Horses and Zebras: September 2015

Tuesday, September 29, 2015

Hyponatremia

Today's case involved an elderly woman with multiple comorbidities including asthma, coronary artery disease, and hypothyroidism. She was brought in for ‘delirium’ and found to have a serum sodium of 113mmol/L.

Today’s case had multiple learning points:

-Delirium is something that we see frequently in medicine. Delirium is an acute change in mental status characterized by a fluctuating course, disordered thought, and agitation or depressed level of consciousness. It has a very wide differential diagnosis, and can be caused by quite a number of things. The typical treatment of delirium is fixing the underlying cause which can vary quite substantially depending on what it is. Around 20% of the time, no definitive cause is found for the delirium in elderly patients. Resolution of delirium does not always correlate with resolution of the underlying illness, and may lead to further disability and cognitive changes. Finally, delirium is independently associated with higher risk of poor outcomes from hospitalization, suggesting that it should be treated as a medical emergency on that basis.

-The mnemonic that many people like is DIMS

Drugs – anticholinergics, benzodiazepines, ‘narcotics’, alcohol, and withdrawal from drugs

Infections - CNS infections (meningitis, encephalitis) and systemic infections

Metabolic – electrolyte disturbances, endocrinopathies, CO2 retention, etc.

Structural – Space occupying lesions, stroke, seizure, intracerebral bleeds

-Hyponatremia is a common problem in hospitalized patients. Think of hyponatremia as a water disorder rather than a sodium disorder. Essentially there is too much free water for the amount of sodium in the body.

-Why do we care so much about hyponatremia? There are a couple of reasons. Acutely, hyponatremia can produce alterations in mental status and seizures a result of cerebral edema (too much water outside brain cells, osmotic shift of water into brain cells, cerebral edema, raised intracranial pressure, seizure). The other component that we care about is overcorrection of hyponatremia which can lead to osmotic demyelination syndrome (previously central pontine myelinolysis). For those who have never seen this complication, it is a devastating injury to the brainstem that can result in “locked-in” syndrome (only able to move eyes). Risk factors include low muscle mass (cirrhotic, malnourished), hypokalemia, and female sex. The classic teaching recommended not increasing the sodium by more than 10mmol/L in a 24 hour period, but nephrologists are now stratifying patients by their risk for ODS, and recommending more conservative correction for those at higher risk.

-There are a lot of ‘approach to hyponatremia’ documents out there but I will try to give you a simplified one that I use. Firstly, there are only THREE mechanisms that can produce hyponatremia:

(1) – free water is unable to be excreted by the kidney leading to an elevated water:sodium ratio in the body (this is the case in extreme renal failure).

(2) – Antidiuretic hormone is turned on, and is the only mechanism that separates salt from water retention. With this on, water is preferentially reabsorbed by kidneys leading to an increased water:sodium ratio in the body.

(3) – there is insufficient solute to excrete the free water. Our kidneys can only dilute urine down to around 50 mOsm/L meaning that guzzling free water and eating things without any solute (sodium, proteins, etc.) will invariably lead to, you guessed it, an increased water:sodium ratio in the body.

-As far as an approach goes, I like to think of things this way:

(1) – is the hyponatremia real? (check the serum osmolality). Things that can cause hyperosmolar or euosmolar hyponatremia are elevated paraproteins, lipids, glucose, etc.

(2) – Now that it’s real, is it symptomatic? (i.e. is the patient seizing)

If it’s symptomatic, the treatment should be to rapidly correct the sodium by 1-2mmol/L until the patient stops seizing. This is done in ICU’s with 200cc of 3% NaCl solution rapidly infused.

(3) – Now that it’s real, and asymptomatic, is it acute or chronic? Most of the time you won’t know whether it’s acute or chronic because people don’t get their labs checked at home. That said, acute hyponatremia can be corrected acutely without risk of ODS. Chronic hyponatremia (48-72h) must be corrected slowly to avoid ODS.

