Tuesday, December 22, 2015

Acute Kidney Injury

Today's case was of a middle-aged man with renal cell carcinoma. He was sent in for an acute rise in his serum creatinine following a nephrostomy change.

We talked about multiple valuable learning points:

-Acute kidney injury (formerly acute renal failure) is one of the most common inpatient referrals that we see as internists.  Although the approach is very rudimentary, it is quite helpful to at least entertain three categories of possible causes in your mind:
-Pre-renal causes: by definition, pre-renal causes will correct completely once circulating volume has been restored.  On history look for things like reduced PO intake, diarrhea, blood loss, etc.  Also, certain volume overloaded states like cardiorenal syndrome or hepatorenal syndrome behave as pre-renal AKI because as far as the kidney is concerned, there is reduced circulating volume.
-Post-renal causes: these relate to obstruction and back pressure on the collecting system of the kidney producing hydronephrosis and reduced urinary flow.  Keep in mind that most people have two functioning kidneys, meaning that severe AKI usually only occurs with lesions below the bladder (obstructing flow to both kidneys) or large retroperitoneal masses that directly compress both ureters.  Our patient has one kidney, so something like a stone or blocked nephrostomy tube would be sufficient to cause AKI.
-Intrinsic renal causes: The simplest way to divide these up is to think of the structures within the kidney.  Glomerular causes of AKI include things that cause acute glomerulonephritis (post-infectious, autoimmune/vasculitis, infectious/viral).  Tubular causes like acute tubular necrosis can occur because of drugs or insufficient circulating volume for sufficient time to induce injury/damage.  Interstitial causes of AKI can result from infection, autoimmune processes, or most commonly drugs (PPI’s are a common medication that can do this).  Finally, vascular causes in the microcirculation can also cause AKI (TTP, HUS, etc.).  Also, macrovascular complications like obstructive tumours or thrombi can lead to AKI through a variet of mechanisms.

-The approach to AKI is two-fold: firstly, you need to try to determine the cause.  Our usual assessment includes a history and physical examination focusing on volume status and indications for dialysis.  Almost every patient with AKI should have urine electrolytes (low urine sodium suggest a pre-renal cause), a urinalysis (blood suggests GN or ATN), a urine microscopy to look for casts, and an abdominal ultrasound or other imaging to exclude hydronephrosis.
-Once you’ve finished your assessment portion, you need to look at a few management things.  Always start with ABC’s (e.g. if the patient is in florid pulmonary edema, he probably requires respiratory support).  Following that, ensure that the patient is adequately volume replete – pre-renal AKI can cause a creatinine of 1000umol/L that corrects with fluid.  Then ensure that there are no medications causing the AKI (antibiotics, NSAIDS, chemotherapy, etc).  After that, ensure that there are no medications that can worsen the AKI (ACE inhibitors, ARBs, diuretics).  Finally, ensure that any medications that need to be adjusted or held in renal failure are examined (digoxin, antibiotics, etc.).
-We talked about indications for dialysis.  Briefly, they can be divided into the mnemonic AEIOU.
A = refractory acidosis
E = refractory electrolyte abnormalities (principally potassium or calcium)
I = intoxication (methanol, ethylene glycol, ASA, lithium)
O = refractory volume overload/heart failure
U = uremic pericarditis or uremic encephalopathy (asterixis)
For the most part, there is no survival advantage to early dialysis before one of these indications is met.  Furthermore, it is generally not advisable to use dialysis (or bicarbonate infusion for that matter) to treat lactic acidosis from hypoperfusion.  The best treatment is correcting the underlying cause (usually shock) because some of the physiologic changes associated with acidosis are actually adaptive.

