Dr. Farrah Nasrollahi
edited by Ilyas Taraki
65-year-old female with heavy alcohol use and other polysubstance use disorder (primarily heroin), hypertension, hyperlipidemia, with poor medical follow-up and otherwise no known medical issues presents with weakness. Her lactic acid is 4.0. She is ultimately admitted for ALI and severe AKI thought to be secondary to UTI with septicemia and is started on IV fluids and antibiotics. Over the course of the evening, she becomes hypoxic and short of breath and ultimately is intubated.
You've intubated. Now what?
Congratulations — tube in, RSI complete, and CXR/EtCO2/physical exam confirm placement. What now? How will you manage her meds on the vent? Infusion? Pushes?
Consider the patient's age, weight, drug/alcohol use, comorbidities, and renal/hepatic functions.
Pick analgesia. Give a bolus and make sure it's adequate, then start an infusion
Pick sedation if necessary, but be wary
What did she actually receive? Fentanyl and propofol. Was this a good choice for her?
When I arrived on the unit the next AM, her lactic acid was 7.9. I noticed HR was decreasing: she was 110-120 on arrival but was now in the 40s-50s. Not good!
Looking over her medications, vent settings, volume status, and overall clinical course, it was decided that the propofol should be switched to Versed.
Lactic acid improved!
What did she have?
Propofol Infusion Syndrome (PIS)
Defined as metabolic acidosis with cardiac dysfunction and one or more of the following: rhabdomyolysis, hypertriglyceridemia, or renal failure.
However, intralipid propofol may impair hepatic lactate metabolism leading to lactate accumulation and acidosis.
The disease commonly presents as an otherwise unexplained high anion gap metabolic acidosis, rhabdomyolysis, hyperkalemia, acute kidney injury, elevated liver enzymes, and cardiac dysfunction. Management of overt propofol infusion syndrome requires immediate discontinuation of propofol infusion and supportive management, including hemodialysis, hemodynamic support, and ECMO in refractory cases.
Why this matters: analgesia and sedation choices
PIS aside, how you manage analgesia and sedation on the vent matters:
Your algorithm for dealing with sedation vs. analgesia
How you personalize your practice to the patient
Current practice favors intermittent bolus doses, daily interruption or dose minimization titrated to light level of sedation (RASS -2 to 0) of continuous infusions . Clinical practice guidelines for the sustained use of sedatives and analgesics in critically ill adults endorse the initial use of intermittent bolus dose, with the initiation of continuous infusions with daily interruption or dose minimization titrated to light level of sedation in patients who require intermittent infusions more often than every two hours .
Early Interventions Matter (ED)
The SPICE trial: deep early sedation within the first four hours was an independent predictor for delayed extubation and increased mortality. (Shehabi 2012)
If you don’t give enough analgesic, you’ll end up unnecessarily giving more sedation
Increase in RASS scores, systolic, and diastolic blood pressure in mechanically ventilated patients receiving sedation only when compared to patients also receiving analgesia (Jeitziner 2012)”
Not all mechanically ventilated patients require sedatives.
