful and when patients have predisposing conditions (HBV), a tumour of 2 cm or greater with typical radiographer pattern in pathognemonic for HCC. Early arterial enhancement and delayed venous washout on a multiphasic scan are suggestive, and indicate tumor vascularity. Tumours less than 1cm. Are difficult to biopsy and require serial scans for monitoring. Intermediate size nodules with atypical pattern should be followed with consideration of biopsy for definitive diagnosis. There are guidelines available on how to approach these nodules which can be very helpful. Alpha-fetoprotein (AFP), when over 500 mcg/L is diagnostic for HCC but intermediate levels can be seen in cirrhosis alone and results need to be taken in context. Levels over 200 mcg/L in the appropriate context have a specificity of over 95%.

Monitoring for HCC is suggested to include liver ultrasound and AFP every 6-12 months in those at risk. This is based on a study published in 2004, where nearly nearly 19,000 Chinese patients with HBV underwent this surveillance. They found a reduction on mortality of 37%. However, A study performed the year prior found no benefit. That being said, this is recommended by the current guidelines. patients that should be monitored include: 

1. Asians men over 40 with HBV
2. Asian women over 50 with HBV
3. Patients with HBV and cirrhosis
4. Blacks with HBV 
5. Family history of HCC and HBV
6. Any patient with cirrhosis

It is less clear when to start screening Caucasians with HBV, and some recommend initating at similar times to the Asian population, despite a lower risk of developing HCC. It may less cost effective to screen in those with cirrhosis from alcohol given a lower risk of HCC, but the epidemiology is not well described. Attached below is a nice NEJM review which contains many of the resources with above information.

HCC review

Wednesday, September 25, 2013


Hypoglycemia is dangerous and common event for many patients with diabetes. Although it is more common in DM1, many patients with DM2 will experience this problem. The Diabetes Control and Complications Trial (DCCT) identified hypoglycemia as a major concern, causing symptoms approximately 2 times a week in those with DM1. As patients live longer with DM2, they also develop an increased frequency of hypoglycemia, where 25% of patients using insulin for over 5 years experience this problem regularly. Much of our focus when caring for patients with diabetes is lowering their blood sugar in the hopes of preventing complications. Microvascular complications are reduced by improving glycemic control in both patients with DM1 and DM2, making it the focus of diabetes care. However, randomized trials targeting lower HbA1c levels (ex. ACCORD), found increased mortality in those randomized to tighter glucose control. Although not directly proven, this is likely a result of increased hypoglycemia. This highlights that severe symptoms can occur as a result of hypoglycemia. A study published in Diabetes Care found 100% of patients with DM1 experienced severe hypoglycemia at some point, requiring medical intervention. Recognizing the problem is an opportunity for prevention. Many diabetics with recurrent episodes lose the ability to sense hypoglycemia, putting them at risk for lower levels and additional risks. Symptoms can be broken down into two categories:

1. Neurogenic symptoms - tremor, palpitations, arousal, sweating, hunger (mediated through catecholamine and acetylcholine mechanisms).
2. Neuroglycopenic symptoms - cognitive impairment, coma, seizure and death.

Patient who experience recurrent hypoglycemia are at increased risk for developing hypoglycemia unawareness. This is when, despite hypoglycemia, patients lack symptoms to suggest a problem. Often the first symptom in these patients is confusion, which makes it hard for them to respond appropriately with increased sugar intake. Hypoglycemia unawareness can lead to hypoglycemia associated autonomic failure (HAAF), a form of autonomic insufficiency from recurrent hypoglycemia. In HAAF, patients are unable to mount an appropriate adrenergic response to low blood glucose. HAAF is associated with a significant risk of severe hypoglycemia (25x those without). If glucose levels improve and are maintained, patients will regain the function of their catecholamine axis in several weeks.

Definitions of hypoglycemia are different whether or not a diagnosis of diabetes is present.In those with diabetes any glucose less than 3.9 mmol is considered low. In those without diabetes the guidelines state that patients must have whipples triad:

1. Symptoms that may be explained by hypoglycemia
2. Documented hypoglycemia at the time of symptoms
3.Improvement of symptoms after taking glucose

There are many causes of hypoglycemia, and the approach is different in those with and without diabetes. The most common cause of low glucose is druge related. Several categories exist and can be separated by either "sick patients/medicated" or "well patients":

"Sick/medicated patient"
1. Drugs-insulin, alcohol
2. Critical illness- sepsis
3. Organ failure- renal/liver failure
4. Cortisol deficiency
5. Non-islet cell tumours
"Well patient"
1. Endogenous overproduction of insulin- insulinoma, nesidioblastosis
2. Autimmune- antibodies against endogenous insulin
3. Use of secretagogue- accidental, serruptitious etc.

