#5 Zorses & Hebras: A New Take on an Old Adage

Pharmacology
Written By Nick Mark

They say that when you hear hoofbeats, you should look for horses. This age-old medical adage makes sense in many circumstances, but what do you do when the paradigm is flawed? What if our calibration of rare and common is off? What if a clinical entity generally accept as a common is actually rare? What about the reverse? In this first episode of Zorses & Hebras, Nick & Cyrus discuss some of these examplesin the context of critical illness, shed some light on them, and explain why focusing just on the Horses & Zebras model may bite you on the tail!


Quick Take Home Points

  1. If you hear hoofbeats, it's reasonable to think about horses first - but it’s not always so simple as differentiating between horses and zebras!

  2. Zorses and Hebras are, respectively, conditions we think are rare but are relatively common, and conditions we think are common but are relatively rare.

  3. Zorses and Hebras can help us correct our calibration when attempting to make diagnoses, may help us revisit and shed some of our diagnostic biases, and ultimately help us take better care of the critically ill.

  4. Consider discontinuing cefepime when clinically able, given the relatively high-incidence of cefepime-induced encephalopathy.

  5. Dexmedetomidine is a great medication, but it can be a cause of cryptogenic fevers in the ICU. 

  6. Consider evaluating high-risk patients for Wernicke’s encephalopathy - it is a diagnosis with significant ramifications that can be easily fixed!

  7. Contrast-Induced Nephropathy (AKI) is probably a worthy concern in high-to-very-high-risk patients, but in general, fear over this condition should be bridled when a contrasted study is warranted.

  8. Fentanyl wooden chest syndrome should be considered in patients who are given fentanyl and develop a temporally associated chest wall rigidity that impairs ventilation. 


Show Notes:

  1. The theory of Horses & Zebras

    1. Coined by Theodore Woodward: “When you hear hoofbeats behind you, don’t expect to see a zebra.”

    2. An unusual presentation of a common disease is much more common, that a usual presentation of a rare disease - in general

    3. Problems?

      1. Implies that diseases are either common or rare

      2. Implies that we know which diseases are common and which are rare



  2. An improved theory: add Zorses & Hebras

    1. A zorse is a condition we think of as rare, that’s surprisingly common

    2. A hebra is a condition we think of as common, that’s actually quite rare



  3. Cefepime Induced Encephalopathy - A Zorse!

    1. Impaired consciousness, myoclonus, seizures and possibly NCSE

    2. Using more of this recently due to resistance, shortages of Pip-Tazo, concerns regarding nephrotoxicity & Pip-Taz + Vancomycin

    3. Up to 15% of ICU patients can develop encephalitis related to cefepime (NNH:1/6)

    4. Clearance: renal, AKI is common in the ICU

    5. Probably broader coverage than we need in a lot of cases, consider narrowing (if/when able) to avoid this potential risk!



  4. Dexmedetomidine-induced Fevers - A Zorse!

    1. 3-10% of patients on a dexmedetomidine infusion can develop fevers, typically 48 hours post infusion

    2. Can be low grade, however in some they can have temps >39.5

    3. Incidence is higher in obesity & following open-heart surgery

    4. Don’t stop using it, just keep in on your differential for unexplained fevers in the ICU



  5. Wernicke’s Encephalopathy - Another Zorse!

    1. Seen in patients with a history of alcohol use - a degenerative brain disorder due to a thiamine (B1) deficiency acquired in the setting of nutritional deficiencies often associated with alcohol use disorder (AUD) - up to 12% of those with AUD

      1. Can also see in patients post-bariatric surgery (up to 5%)

      2. In general population, those that are chronically undernourished 

    2. Thiamine is necessary in the TCA cycle, when absent in specific brain areas, metabolism shifts to lactate production 

    3. Classic triad: ophthalmoplegia (lateral rectus palsy or nystagmus for example), ataxia, confusion

      1. Many cases related to alcohol use do not feature all the elements of the triad

      2. Eye findings require a thorough exam to identify, can often be missed



  6. Contrast Induced Acute Kidney Injury (CI-AKI) - A Hebra!

    1. Maybe it was once common (aka a horse) … but now it’s rare (a hebra!)

    2. CI-AKI: increase in Cr of 0.5mg/dL or >25% from baseline, within 48 hours of receiving contrast

      1. Also not a very patient-centered outcome

      2. No significant associations between a rise in Cr potentially associated with modern IV contrast and need for renal replacement therapy

    3. In the past, IV contrast was high-osmolality and likely did contribute to kidney injury 

    4. At least 8 large, observational studies with modern contrast, that did not find evidence of CI-AKI

      1. Recent study looked at contrast administration in the setting of D-Dimer… no association there either

    5. Arterial contrast seems to be a different ball game

      1. Patients get bigger doses of contrast with cath-lab studies, for example

      2. Arterial contrast doesn’t get metabolized before making it to the renal arteries

    6. So should we just give contrast to everyone?

      1. Maybe not quite…

      2. … significant pre-existing CKD may give you pause

      3. .... significant pre-existing comorbidities such as poorly controlled diabetes should be considered in the risk-benefit analysis, even though the risks in 2023 are admittedly very small



  7. Fentanyl Wooden Chest Syndrome - Maybe a Zebra… maybe a Zorse!?

    1. First described in the 1950s with high-doses of IV fentanyl → chest wall muscle rigidity → difficulty with mechanical ventilation

    2. Occurs due to nor-adrenergic signaling, not opioid receptors 

    3. 1993 study looking at ultra-high doses of fentanyl and chest wall rigidity: 6/12 healthy participants developed chest wall rigidity

      1. Dose: 15mcg/kg - an INSANE dose

    4. Other case reports with lower doses, fentanyl patches

    5. If you are concerned about fentanyl wooden chest syndrome:

      1. Stop the fentanyl

      2. Give naloxone and/or give a low dose of a neuromuscular blocker (relaxes muscles so the patent can be ventilated again, assuming they are on invasive mechanical ventilation)

    6. How common is this?

      1. In the OR patients get both fentanyl and neuromuscular blockade often… so we could be missing it

      2. There are case reports of opioid overdoses where patients were noted to be incredibly difficult to ventilate due to presumed chest-wall rigidity

      3. In conclusion… this may be more of a Zorse than a true Zebra!

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Nick Mark
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