(4) – Now that it’s real, asymptomatic, and chronic, what is the patient’s volume status? What volume status is the kidney seeing? Ordering the urine lytes answers the second question (if the kidney is seeing low volume, the urine sodium will be under 20). Diuretics will interfere with this. The rest of your physical exam answers the first question. Many people will order urine osmolality as well. This tells you whether ADH is acting or not (it is high if ADH is acting). An example of hyponatremia when ADH is not acting would be psychogenic polydipsia, or insufficient solute intake.

From here, it’s helpful to break things down into causes by volume. Hypovolemia causes ADH to be released to maintain plasma volume. This is not because extracellular water stays intravascular, but because ADH acts as a potent vasoconstrictor to maintain systemic vascular resistance. So patients with diarrhea, vomiting, sepsis, etc. may have appropriate ADH on board.

Hypervolemic patients like CHF, cirrhotic, or nephrotic syndrome patients are hypovolemic from a renal perspective, meaning that their kidneys behave like the first group. Treatment of their underlying problem may resolve the hyponatremia.

The euvolemic group has a lot of causes: hypothyroidism, adrenal insufficiency, medications (diuretics, antiepileptics, SSRI’s), “tea and toasters”, psychogenic polydipsia, and the ever-famous SIADH (syndrome of inappropriate antidiuretic hormone).

SIADH occurs for a number of reasons: lung pathology, tumours, CNS disease, pain, nausea, etc.

So based on the above, you can see that the treatment varies widely. If you give someone with SIADH normal saline, their sodium may go down because that potent ADH will reabsorb all the water, and allow excretion of all the sodium. On the contrary, someone with hypovolemic hyponatremia will correct their sodium rapidly because the saline restores intravascular volume, leading to a shutoff of their ADH release, and a water diuresis. That’s why we sometimes give salt cubes, or urea, to patients with low solute intake – it drags out some of the excess water and increases the capacity for free water excretion.

Thursday, September 24, 2015

Severe Clostridium difficile Infection

Today’s hypothetical case centred around a middle-aged man recently diagnosed with diffuse large B-cell lymphoma. He had been treated with R-CHOP, experienced an episode of neutropenic fever with no obvious source, and was admitted to hospital. He received broad-spectrum antibiotics, and his counts improved. Two days after discharge, he began to have non-bloody diarrhea. This progressed for 7 days until he presented back to the ED with profuse, non-bloody diarrhea and crampy abdominal pain. He was afebrile, but had tachycardia as well as orthostatic symptoms. His physical examination was remarkable for volume depletion, but not peritonitis. Laboratory investigations showed a leukocytosis, lactic acidosis, and acute renal injury. Imaging did not demonstrate toxic megacolon.

The working diagnosis was acute C. difficile colitis with sepsis. There were multiple learning points:

-Clostridium difficile is an interesting clinical entity. Much of its pathogenesis depends on the absence of normal colonic flora, which is why it is so commonly associated with the use of broad spectrum antibiotics. There is some variability in which antibiotics are more likely to precipitate a CDI (Clostridium difficile Infection) but not to the extent that some are certain to do so and others definitely won’t.

-The test for CDI is a stool PCR. The test characteristics are very favourable to the point that repeat tests within 7 days for negative results are essentially forbidden by some electronic medical records. In rare cases, the medical microbiologist will allow a second sample, but we’re talking about a very good test here. Unfortunately, the nucleic acids can remain for quite a long time following resolution of infection, which makes diagnosis of a relapse challenging.

-Treatment of CDI depends on its severity, and whether it is an initial episode, or a recurrence. The markers of severity are essentially the renal function (whether creatinine is greater than 1.5-fold increased) and the WBC count (> 15,000). Very severe infections are characterized by peritonitis, toxic megacolon, and septic shock. The IDSA guidelines and recent NEJM review summarize these.