More details regarding investigations for hypoglycemia and management of this illness in patients with diabetes can be found in the guidelines linked below.

Hypoglycemia guidelines

Thursday, September 19, 2013

Suspected overdose

Paracelsus, the Renaissance physician said that "the dose determines that a thing is not a poison", recognizing that most things in excess can be harmful. In the US there are over 2.4 million documented toxin exposures reported to poison control centres, the majority of which occur in children. The leading agents causing death are analgesics, antidepressants, cardiovascular medications, stimulants and illicit drugs.

Your approach to the poisoned patient is two pronged, containing a diagnosis and a treatment are in parallel. The treatment consists of ABC's, D (decontamination/DONT antidotes), E (enhanced elimination), F focused therapy and G (get help). The diagnostic are requires a history, physical exam, search for toxidrome and diagnostic testing.

History is key. How much? When? What? Why? All these can be helpful and alter your approach to the patient. Often patients cant name the medications they're taking or they do so incorrectly (Tylenol vs aspirin). If it is not available, obtaining information from family, work, family physician may be helpful. Specific symptoms to consider include:

protracted coughing - hydrocarbon exposure
inability to swallow/drooling - costic ingestion
hematemesis with iron ingestion
persistent seizures with INH overdose
decreased LOC with carbon monoxide

There are a number of pneumonics to help you remember toxidromes. Below is an article that contains an extensive list. Things to focus on include vital signs (HR, BP, temp, GCS, seizure), pupils (meiosis, mydriasis), odour (garlic-organophosphate, wintergreen - methylsalicylates, almond - cyanide), neurologic exam (rigidity/clonus - SS/NMS), skin (rash, diaphoresis, track markrs, fentanyl patches).

Preliminary labs will include routines, plus toxicology screen, osmolal gap and anion gap. Toxicology can be performed on serum and urine, where urine test tend to identify metabolites and will have positive results for longer duration compared to serum. Quantitative levels should only be performed if it suggests higher toxicity and will alter management. Levels can be performed on: tylenol, ASA, Li, Fe, CO, digoxin, anticonvulsants, toxic alcohols and theophylline. Other aspects of urine testing include any visual change, such as a change in UV light with ethylene glycol, orange with rifampin, pink with ampicillin, green with copper or methylene blue. Microscopy for calcium oxalate crystals also suggests ethylene glycol poisoning (see link below). Imaging tests may include CXR/AXR to look for iron or ingested street drugs (body packing with cocaine). Drugs causing pneumonitis or pulmonary edema can be remembered as MOPS (methadone, opioids, phenobarbitol/phosgene, salicylates).

Today we mentioned that "one pill can kill", although this tends to be targeted more towards children it highlights the potential toxicity of these medications. A top ten list of these drugs includes, but is not limited to:
1. TCA
2. antipsychotics
3. antimalarials
4. anti-arrhythmics
5. camphor
6. oral hypoglycemics - sulfonylureas
7. opioids
8. theophylline/podophylline
9. salicylates
10. calcium channel blockers

Calling poison control is always the right thing to do. You will be put in touch with an experienced nurse and have access to a clinical toxicologist if necessary. They also document each case and follow-up on the patient. For a more detailed approach to therapy see the article below.

Approach to unknown overdose
calcium oxalate cyrstals
fluorescent urine in ethylene glycol ingestion

Wednesday, September 18, 2013

Alcohol use - keeping an eye open

The complications of alcohol use are many. We are very good at listing the extensive number of possible problems that come along with alcohol use; nutritional deficiencies, myopathy, cognitive impairment, cirrhosis, cardiomyopathy, etc. however we are often fail to characterize the problem. Physicians underestimate the amount of alcohol ingested and when its identified, fail to capitalize on opportunities for rehabilitation. A US study found that only 48% of patients identified as having problem drinking were asked to follow-up, leaving the majority without ongoing monitoring. Patients may fail to have recognizable signs of cirrhosis despite significant liver injury, requiring probing questions to first identify the problem.

There are many tools for evaluating alcohol abuse. The most commonly used tool is the CAGE questionnaire. This method is great because of its simplicity and ease of administration, but fails to determine long term or changes in drinking patterns.It also lacks a quantitative component, which can be helpful to gauge severity of disease. A meta-analysis evaluating its use found the test to be more useful in inpatients compared to ambulatory assessment with a sensitivity of 87% and specificity of 90% for >2 components. Other tests do exist.