-Finally, we talked a little bit about Septra®/Cotrimoxazole/Trimethoprim-Sulfamethoxazole.  There are a couple of things to recognize about this medication.  The spectrum that it has is actually quite broad, and it is on the common list of first-line agents for urinary tract infections.  This drug is highly bioavailable when taken orally, so there is almost never an indication to use the intravenous formulation.  The gram positive coverage is generally very good, and this drug can be used to treat infections with methicillin-resistant Staphylococcus Aureus (MRSA).
-That said, it is quite old and has a number of side effects.  Septra has been associated with Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis, it has many drug interactions because of its inhibition of cytochrome P450 hepatic enzymes, it can cause bone marrow suppression and cytopenias, and can cause AKI.  Additionally, the trimethoprim component actually behaves like a potassium-sparing diuretic leading to hyperkalemia independent of renal failure.  Furthermore, the sulfamethoxazole component behaves like a sulfonylurea secretagogue which can lead to hypoglycemia.  There have been associations between Septra and sudden death, presumably on the basis of hyperkalemia, in database studies.

Further Reading:
Fralick, M., Macdonald, E. M., Gomes, T., Antoniou, T., Hollands, S., Mamdani, M. M., & Juurlink, D. N. (2014). Co-trimoxazole and sudden death in patients receiving inhibitors of renin-angiotensin system: population based study. BMJ, 349, g6196.

Star, R. A. (1998). Treatment of acute renal failure. Kidney international, 54(6), 1817-1831.

Friday, December 18, 2015

Septic Shock and Toxic Alcohols

Today's case involved a middle-aged man presenting with an acute onset of fever and symptoms compatible with pneumonia.  He was hypotensive, tachycardic, febrile, and hypoxemic requiring supplemental oxygen.  His X-ray was consistent with community-acquired pneumonia, and he was treated with antibiotics and

admitted to internal medicine.

There were several valuable learning points:

-Prior to the case discussion, we talked about some toxic alcohol ingestions.  The main four alcohols you’ll deal with are ethanol (drinking alcohol), ethylene glycol (antifreeze, bright yellow), methanol (windshield washer fluid), and isopropanol (rubbing alcohol).  Ethanol causes an osmolar gap but should not in and of itself cause an anion gap (it can produce alcoholic ketoacidosis and occasionally a lactic acidosis).  Isopropanol is a secondary alcohol meaning that when it’s oxidized, it forms a ketone, not a ketoacid as in DKA.  Thus, it produces an osmolar gap, profound intoxication, but no anion gap.  Ethylene glycol and methanol both produce an osmolar gap initially, and then as they are converted to their acid counterparts by the liver, they produce increasing anion gaps.  Ethylene glycol produces oxalate nephropathy and is quite toxic.  Methanol produces formic acid which is extremely neurotoxic.  The ultimate therapy to remove either one is fast, high throughput dialysis.

-The actual alcohols themselves are relatively innocuous, so the main goal is preventing conversion into acids.  To do that, you need to inhibit alcohol dehydrogenase.  The easiest and cheapest way if there are no other options is with ethanol.  This can be given orally (e.g. whiskey) or IV.  The less intoxicating option is fomepizole which inhibits alcohol dehydrogenase, but is quite expensive and only available in hospitals.  In addition to preventing conversion from the initial alcohol, steps can be taken to prevent conversion into the final toxic byproduct.  Pyridoxamine and thiamine help shunt metabolites of ethylene glycol away from the oxalic acid pathway.  Folate helps shunt methanol byproducts away from formic acid.  Thus, in suspected cases of toxic alcohol ingestion (e.g. high anion gap, high osmolar gap, altered mentation) it is reasonable to start all of those shunting cofactor therapies while preparing for dialysis.

-We spoke about the SIRS (systemic inflammatory response syndrome) criteria which are: temperature above 38C or less than 36C, respiratory rate above 20 or PaCO2 less than 32mmHg, heart rate above 90/min, and WBC count <4 or="">12,000 or >10% band neutrophils.  This syndrome does not have to accompany an infection, and can classically be seen in patients with burns, or patients with pancreatitis.  If it is accompanied by infection, we call it sepsis. If sepsis is accompanied by end-organ dysfunction (renal failure, altered mentation, heart failure, etc.) we call it severe sepsis.  If after a fluid challenge of around 20-30cc/kg crystalloid, the blood pressure is still less than 90mmHg systolic, we call it septic shock.

