Critical Care Scenarios

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We dive into fluid resuscitation in sepsis, with Dr. Jon-Emile Kenny, pulmonary and critical care physician, author of the physiology textbook Heart-lung.org, and inventor of the FloPatch device.

Disclosures: Dr. Kenny appears here as both a clinician as well as a representative of his company and product, and should be presumed to retain a degree of bias in this discussion. However, his appearance is not part of a commercial relationship with our show; no compensation was provided, and neither he nor his company have any input in the episode’s content, nor the right to review it (or prevent its publication) after recording.

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Takeaway lessons

1. Before giving IV fluids, ask: 1) Is there an indication to give fluids? 2) Is giving fluids safe? 3) Will giving fluids be effective?
2. One of the most common misconceptions is that safety and efficacy are opposite ends of a spectrum, and efficacy necessarily implies safety. This is not so. Think instead of fluid like a drug, which could be effective, yet also dangerous (e.g. anaphylaxis), or vice versa. A volume overloaded patient could be fluid responsive, but giving fluid could be a poor idea.
3. Interpreting heart function and cardiac output is difficult in sepsis, particularly on the venous or filling side. Many have some degree of diastolic dysfunction, which sepsis itself can induce.
4. Kenny likes to phenotype patients into a 4-quadrant grid, similar to the traditional Diamond-Forrester heart failure classification, characterizing a patient as either wet/dry and normal/low cardiac output. POCUS can be used to assess both of these; LVOT VTI >17-20 is a normal-ish stroke volume and IVC is a surrogate for preload.
5. The only phenotype likely to benefit from fluid is the cold, dry patient (warm patients don’t need fluid, wet patients are unlikely to respond and maybe shouldn’t have it even if they will), although in sepsis, 20-30% of even this group are not fluid responsive and fluid will simply congest them.
6. Using BP response to fluid challenge is insensitive; in a significant number of patients, cardiac output will increase but BP will not. A marker of flow, e.g. doppler ultrasound, is more sensitive.
7. The FloPatch is a wireless, wearable, continuous-wave doppler ultrasound. It adheres over the neck and continuously monitors both the carotid and jugular vessels. The jugular provides a CVP-like waveform for qualitative clinician inspection, while the carotid is used to automatically measure the systolic flowtime duration, which is associated with stroke volume (better evidence than calculating a stroke volume).
8. The height of the carotid waveform may change with alterations in inotropy, afterload, and other factors, but if those are consistent, fluid responsiveness is best associated with the duration alone (base of the triangle).
9. An increase in flowtime duration of >7 milliseconds after a preload challenge (Trendelenburg position or ~250-300 ml rapid fluid bolus) is associated with 10% increase in stroke volume. (This cutoff is meant to match existing literature on fluid responsiveness.)

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We discuss propofol infusion syndrome (PRIS) and propylene glycol toxicity from lorazepam infusions, with medical toxicologist Dr. Jerry Snow, director of the toxicology fellowship at Banner University Medical Center in Phoenix.

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Takeaway lessons

1. PRIS is a defect in the electron transport chain leading to a failure of ATP production and fatty acid metabolism. There seems to be a susceptibility in some part of the population, but not a clearly understood or monofactorial one. People with mitochondrial disorders are at higher risk, but there is no definitive testing for PRIS risk.
2. PRIS has mostly been described with infusions greater than ~67 mcg/kg/min infusions, running for >48 hours.
3. The most common presentation is some combination of: elevated lactate, rhabdomyolysis, and new cardiac changes (which may be varied, including new bundle branch block, bradycardia, Brugada-like ST elevations, and changes in function on echo). Trending lactate and CK periodically on high-dose propofol is not a bad idea.
4. Triglyceride elevation probably has some association with PRIS, as it is also associated with high propofol doses, but there is not a direct link.
5. The primary treatment is stopping propofol and supportive care. There have been some case reports of ECMO being used.
6. It is not clear whether patients might be treated by dose-lowering propofol rather than stopping entirely, but it would be a fairly bold move; a safer option might be discontinuation and later rechallenge, but many experts recommend avoiding propofol in the future. Data is limited, but it should probably be added to allergy lists.
7. Propylene glycol is a toxic alcohol used as diluent for lorazepam, diazepam, and phenobarbital infusions. It is lower amounts in the latter two, and they are less often used, so toxicity is almost always in lorazepam, and almost always in infusions (not intermittent boluses).
8. It is associated with higher infusion rates for prolonged periods. This is probably above >6-7 mg/hr, or >0.1 mg/kg/hr, or >1mg/kg/day, depending on who you ask.
9. Propylene glycol is an alcohol, which behaves similarly to other toxic alcohols like ethylene glycol; it creates an elevated osmolar gap, and is metabolized via alcohol dehydrogenase (ADH) to lactate, creating a lactic acidosis.
10. Presentation is predominantly an unexplained lactic acidosis. An elevated osmolar gap will help confirm. Mental status can be affected as well. Trending a daily lactate and/or osmolality is not a bad idea on high-dose lorazepam infusions.
11. There is no common confirmatory testing, although some centers can probably obtain propylene glycol levels.
12. Treatment of propylene glycol toxicity is predominantly stopping or weaning the drip and supportive care. In the most severe cases, it can be treated similarly to other toxic alcohols, including fomepizole and/or renal replacement therapy (especially in patients with renal failure who are more likely to accumulate the compound and its metabolites). It probably does not need to be listed as an allergy/drug reaction.