The alcohol use disorders identification test (AUDIT) is a longer test with higher sensitivity and specificity (96% and 97%). This was developed by the World Health Organization, and as a result was created for international use, validated in multiple languages. Of its 10 questions, it covers consumption, consequences and dependence issues, covering more areas than shorted questionnaires. Values of 8 and 20 are important to remember, being markers of harmful alcohol use and dependence.

Other markers of alcohol use which are mentioned on the wards and in the literature are macrocytosis and GGT levels. Unfortunately, these tests have limited sensitivity and specificity. A study in Hepatology from 1984 found GGT did offer some prognostic information in patients with acoholic cirrhosis, where only 60% of those with a level of 100 IU survived to 1 year.

An additionally proposed test for alcohol consumption is measurement of carbohydrate deficient transferrin. Transferrin circulates in our bodies in glycosylated forms. There is a variety of sugars attached to transferrin in different amounts. Alcohol consumption results in reduction of carbohydrate numbers on the transferrin molecule, something that can be detected in the blood. Studies have found that patients with low AUDIT scores are unlikely to have carbohydrate deficient transferrin. The test characteristics have been proposed to be better than that of GGT. I am not familiar with the cost of this assay and have never heard of anyone ordering this test.

All patients admitted with alcohol related complications, and more importantly those seen as outpatients with risk factors for alcohol abuse should be screened. Multiple methods exist, but when you have time the AUDIT form seems like an appropriate choice. See additional details below.

AUDIT score from BMJ best practices

Friday, September 13, 2013

Malignancy and diarrhea

Infectious causes dominate the majority of causes for acute diarrhea, and its often what we first consider based on investigations, and possible treatments. However, with diarrhea lasting more than 2 weeks, persistent and chronic diarrhea are considered, and after the infectious group we have to think about other classes of disease.

Malignancy is an uncommon but ominous cause of diarrhea. This association can result from several ways, and categorizing the type of diarrhea can be helpful. Typical groups include the following:

1. Watery diarrhea - secetory vs. osmotic
2. Fatty diarrhea
3. Inflammatory diarrhea

Watery diarrhea can be identified on history, where patients tend to have large volume, frequent stools, without solid material. Patients will often describe diarrhea despite not eating, and having to wake in the night to have a bowel movement in secretory/osmotic causes. Although its often not necessary, the stool osmolality gap can be calculated to differentiate between osmotic and secretory where a gap of greater than 125 suggests a osmotic cause. Cancers causing secretory diarrhea include the islet cell tumours which secrete hormones including: gastrinoma, glucagonoma, vasoactive intestinal peptides tumours, and pancreatic polypeptide tumours. Increased seratonin is also felt to be the cause of secretory diarrhea that occurs in carcinoid syndrome. Patients with medullary thyroid cancer complain of diarrhea as a ommon symptom in metastatic disease present in 40% of patients. The mechanism is controversial, but calcitonin production is thought to play a role. The diarrhea in this disease was clasically considered a secretory diarrhea, though some studies have found an increased electrolyte gap in the stool suggesting an osmotic cause. Lymphoma (when present in the gut) and villous adenomas of the bowel are also felt to produce a secretory pattern of diarrhea.

Fatty diarrhea is diagnosed using a 72h quantitative fecal fat test. Additional sudan staining can confirm the presence of fat in the stool. Patients will often say that they have greasy, oily stool that doesnt go down the toilet after flushing because it floats. Malabsorption from multiple causes can present like this, the most common likely being celiac disease. However, again malignancy can cause a similar presentation. Pancreatic cancer that results in exocrine dysfuntion can impair fat digestion in the bowel and lead to fatty diarrhea. Biliary obstruction from pancreatic cancer will decrease the release of bile salts in to the bowels and again impair fat absorption as a result, contributing to diarrhea. Somatostatin secreting tumours are documented as causing fatty diarrhea, these are islet cell tumours that produce octreotide, inhibit pancreatic function and bicarbonate release, which results in fat malabsorption. 

Many patients with cancer are on chemotherapy and are therefore immunosuppressed. Diarrhea may be a direct result of chemotherapeutic agents, or newly acquired infection. Our first focus of care in diarrhea should be to rule out infection and avoid exacerbating medications given these things can be life threatening and are treatable. 