A randomized controlled trial of 140 patients: patients in the solo analgesia group had statistically significantly more days without mechanical ventilation and on average shorter ICU length of stays. (Strom 2010)
Use of succinylcholine compared to longer acting NM blocking agents for RSI associated with higher likelihood of post RSI sedation. (Lembersky 2019)
CNS and peripheral tissue
Mu- 1 receptor binding: analgesia
Mu-2 receptors: respiratory depression, vomiting, constipation, and euphoria
Kappa receptor: sedation, miosis, and spinal analgesia
Provide mild anxiolysis, but no amnesia
Good for dyspneic and suppresses cough reflex
Little cardiovascular effect in euvolemic patients
In hypovolemic patients with reduced cardiac output, decreased venous return, reduced sympathetic tone, and reduction in heart rate can result in hypotension
Synergistic effect on hemodynamics (ie. hypotension) and sedation when coupled with benzos
MOA: NMDA receptor antagonist, phencyclidine derivative
Analgesic and sedative
Great for the status asthmaticus (relaxes bronchial smooth muscle)
Great for the hypotensive patient
Contraindicated in hypertension, cardiovascular disease, high intracranial pressure (controversial), preeclampsia, glaucoma, seizure (lower seizure threshold) and history of psychosis (altered mood/delirium), laryngospasm
MOA: central α2 agonist similar to clonidine, but more specific
Analgesia and sedation
Provides sedation and analgesic without respiratory depression
Provides lighter sedation, great for delirium and best to use when attempted to extubate
Bradycardia and hypotension if titrated too quickly
Extensive hepatic metabolism
MOA: g-aminobutyric acid (GABA) receptor CNS blockade
Anxiolytic with sedative and hypnotic effects at increasing doses
Subtle drug-drug interaction because of above
Propylene glycol toxicity with some
Some data suggesting worse outcomes with benzos compared to propofol or dexmedetomidine: delirium, oversedation, delayed extinction and longer time to discharge
Have to be mindful in patients with hepatic and renal dysfunction
MOA: Unclear mechanism; GABAergic effects on CNS
Lipophilic: onset in seconds/minutes with redistribution to peripheral tissues and a large volume of distribution
Powerful anxiolytic and amnestic
Allows for serial neurologic assessments due to rapidity of action, ease of titration, and lack of active metabolites
Preferred in TBI as may decrease cerebral oxygen consumption and reduce ICP
Can cause hypotension, particularly in under-volume-resuscitated patients
Lactic acidosis, hypertriglyceridemia, propofol infusion syndrome
Special Case: Bad Liver
56-year-old male with alcohol abuse without known cirrhosis, HTN, DM, HLD with history of DTs and withdrawal seizures. He is being transferred to your ICU for acute liver failure. On arrival, he is confused and becomes more agitated, confused, tachycardic, and hypertensive, and a decision is made to administer medications. What would you try, and why?
Overnight he becomes acutely hypoxic to 70s and develops respiratory distress. A decision is made to intubate him. What would you give, and why?
Opioids and Anesthetics
Opioids are successfully used in patients with liver diseases, and Fentanyl is the drug of choice for these patients. As the average dosage of drug is used, oxygen content of the liver and liver blood flow are not affected [14, 16].
Among the drugs used for induction of anesthesia, propofol is the drug of choice in patients with liver diseases . As a rule, any type of long-acting local anesthetic in patients with cirrhosis should be avoided. Fentanyl from narcotics, lorazepam and oxazepam from sedatives, along with some volatile anesthetic agent such as Sevoflurane or intravenous anesthetics such as propofol are recommended in these patients [18-20].
The ‘LOT’ drugs are those metabolized mostly by conjugation:
L – Lorazepam
O – Oxazepam
T – Temazepam
These do not have active metabolites, and the half-life remains relatively the same even in the setting of liver disease.
The rest of the benzodiazepines are primarily metabolized via hepatic CYP-mediated oxidation. These may have prolonged duration of effect in patients with marked liver impairment, particularly the drugs with active metabolites such as diazepam, clonazepam, and midazolam. Some practitioners like to take advantage of the longer duration of action and active metabolites. Others prefer to have more predictable kinetics in patients with liver disease and stick with the ‘LOT’ options.
Special Case: Bad Kidney
78-year-old female with CKD stage 4 (nearing ESRD), HTN, HLD, and DM2 admitted to the ICU for pneumonia. In your ED she becomes hypoxic and confused and is subsequently intubated. Your colleagues have made you aware she will be boarding in the ED because the ICU has no beds yet. She was intubated with rocuronium and etomidate. Her BPs have been soft despite 2L fluids; MAP is 60. You’re about to place your orders s/p intubation. What are you choosing, and why?
Go hard on those opioids
Add a pressor
Sedation in patients with severe RD shows poorer outcomes
Midazolam has delayed metabolism/elimination in renal impairment and should be avoided
Dexmedetomidine has been used and is effective
The Current Recommendations
Start with picking your analgesic:
Opioids, dexmedetomidine, ketamine
If you must pick a sedative:
Propofol over benzos in cardiac surgery patients, neurosurgical patients, any other cardiac/neuro dysfunction, and hepatic dysfunction
Dexmedetomidine over benzos in surgical and medical patients
Benzos over propofol/dexmedetomidine in alcohol withdrawal
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