-More than 10 years ago, a landmark trial (Rivers trial) demonstrated that Early Goal Directed Therapy in the emergency department had a mortality benefit for patients with septic shock.  Most of the principles of sepsis management from that trial have been incorporated into our daily practice, but more recent trials have demonstrated equivalency between “usual care” and “protocolized care” in sepsis.  That said, the initial principles from the Rivers trial were: early antibiotics and crystalloid fluids given until a central venous pressure of 8-12mmHg was reached.  If the mean arterial pressure (MAP) was less than 65mmHg despite those fluids, vasopressors like norepinephrine were started to achieve a MAP of 65mmHg.  Once those goals were reached, the patient’s central venous oxygen saturation (a measure of how much oxygen the body is extracting from the blood) was measured.  If it was under 70%, there was deemed to be some degree of septic myocardial dysfunction.  The intervention was dobutamine (an inotrope) if the hematocrit was normal, or transfusion if the hematocrit was < 30%.  Urine output less than 0.5cc/kg/hr was also an indication for either inotropes or transfusions.

-There were many criticisms of this trial.  The ED had a “code sepsis” area where ER physicians managed the majority of the patients’ early care.  All patients received central venous catheterization (no longer a real practice here).  There were issues involving the cost and financial incentives from the trialists around the central venous catheter’s oxygen saturation probe which could measure it in real time.

-We talked about the organisms that typically cause community-acquired pneumonia (CAP).  They include S. pneumoniae, M. catarrhalis, and H. influenza.  Additionally, atypical organisms like legionella, chlamydophila, and mycoplasma can cause this syndrome.  Legionella is acquired from contaminated water sources and not airborne transmission.  It is typically tested with a urinary antigen test, and should be considered in those with septic shock, elderly patients, or immunocompromised patients.  Patients ill enough to require hospital admission should be treated with a beta lactam (ceftriaxone) and macrolide (azithromycin) combination or a respiratory quinolone (moxifloxacin or levofloxacin).  Just because the patient is “sick” does not mean that he or she requires piperacillin/tazobactam in the absence of Pseudomonas risk factors or previous antibiotic exposure.  Piperacillin is inferior therapy to ceftriaxone for most causes of community-acquired pneumonia.

Further reading:

Rivers, E., Nguyen, B., Havstad, S., Ressler, J., Muzzin, A., Knoblich, B., ... & Tomlanovich, M. (2001). Early goal-directed therapy in the treatment of severe sepsis and septic shock. New England Journal of Medicine, 345(19), 1368-1377.

Kraut, J. A., & Kurtz, I. (2008). Toxic alcohol ingestions: clinical features, diagnosis, and management. Clinical Journal of the American Society of Nephrology, 3(1), 208-225.

Tuesday, December 15, 2015

Rapid Fire Morning Report - ACS, Hypertensive Urgency, Dementia, and Eating Disorders

Today, we had the first Rapid Fire or Post-Call Morning Report at Toronto General Hospital since 2013!  For those familiar with this in other hospitals, the goal of this type of morning report is to discuss high-level management issues regarding a number of the patients referred overnight.  Rather than focusing on a single case more from a diagnostic perspective, we focused on several cases with valuable teaching points and more of a management perspective. 

There were multiple learning points:

-We don’t see a lot of patients with acute coronary syndromes on the medicine service as many of these patients go to cardiology.  The first patient was a patient with previously documented coronary disease and acute coronary syndromes, who presented with chest discomfort not unlike prior MI’s.  The pain began at rest and resolved at rest, but was otherwise relatively typical in character.  The patient was treated as a NSTEMI.  We discussed the role of Clopidogrel (Plavix®) in this situation.  The original CURE trial would have only recommended clopidogrel in very high risk situations.  The latest AHA 2014 guidelines, however, do recommend dual antiplatelet (ASA and clopidogrel) in all patients with NSTEMI for 12 months regardless of management strategy.  New players in the dual antiplatelet market are Ticagrelor (Brilinta®) and Prasugrel (Effient®).  These drugs are recommended in lieu of clopidogrel if PCI and stenting is likely, or if patients are presenting with an ST-segment elevation event.  They are much more effective antiplatelets than clopidogrel.  In addition to ASA and a second antiplatelet, the 2014 AHA guidelines recommend that all patients receive anticoagulation with a  low molecular weight heparin, unfractionated heparin, or fondaparinux (helpful here because it’s the lower DVT prophylaxis dose) for the duration of the hospitalization, or until PCI is performed.

-We talked briefly about hypertensive urgency and emergency.  The case involved a woman with a bloodpressure of 220/110mmHg.  There are no definite blood pressure cutoffs for urgency vs. emergency.  The usual way of distinguishing them is whether end-organ damage is present.  This would include hemorrhagic stroke, aortic dissection, flash pulmonary edema, chest discomfort or a demand-related troponin elevation, acute kidney injury from hypertension, limb ischemia, etc.  If emergency is present, this usually warrants ICU admission with invasive blood pressure monitoring, and IV antihypertensive agents.  The goal is to reduce the MAP by around 25% within the first 24 hours because cerebral autoregulation may be accustomed to much higher blood pressures – reducing them to normotension immediately could be dangerous.  Hypertensive urgency on the other hand does not even always require hospital admission, and can be followed up as an outpatient with changes or adherence to oral medications.

-We talked about a young man (30’s) who had been found wandering the clinical areas and was referred to internal medicine for a presumed delirium or altered level of consciousness.  Because there were volitional changes in his level of consciousness and alertness, a psychiatric cause was much more likely.  The patient chose to leave AMA.  The learning point is that, despite it being a little bit ageist, the approach to a 30-year-old who is wandering, aggressive, or disoriented is usually different than that of an 80-year-old with the same syndrome.  A primary, new diagnosis of a psychiatric disease is almost impossible in the latter case.

-We talked about a young woman with disordered eating behavior who had substantial electrolyte disturbances.  In these situations, it is helpful to exclude diuretic abuse as a cause of weight loss and electrolyte abnormalities (an abnormally high urine chloride level >40mEq/L is usually sufficient).  The other teaching point was related to refeeding syndrome and intravenous volume expansion. Giving high volumes of isotonic fluid may exacerbate hypokalemia leading to arrhythmias.  Also, it is extremely challenging to correct hypokalemia without correcting hypomagnesemia first.  Finally, the patient had a very low phosphate which will predispose to weakness and even rhabdomyolysis.  The challenge is that with feeding these patients, their endogenous insulin secretion increases leading to potassium and phosphate shifting inside cells and exacerbating measured electrolyte abnormalities.  This must be done carefully, with monitoring, in a controlled environment.

-Finally, we talked about someone with severe dementia and an inability to feed herself.  We often associate malignant (cancerous) diagnoses with the need for palliation, but two overlooked clinical conditions are congestive heart failure and dementia.  Patients with severe dementia and inability to drink water or feed themselves have a six-month mortality worse than most cancers.  Likewise, patients with severe refractory heart failure and complications like cardiorenal syndrome are similar.  Our palliative care colleagues can be a tremendously helpful resource in this situation, as education to families about the futility of treatments like IV hydration and G-tubes is vital.

Image Credit: nursingcrib.com

Further Reading:

Amsterdam, E. A., Wenger, N. K., Brindis, R. G., Casey, D. E., Ganiats, T. G., Holmes, D. R., ... & Levine, G. N. (2014). 2014 AHA/ACC guideline for the management of patients with non–ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Journal of the American College of Cardiology, 64(24), e139-e228.

Marik, P. E. (2015). Hypertensive Crises. In Evidence-Based Critical Care (pp. 429-443). Springer International Publishing.

Mitchell, S. L. (2015). Advanced dementia. New England Journal of Medicine, 372(26), 2533-2540.