Thursday, September 12, 2013

Renal artery stenosis

In hospitalized patients acute kidney injury is largely attributed to pre-renal disease, with additional renal and post renal causes being much less likely. Although a trial of fluids is usually tried in the majority of patients its important to recognize when this therapy is failing and other causes of renal should be considered. Renal artery stenosis (RAS) is an uncommon cause of chronic hypertension (less than 1%), but is more likely to be causative in acute refractory cases. In general, RAS can be broken into two classes:

1. Atherosclerotic stenosis (90%)
2. Fibromuscular dysplasia (10%)

Atherosclerotic disease is much more common than FMD given the presence of CAD, DMII, HTN, dyslipidemia and smoking prevalence. It is a progressive disease which usually results in small kidneys and CKD. Fibromuscular dysplasia is an abnormality of the intimal, medial and adventitial layers of the blood vessels of unclear cause. It results in narrowing of the renal arteries, typically at the distal third. Risk factors include being female and HTN prior to age 50. These patients can develop other complications, including artery dissection or thrombosis (most common with intimal involvement).

The pathophysiology is related to poor renal perfusion leading to activation of the renin-angiotensin system, impacting sodium homeostasis, vasodilatory factors and results in renal hypertension. Clinical clues to suspect renal vascular disease in patients with CKD and HTN include:

1. Worsening kidney function of 30% in started and ACEi
2. Systolic/Diastolic renal bruit
3. Onset HTN after 55
4. Flash pulmonary edema
5. Asymmetry in renal size >1.5 cm

Testing for these disease used to involve a captopril renal scan where differences in renal perfusion were examined following administration of an ACEi. However, this is no longer done and has largely been replaced by imaging. Ultrasound with arterial dopplers are helpful, and certain flow velocities through the artery can predict the degree of stenosis. This does however require an experienced radiologists and can be difficult to get appropriate view. CT angiography and MRI are useful tests, but are less likely to image distal vessels appropriately.

All patients are recommended to undergo medical therapy, which involves modification of CAD risk factors, including smoking cessation. ACEi will preferentially vasodilate the efferent renal artery, counteracting the natural response to improving GFR in patients with afferent renovascular disease. The addition of an ACEi can decrease GFR and worsen AKI. That being said, they can still be used in this disease and one must consider the clinical context. This is more problematic inpatients with atherosclerotic disease as opposed to FMD.

Renal artery angioplasty has not been shown to be superior to medical therapy in a meta-analysis published in the American Heart Journal in 2011. However, patients with refractory hypertension and flash pulmonary edema, may be considered for angioplasty. See this NEJM review on RAS for additional details.

Renal artery stenosis review

Wednesday, September 11, 2013

Thiamine and lactic acidosis

The approach to a lactic acidosis involves separating it into two possible classes, termed type A or type B. Type A is classified as lactic acidosis secondary to tissue hypoperfusion. This is usually not a mystery, and the patient has signs of end-organ damage, tissue hypoxia and hypotension. Type B lactic acidosis is felt to be from some derangement in metabolism of lactate, including:

1. Drugs - metformin use, HIV medications (through mitochondrial dysfunction)

2. Alcohol - decrease gluconeogenesis

3. Malignancy - suspected to be secondary to increased cell turnover, though the mechanism is somewhat unclear, this is more often seen in leukemia/lymphoma

4. Type-D-lactate- present in patients with short gut syndrome, bowel bacteria (usually lactobacillis) produce D-lactate which is absorbed but cannot be metabolised by endogenous LDH leading to accumulation.

5. Liver dysfunction

Today we discussed a patient that had an elevated lactate of unclear cause. The patient was treated with thiamine with rapid improvement, which raises nutritional deficiency as a potential contributor to type B lactic acidosis.

Thiamine (vitamin B1) is a water soluble molecule that is required for aerobic metabolism. It acts as a cofactor for several enzymes present in the glycolysis pathway. Thiamine deficiency prevents pyruvate from converting into Acetyl-CoA, which is the entry point into the Krebs cycle, which is responsible for ATP production and NADH which is utilized in the electron transport chain. As a result, pyruvate accumulates and is metabolized into lactate resulting in acidosis.

Thiamine deficiency can occur quickly. Because it is water soluble it is not readily stored in fat and levels lowering the total body amounts. It is estimated that thiamine deficiency can develop as quickly as four weeks in poor nutritional intake. In cases of thiamine deficiency lactate production has been seen as early as 1-3 weeks. Risk factors for thiamine deficicency include, poor nutritional intake, folate deficiency, alcohol use, malabsorption, TPN and renal disease (specifically dialysis/peritoneal dialysis).