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Brandon and Bryan mock up a goals of care discussion for a critically ill patient, and reflect on the right and wrong ways to execute this complex procedure.

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Resources

Center to Advance Palliative Care

The Conversation Project

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We chat about neuromuscular blockade, monitoring, and reversal in the ICU, including why sugammadex isn’t more widely used, with Sara J Hyland, PharmD, BCCCP, FCCP, researcher and clinical pharmacist in perioperative and emergency medicine.

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Takeaway lessons

1. Aminosteroids (rocuronium, vecuronium) can be reversed by neostigmine + glycopyrrolate (the latter to mitigate peripheral cholinergic effects of neo), or sugammadex. Benzylisoquinoliniums (e.g. cisatracurium) can only be reversed by the neostigmine option.
2. Neostigmine is an acetylcholinesterase inhibitor; in other words, it doesn’t directly antagonize the effect of the paralytic, it simply helps boost the supply of ACH at the neuromuscular junction to overcome it. This means its reversal effect is indirect and imperfect.
3. Neo is completely ineffective when blockade is deep. In fact, it can have a paradoxical effect of prolonging paralysis when used in these situations. It should really only be used when the train-of-four is 4 twitches. It is also slower acting than sugammadex, and even given with glyco, has inevitable risk of cholinergic toxicity (e.g. bradycardia).
4. Neo + glycopyrrolate costs around $30 for a dose, versus around $150-200 for a sugammadex approach. (This does not take into consideration broader system costs from a less effective and less efficient reversal method.) Overall cost with sporadic ICU use will always pale in comparison to high-volume perioperative use, though.
5. Sugammadex is a direct binder of the rocuronium/vecuronium molecule, and can attract even already-bound compound from its receptor; hence, it can function at any level of blockade (even very deep).
6. A large number of our patients who appear to have cleared their paralysis (seeming clinically “strong,” TOF 4) still have a significant continuing effect of neuromuscular blockade. This may contribute to failures of extubation and other complications. In one ICU study of random ICU patients, >40% had active neuromuscular blockade to a degree that would have precluded extubation by anesthesia standards.
7. As a result, the international, guideline-directed gold standard for reversal of neuromuscular blockade is now using quantitative, objective neuromuscular monitoring (before and after reversal agents) to confirm resolution to a >90% TOF ratio.
8. What’s that? Normal train-of-four devices (qualitative peripheral nerve stimulators) are inadequate; 4 out of 4 twitches may be present despite 70% of nicotinic ACH receptors still blocked. Better devices (with accelerometers, myometers, EMG, etc) can measure the actual twitch strength and compare the ratio of first to last twitch—i.e. does it fade or maintain strength? The fourth twitch should be >90% the strength of the first before extubation. (All four twitches must be present to even attempt this technique; other techniques can be used at levels of blockade deeper than this.)
9. Although sugammadex will be effective at any degree of block, it is dosed differently at different levels, so pre-drug assessment is still important. (It may also reveal the option of using neostigmine, if desired.) Post-drug assessment is then needed to confirm adequate response.
10. “Recurarization,” or recurrence of paralysis after reversal, is a known phenomenon. It is rare after sugammadex, and tends to occur when it was underdosed; the immediate effect may be good but the paralytic may outlast the reversal. This phenomenon should be considered in a patient with unexpected weakness/coma or respiratory failure after reversal, and either neuromuscular testing or empiric sugammadex should be considered.
11. There is an anaphylaxis risk with sugammadex, as the molecule type is also found (and could have induced sensitization) in many everyday cosmetic compounds. But the risk is extremely low (well under 1%)—lower than rocuronium, and in fact, anaphylaxis to rocuronium potentially could be treated with sugammadex.
12. There is a small risk of mild bradycardia and hypotension after sugammadex, as well as rare reports of sudden unexplained cardiovascular collapse. The cause of these is not well understood, and in many cases may be mere confounders.
13. Why isn’t sugammadex widely used in the ICU, as it is in the perioperative world? Unclear; we may not realize how common residual paralysis is (i.e. very), and over-rely on insensitive clinical assessments (squeezing hands, tidal volumes, lifting the head, etc). This was the situation in anesthesia two decades ago and we may be lagging behind.
14. In some cases rocuronium may be having residual effects hours to days later; the duration of effect on the package insert is defined as median time to >25% of first twitch height reemerging, a standard far below what clinically-relevant paralysis might entail. This residual effect might cause failures of extubation, especially in tenuous patients.
15. Even in intubated patients, persistent paralytic effect may be a cause of distress and PTSD if sedation has been inadvertently weaned (i.e. awake paralysis).
16. In the absence of quantitative monitoring, a good clinical assessment, confirmation of four twitches on TOF, and at least an eyeball assessment of twitch strength is a reasonable starting point.
17. In a patient remaining intubated (e.g. reversed to facilitate neuro exams), the demands for monitoring are less; an empiric low-dose sugammadex (e.g. 200 mg) titrated to a patient who can engage in your exam is probably fine—they don’t need complete strength. Even simple “bugzapper” TOF devices can rule out deep blockade in these situations.
18. In a failed airway situation, give a hefty dose empirically. A post-sugammadex check may still be appropriate, though. Don’t expect this to rescue you in a crashing patient. Note that if you gave sugammadex, it may linger in the body for days, making it difficult to reparalyze with an additional dose of rocuronium if your airway approach requires that. (You may need to use a higher roc dose later, or succinylcholine, or cisatracurium.) Tell anesthesia if they’re taking a patient to the OR, or reattempting an RSI, if you previously gave sugammadex.
19. The paralytic/sugammadex complex circulates in the blood until it’s renally cleared. With a low GFR, this can take a long time; there is a theoretical risk of the complex dissociating at some later point and re-paralysis occurring. In a dialysis-dependent patient, in fact, it may not clear very efficiently with lower-flux filters, such as during CRRT. For these reasons, in the past, renal failure was a contraindication to sugammadex, but data and clinical experience has since shown it to be generally safe.