-Although the Surviving Sepsis Campaign has dismantled some of our definitions, words like “SIRS” and “Severe Sepsis” are thrown around so frequently that it is helpful to know their definitions. SIRS (Systemic Inflammatory Response Syndrome) is characterized by two out of the following four criteria being present: HR > 90/min, Temperature < 36C or >38.5C, WBC count < 4, > 12, or 10% bands, and respiratory rate > 20 or PCO2 < 32mmHg. SIRS indicates just what it says – an inflammatory systemic response – it is not specific to infection and can occur with other illnesses (classically pancreatitis among others). SIRS + a documented or suspected source of infection is considered sepsis. Sepsis with end-organ dysfunction (decreased or altered level of consciousnes, renal impairment, skin mottling, liver dysfunction, coagulopathy/DIC, etc.) is considered severe sepsis. If the BP remains under 90mmHg systolic (despite the arbitrary nature of this number) even after a fluid challenge of 20-30cc/Kg, the patient is said to have septic shock.

-The Rivers trial in 2001 (before everyone used acronyms to name their trials) looked at Early Goal-Directed Therapy for sepsis. Their protocol is a little unfathomable to us, because they had a dedicated area of the ED for patients essentially deemed to be “code sepsis.” Early broad-spectrum antibiotics were administered, and ED physicians inserted central venous catheters in all patients. The patients received intravenous fluids until their central venous pressures were 8-12mmHg. If at that point, their mean arterial pressures were under 65mmHg, they received pressures (typically norepinephrine/Levophed®) to achieve that MAP. Then the central venous saturation was measured and, if under 70%, they were either transfused (if low hematocrit) or given dobutamine (an inotrope) for presumed septic cardiomyopathy to improve oxygen delivery. More recent trials including ProCESS (acronyms are in now) demonstrated that protocolized care like this is no more effective than usual care (probably because usual care incorporates the features of the Rivers protocol). Critiques of Rivers include that certain portions of the protocol make a lot of sense, but others make a little less sense: most people do not transfuse for a low urine output or central venous saturation. Furthermore, no one uses the special central cathether used by Rivers, which had a live measurement of the central venous oxygen saturation. Finally, there may have been issues with conflicts of interest centred around patents for the aforementioned central venous catheters.

Image Credits: C. difficile image from www.bionews-tx.com, Surviving Sepsis Campaign image from survivingsepsis.org

Tuesday, September 22, 2015

Dyspnea in an Immunocompromised Patient

Today's case involved a gentleman with a previous bone marrow transplant for lymphoma. He was immunosuppressed on account of his lymphoma and prednisone use (7.5mg daily). He presented with dyspnea of 2-3 weeks’ duration, productive cough, and no response to empiric antibiotics.

There were a number of learning points:

-An important role for a physician on internal medicine is to reconcile the past medical history of with the current medications. Do not be afraid to stop medications for which you have an outdated rationale (e.g. dual antiplatelet therapy) or no rationale.

-There are a number of problems on the differential diagnosis that can lead to pulmonary syndromes in a patient like this: Bacterial infections (S. pneumoniae, M. catarhalis, H. influenza), viral infections, mycobacterial infections such as tuberculosis, and fungal infections with endemic fungi, or opportunistic organisms like Pneumocystis. In addition to infectious causes, we must always think about other causes such as pulmonary edema/CHF, venous thromboembolic disease, COPD, organizing pneumonias like BOOP/COP, primary lung tumours or involvement of lung in other cancers such as lymphoma, etc.

-A bronchoscopy can be a helpful diagnostic tool in cases like these to determine which organism is causing the problem. Remember that empiric therapy for fungi, viruses, and bacteria can limit the diagnostic aid of a bronchoscopy.

-RSV (Respiratory Syncitial Virus) is a common viral infection which is underappreciated. It’s effects are even more pronounced in immunocompromised patients, and it can have a mortality similar to the revered influenza virus.

Horses and Zebras