So next time you see a lactic acidosis in the absence of tissue hypoperfusion, consider vitamin B1 deficiency.

Tuesday, September 10, 2013

VBG versus ABG

The purpose of performing an arterial blood gas (ABG) is to identify alterations in acid base status or ventilation/oxygenation. Arterial blood gases can be troublesome at times. Patients may have hemodynamic instability (miking it tough to find the pulse), be unable to hold still for sample collection, and the procedure can occasionally be technically difficult. As a result, venous blood gases are often taken as a surrogate for arterial measures given they are easier to perform, less painful, and patients in the ICU often have central venous access.

There are several different areas from which a blood gas can be drawn:

1. Arterial blood gas - usually radial artery, though can be taken from brachial/femoral stab
2. Peripheral venous blood gas - any peripheral vein
3. Central venous gas - from right atrium, usually drawn from central line
4. Mixed venous gas - taken from the distal port of pulmonary arterial catheter

Of these different types of blood gas', the correlation with ABG's are variable:

1. Central venous vs ABG - pH 0.003-0.005 lower, pCO2 4-5 mmHg higher, no change in HCO3
2. Mixed venous vs ABG - similar to above
3. Peripheral venous vs ABG - pCO2 3-8 mmHg higher, HCO3 1-2 meq higher

pO2 values can not be reliably calculated from any form of venous gas.

Of these options central venous gas is preferred given its correlation with the ABG is most consistent and most studied, that being said, many patients dont have central lines.There was a study examining the effects of tourniquets on venous blood gas values and found that their use doesnt alter blood gas variables when used, which is reassuring.

The clinical context needs to be considered. If pateints are hypotensive and in shock, venous values are less reliable and ABG's are preferred. A study from NEJM in 1989 showed that as patients become more unstable, the arterial-venous difference gets larger. The difference between central venous and ABG pH in patients with shock was 0.1, highlighting that both measures need to be evaluated. They also concluded that tissue hypoperfusion is better assessed with central venous gas than ABG. Another NEJM study looked at a similar question in patients during cardiac arrest. The average ABG pH with during CPR was 7.41, while the mixed venous was 7.15! The pCO2 also changed dramatically. ABG may not reveal the true extent of tissue hypoxia compared to the mixed or central venous blood gas.

So, when in doubt, I say get an ABG, but in the critically ill patient/post CPR, a venous gas may show the true extent of the disease.

Thursday, September 5, 2013

UTI prophylaxis

Recurrent urinary tract infections (UTI), defined as 2 or more infections in six months, or over three in a years period, is a frustrating disease for patients and physicians. This disease is common, where 20% of women presenting with a UTI will experience a recurrent episode at sometime. For the most part, these are new infections as opposed to persistence of the previous infection. When encountered, it raises the question as to whether patients should be treated with antibiotics on a more frequent basis in a prophylactic manner. Many women experience symptoms in relation to sexual activity, though in post-menopausal women, recurrent UTIs may have a different mechanism. Ageing results in changes in bladder function and anatomy, with increasing risk of prolapse. This can lead to urinary stasis and predisposition to recurrent UTIs. There are in general three approaches to this topic:

1. Continuous antibiotic prophylaxis
2. Post-coital prophylaxis
3. Intermittent therapy (not really preventative)

Choice of prophylactic strategy should be tailored to the individual patient. Cultures should be taken from the urine to confirm the presence of recurrent infection. Antibiotic choice should be based on culture and sensitivity results.

For women with recurrent UTI's, not in relation to coitus, continuous prophylaxis can be prescribed to patient as daily or three times weekly regiments. Usual antibiotics include: septra, nitrofurantoin, cephalexin, ciprofloxacin. Several studies have shown decreased rates of infection with this approach, and in 2004 a Cochrane review was published finding similar results. The number needed to treat in this review was 1.8 for one years therapy (which was the duration in the majority of studies). There was however increased side-effects in the therapy groups compared to placebo, where GI upset, rash and vaginal irritation was most common. In this study, there was no supreme antibiotics that performed better compared to others.
Following discontinuation of antibiotic therapy, women will tend to revert back to having recurrent UTI's. A reasonable approach is to trial antibiotics for 6 months, and after stopping see if the patient improves. Some individuals will have clusters of infection, which will be best treated with a period of drug followed by a holiday period. Longer prophylactic periods, upwards of two years, have also been advocated by some in the literature.