References

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2. Grabitz SD, Rajaratnam N, Chhagani K, Thevathasan T, Teja BJ, Deng H, Eikermann M, Kelly BJ. The Effects of Postoperative Residual Neuromuscular Blockade on Hospital Costs and Intensive Care Unit Admission: A Population-Based Cohort Study. Anesth Analg. 2019 Jun;128(6):1129-1136. doi: 10.1213/ANE.0000000000004028. PMID: 31094777.
3. Frenkel M, Lien CA. Eliminating residual neuromuscular blockade: a literature review. Ann Transl Med. 2024 Aug 1;12(4):65. doi: 10.21037/atm-23-1743. Epub 2024 May 14. PMID: 39118951; PMCID: PMC11304418.
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   https://pubmed.ncbi.nlm.nih.gov/35042888/
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11. Hyland SJ, Pandya PA, Mei CJ, Yehsakul DC. Sugammadex to Facilitate Neurologic Assessment in Severely Brain-Injured Patients: A Retrospective Analysis and Practical Guidance. Cureus. 2022 Oct 19;14(10):e30466. doi: 10.7759/cureus.30466. PMID: 36407180; PMCID: PMC9673186.
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19. Bowdle TA, Haththotuwegama KJ, Jelacic S, Nguyen ST, Togashi K, Michaelsen KE. A Dose-finding Study of Sugammadex for Reversal of Rocuronium in Cardiac Surgery Patients and Postoperative Monitoring for Recurrent Paralysis. Anesthesiology. 2023 Jul 1;139(1):6-15. doi: 10.1097/ALN.0000000000004578. PMID: 37027807.
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