For females that develop infections in relation to sexual activity a post coital strategy can be taken, and has been found to have similar rates of success to continuous prophylaxis.  One study randomized 135 women to daily prophylaxis with 125mg of cipro versus a post coital strategy. They found similar results between groups and a third of the amount of antibiotic used. A study published in JAMA 1990, comparing placebo to septra using a post-coital strategy showed a significant reduction in UTI's. Where 81% in the placebo group developed a recurrent UTI compared to 12.5% in the therapy arm.

Intermittent therapy that is self administered is a useful approach for patients who are compliant and motivated. This strategy results in a higher number of infections, given it is not a truly preventative approach, but symptomatic duration and total antibiotic dosing is minimized. One study testing this approach found that symptomatic episodes had a culture negative rate of 14%, suggesting that women were able to accurate identify the presence of a UTI based on symptoms in over 85% of cases.

With the ever-growing use of antibiotics, resistance to these medications is a concern, and should be considered in patients receiving chronic therapy. There have been studies of patients taking chronic antimicrobial therapy for UTI prophylaxis identifying breakthrough infections with bugs that were resistant to the antibiotic prescribed. Separate studies using septra and cipro found breakthrough infection rates with resistant organisms at a rate of 44% and 3% respectively. This high rate of septra resistant organisms in this group is concerning, and provides some evidence that its use as prophylaxis results in significant alterations in microbe susceptibility patterns. See this NEJM review from 1993.

Urinary tract infections NEJM

Wednesday, September 4, 2013

Metformin and Anemia

The list of causes of anemia are many, making the work up timely and at times invasive, where patients may require endoscopic procedures and occasionally bone marrow evaluation. B12 deficiency is a common problem and in itself has a long list of contributors, ranging from common (pernicious anemia) to zebra (nitrous oxide toxicity). The case of anemia discussed today involved a patient with DM2 who was taking metformin, which raised the question of metformin induced B12 deficiency. Given the widespread use of metformin in the treatment of diabetes, I felt a review of the literature surrounding this topic would be useful.

Metformin is from the biguanide class of oral hypoglycemics, which decrease hepatic gluconeogenesis and insulin dependant glucose utilization in peripheral tissues. It is supported as first line therapy for diabetes by the American Diabetes Association consensus guidelines and has become the most commonly used medication in this disease. Metformin results in decreased intestinal absorption in upwards of 30% of patients through a reduction in  intestinal absorption. A randomized study involving nearly 400 patients randomized diabetics on insulin to metformin or placebo and monitored their B12, folate and homocysteine levels for 4 years. Compared to placebo, metformin resulted in decreased B12 levels and increased homocysteine levels. There was no difference in folate concentration when controlling for BMI and smoking. They felt that the number needed to harm was roughly 9 individuals per 4.3 years. B12 deficiency was found to be progressive, worsening over time in these patients where some did reach levels requiring supplementation.

The mechanism was initially felt to be related to impaired bowel motility and subsequent bacterial overgrowth. However, B12 deficiency has been identified in the absence of bacterial overgrowth bringing this mechanism into question. Metformin is known to have activity against calcium absorption at the intestinal wall. As well, intrinsic factor absorption is calcium dependent, which raised the idea that calcium alterations may be involved in the mechanism of B12 deficiency. A study published in Diabetes Care looked at B12 levels in diabetics newly started on metformin. B12 levels dropped significantly after three months of therapy as did B12 precursors. Supplimentation with calcium led to an increase in B12 precursor within a month, with a non-significant increase in total B12 levels. There was no evidence of bacterial overgrowth in the study population as tested with hydrogen breath testing.

Rarely will the B12 deficiency associated with metformin result in hematologic or neurologic complications, though there are case reports of peripheral neuropathy from B12 deficiency. Neuropathy may be under diagnosed as well, given diabetic neuropathy presents in a similar fashion to B12 deficiency and is a common complaint amongst diabetics.

Below is the article linking calcium supplimentation and improved B12 levels.

B12 deficiency and metformin

Friday, August 30, 2013

Less common opioids

As part of our palliative care week curriculum, we discussed analgesia management at the end of life. I find there are numerous opioids that residents tend to become familiar with and feel relatively comfortable prescribing, and then there are those that we use less frequently. This blog instalment will focus on those used less frequently: buprenorphine, methadone, fentanyl and tramadol.

Approved in 2007 by Health Canada, buprenorphine is a partial mu receptor agonist, kappa receptor antagonist. This is felt to have a beneficial profile for treating opioid dependence, considering, as a partial agonist, it will provide some activity at the receptor, but carry a ceiling effect that would limit the development of serious toxicity. For this reason buprenorphine alone or incombination with naloxone has become a commonly used drug in addictions medicine. Its been shown to have similar efficacy in reducing illicit substance use, associated with less mortality than methadone and can be taken as an outpatient on a non-witnessed protocol (unlike methadone). Its prescribed in dozens of countries around the world, where over 95 thousand patients receive this for opioid dependence in France. Despite the safety profile being improved from other opioides, there are multiple case series of overdose deaths related to intravenous and oral ingestions. In Finland, buprenorphine is a leading drug of abuse, likely due to its higher rate of availability compared to North America.

Fentanyl binds to mu receptors, having a potency of nearly 100 times that of morphine. It was produced in the 1960's, and in the 90's transitioned to a patch form, mixing drug with a gel alcohol. Its felt to offer a unique profile for pain control, in that it does not have active metabolites, provides a steady stream of drug into the blood, and may be safer in patients with renal insuffuciency. A systematic review in the journal of palliative care found that GI side-effects were reduced with fentanyl compared to oral morphine. There are also health concerns with fentanyl, as there have been many reports of accidental overdose. Many of these cases involve children who may mistake the patch as a band-aid and place it on their skin.

Methadone has been around for a while. Created in Germany during world war II it was used on soldiers to treat pain and boost morale. It likely did one of the two. The German scientists that created methadone lost their patent following the war, which allowed American scientists to manufacture the medication widely, selling the patents to various pharmaceutical companies for the steep price of one dollar. Methadone is still inexpensive when compared to its alternatives (buprenorphine). The half life can vary in individuals, but can spans from 12-160 hours. It provides analgesia through acting on opioid and NMDA receptors. Its long half life is what makes it useful in treating opioid dependence, and its been shown in multiple RCTs to be superior to placebo in preventing illicit substance use and decreasing withdrawal symptoms. This comes with the cost of roughly 5000 overdose cases per year in the US. Other adverse effects include QTc prolongation and drug-drug interactions, as it is metabolized via CYP3A4.

Tramadol is being tested to treat many different conditions, from chronic nociceptive pain, to post-herpetic neuralgia and post-traumatic stress disorder. It acts on the mu opioid receptors and inhibits monoamine reuptake (nor-epinephrine and serotonin). Its mechanism of analgesia is not completely understood, but may offer some effect against neuropathic pain. The effects of tramadol have been said to be similar to codeine, for the treatment of moderate to severe pain. Side-effects are common and similar to other opioids, where one study suggested up to 70% of patients developed some kind of side effects, commonly GI upset. Seizures are also possible when taken in high doses. Because of tramadol's activity on monoamine receptors, its use with SSRI's and other medications resulting in increased levels should warrant careful consideration as not to trigger the serotonin syndrome.

These medications are all potentially dangerous, and some require a special license, or suggested clinical education prior to prescribing. Using these medication in the palliative care setting is also different that using these in patients with chronic pain. A recent Cochrane Review found there to be a lack of evidence for the long term use of opioids to treat chronic low back pain. Something to think about:

Cochrane review summary for opioid use in low back pain

Thursday, August 29, 2013

SLE and lung disease

Lupus can present in many ways, involving nearly any organ in the body. Pulmonary complaints are common in lupus and take on different forms. 

Pleural disease can present with chest pain with inspiration, a symptom described in nearly 50% of SLE patients at some point in their disease. Pleuritis can be identified with a rub on clinical exam and may or may not be associated with a pleural effusion. When present, pleural effusions in SLE are typically exudative, with low glucose, low complement levels and positivity for ANA. This disease is usually mild and can be treated with anti-inflammatory medication. However, it has been associated with additional lung disease in SLE including the shrinking lung sydrome (SLS - see below).

Pulmonary infections should be considered, given the relative immunosuppression in SLE patients as well as their typical immunosuppressing drug regiments, these patients are increased risk for infection. Infections typically present as they would in patients without SLE, with cough, dyspnea, and fever. A study looking at risk factors for infection in SLE identified corticosteroids and renal disease as risk factors, and found no association with leukopenia or azathioprine use in isolation. 

Pneumonitis is an uncommon but serious complication of SLE (~1-4%). Short term mortality can reach upwards of 50%. Patients present with significant respiratory symtpoms and ground glass opacities on CT scan, usually bilaterally. This is treated with immunosuppressant, sometimes requiring pulse steroids. 

Interstitial lung disease can occur in up to 10% of patients with SLE. It tends to be a subacute presentation with dyspnea, cough and exertional symtpoms. There is variability in this clinical presentation, where patients may have a fibrotic or inflammatory pattern on imaging. Most commonly patients will have ground glass on CT scans suggesting a non-specific interstitial pneumonia (NSIP) pattern. Those with the fibrotic form can have imaging similar to that of idiopathic pulmonary fibrosis, which is termed a usual interstitial pneumonia (UIP) pattern. Sometimes a lung biopsy is required to confirm the diagnosis, and bronchoscopy can be useufl in excluding infection.

Pulmonary hypertension is a known complication of SLE. It has a similar pathophysiology to that of primary arterial hypertension, which is different than that of left sided heart failure and chronic venous thromboembolic disease. However, as noted in morning report today, patients with SLE may have anti-phospholipid antibodies, putting them at risk for thrombosis and PE. Treatment may require vasodilating agents like bosentan or sildenafil.

Shrinking lung syndrome, characterized by decreasing lung volumes, dyspnea and chest pain. It is felt to be a relatively rare condition, though patients may not be monitored for this disease appropriately with repeated lung volumes. The mechanism may involve worsening diaphragmatic dysfunction though this is somewhat controversial. Some data suggests that nerve conduction to the diaphragm or even chest wall disease may be responsible as opposed to true myopathy of the diaphragm. There have also been multiple studies associating pleural inflammation with development of SLS, pointing to an additional mechanism.

Pulmonary hemorrhage tends to be a more commonly recognized presentation of other rheumatologic conditions (granulomatous polyangiitis, goodpastures syndrome etc), but can rarely occur in SLE. This was documented in 4% of SLE patients in a study spanning ten years. There was a strong association with pulmonary hemorrhage and nephritis, where only one patient who had pulmonary hemorrhage did not have renal involvment. Imaging and bronchoscopy are often indicated to support the diagnosis. 

Acute reversible hypoxemia is a relatively new entity described in the early 1990's. Patient experience transient hypoxemia as a result of leukocyte agreggation and vascular occlusion, which is felt to result from hypercomplementemia and leukocyte activation. See one of the initial articles below from the annals of internal medicine.

Wednesday, August 28, 2013

Sickle Cell Disease

Sickle cell disease (SCD) is a common admission to hospital in the city of Toronto. We have a multicultural population in the city and subspecialty clinics at the University Health Network. These patient suffer from multisystem disease as a result of chronic vaso-occlussion, infections and anemia, often requiring hospitalization for analgesia. However, there is a spectrum of disease activity, and not all forms are equivalent. Different forms of sickle cell disease are based on the specific mutations in the beta globin gene, which can result in varying combinations of alleles Some include:
HbSS - typical form of SCD
HbSC - C genotype is as a different point mutation at the same amino acid residue
HbSthal - patients with one S genotype and beta-thallasemia trait on the other chromosome

These three are the most common forms, but others do exist including:

Hb Lepore disease

These different mutations result in varying disease penetrance. Some patients will have disease very similar to that of typical SCD. Its important to recognize differences in genotype as the frequency of certain sydrome may vary. For example, HbSC is a milder form of disease and hence may present with sequestration crisis later in life (adult years), as opposed to HbSS disease where this occurs solely as a child. Patients with HbSC disease tend to have milder symptoms, developing the same complications but later in life.

Presentations of sickle cell disease are many and can include vaso-occlusive crisis, chest crisis, aplastic crisis and sequestration crisis. Patient present with pain, usually located to bone/muscle in VOC, and chest pain/dyspnea in patients with chest crisis. Triggers for VOC are things that impact the oxygen dissociation curve, which results in deoxygenation of Hgb, polymerization and sickling of red blood cells. This include:

Hypothermia, acidosis, hyoxemia, dehydration, and infection to name the common ones.

Treatment is usually supportive, with investigations targeted towards identifying an infection. Fluids, analgesia, oxygen therapy and antibiotics as needed. Transfusions are reserved for only those who truly require it. Usually a cut-off of 50 is targeted, though discussion with the patients hematologist and blood bank should be had.

An acute chest crisis is a dreaded complication of SCD and a previous blog entry has discussed the entity. See this link for details: Acute Chest Crisis.

The long term management usually involves hydroxyurea, which results in increasing HgF levels which improve oxygen carrying capacity and decrease the percentage of HbSS. This medication is usually inititated when patients experience frequent crises ( 3 or more per year), chest crisis, or severe VOC. It was found to have a survival benefit in these patients (see NEJM link).

Hydroxyurea and SCD