Post-Intubation Strategy- Sedation or Pain Control?

Author: Stephen G. Meigher MD, PGY-3
Associate Editor of Emergency Medicine Pharmacology, EMRounds

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Congratulations, a picture perfect intubation! No better way to celebrate than with our two intoxicants of choice – versed and fentanyl…That is, you remembered to plan for post-intubation sedation ahead of time, right? You were meticulous at that, when preparing your 7 P’s and readying your patient for intubation in the resuscitation bay? 

If not, no worries…the patient doesn’t seem bothered. What’s the duration of effect of rocuronium in renal disease again? 

As any good junior resident, you’d be oblivious to patient care without your nursing colleagues at bedside. “Hey, don’t forget to order the RSI meds.” your nurse friend reminds you. “Also, what do you want to give for sedation? I think they’re waking up.”

“Versed” you mutter, fumbling through your pocket drug reference cards….”How much ever we normally give…2 is it? 4 I think?” quietly trailing off, hoping your nearby attending or chief hears your verbal flailing and recites the drip dose for you. 

Their MAP is a little soft- good thing midazolam is fast-off and fast-on no matter the context of the patient, right? 

Respiratory Therapy advises you your patient is “bucking the vent!” Peak pressure is alarming and your patient is over-breathing the machine at a rate of 30 and a tidal volume of 100 cc. 

You’ve found your reference card in time to realize your versed drip is already maxed…looks like this is a problem only propofol can solve.  How much you wonder just before being asked the same- “enough” is your answer. 

Enough? Enough.  

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The above scenario plays out all too often in Emergency Departments and ICUs across the world.  We have all been in this scenario. As a seasoned resident you should be able to list out the failings and fallacies of the above post-intubation regimen.  Furthermore, an exceptional resident physician knows what to do instead and why.  The pitfalls experienced in this case include the following:

• Failure to prepare and select a post-intubation pain management/sedation package prior to induction, paralysis, and intubation.  

• Delayed comfort measures as a result of failed planning leading to patient awareness and discomfort while still paralyzed.  

• Patient-ventilator de-synchronicity and poor mechanical ventilation as a result of patient pain and awareness. 

• Lack of standardized measurement of sedation and comfort with which to titrate analgesic and sedative agents to patient needs.  

• Exclusive use of sedative-hypnotic medications leading to depressed cardiovascular hemodynamics and high-risk for ICU delirium as well as prolonged time to extubation in the ICU.  

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Medications for Ventilator Management 

Post-intubation sedation medications run a spectrum from hypnotics to opioids, IV boluses to continuous drips, and sympatholytics to dissociatives. Benzodiazepines, Opioids, and CNS depressants like Propofol are most commonly used in the Emergency Departments of the United States.  Ketamine has seen a resurgence in use and now Dexmedetomidine ventures into some ED landscapes. 

Opioids for post-intubation sedation and analgesia classically include:

1. Morphine was used more in the yesteryear of Emergency Medicine, especially given in IV push aliquots for patients with impending ICU transfer when an IV drip would take as long to set-up as the ICU bed upstairs.  0.1 mg/kg IVP every 1-2 hours (the usual pain management dose) can be given as needed to ventilated patients who demonstrate discomfort, narcotic-sedation is a secondary effect to pain management.  Morphine demonstrates the most histaminergic activity of the IV opioids and should be used only when cardiovascular depression is tolerable or desired.  Morphine has an onset of effect in 5-10 minutes and a duration of 240 to 300 minutes.  Morphine is eliminated by glucuronidation to inactive metabolites can be given in hepatic disease as well as alongside CYP-inhibiting medications.
   
2. Hydromorphone can be used in IVP aliquots or a continuous drip.  Hydromorphone follows the same rationale as morphine, it can be given in pain-management doses as needed for comfort with narcotic-sedation as a bonus.  0.015 mg/kg IVP (~0.5 to 2 mg) can be given every 1-2 hours as needed.  Hydromorphone has a 5-10 minute onset of effect and lasts for 240-300 minutes.  Alternatively, a continuous drip of 0.5-3 mg/hour can be started to titrate to comfort.  Analgesia and sedation drips can be easily approximated by giving the usual pain-based IVP aliquot dose at an hourly rate.  Hydromorphone too, is metabolized by glucuronidation in the liver and will not be impacted by CYP-inhibiting medications, however it can accumulate in the CNS where it is excitotoxic when given for prolonged periods or in renal or hepatic disease.  Its histaminergic hypotension side effects can be moderate. 
   
3. Fentanyl is commonly used as a continuous drip with a rate of 0.7 to 10 mcg/kg/hour (approximately 50 to 700 mcg per hour).  Fentanyl too can be given as needed in pain-dosed aliquots of 1.5 mcg/kg (25 to 100 mcg) IVP. Fentanyl has the least vasodilation and hypotension due to its synthetic nature and minimal histaminergic cross-reactions.  Fentanyl requires hepatic CYP enzymes for clearance and is lipophilic, accumulating in adipose tissue when used for prolonged periods of time.  Fentanyl demonstrates the least cardiovascular instability of the opioids and is often a superior choice to benzodiazepines in the hypotensive patient.

Benzodiazepines are sedative-hypnotics and provide neither analgesia nor anesthesia and include:

1. Midazolam is run at a 0.02 to 0.1 mg/kg/hour (~1-7 mg/hours) continuous infusion with 2-5 minutes of onset and 30-60 minutes of duration.  Midazolam accumulates when given in high-doses or over long periods of time and its brief duration of affect prolongs dramatically.  It is not fast-on and fast-off as often purported when used for sedation.  Midazolam is cleared by hepatic CYP enzymes, further it is the only benzodiazepine not to be transported in a cardiotoxic propylene glycol medium. It is the preferred benzodiazepine for sedation in the ED as the side effects of lorazepam and diazepam are much more pronounced, as below.  
   
2. Lorazepam is run at 0.02 to 0.6 mg/kg/hour continuous infusion with 15-20 minutes to onset of action and a duration of effect 360 to 480 minutes. Lorazepam can accumulate to provide sedation lasting weeks when used improperly.  It is cleared by glucuronidation. 
   
3. Diazepam is run 0.03 to 0.1 mg/kg/hour with 2-5 minutes of onset and 20-60 minutes of duration of affect. Diazepam is metabolized to active compounds that continue to provide sedation with long half-lives by the hepatic CYP enzymatic system, it is known to produce profound sedation extending well past desired length in the critically ill patient.  

Propofol is a GABA-agonist CNS depressant used for sedation, it acts only as a sedative and offers no hypnosis nor analgesia.  Propofol is given as a continuous drip with a rate of 5-50 mcg/kg/minute, titrated every 5 minutes to desired level of sedation by increasing or decreasing by 5-10 mcg/kg/minute.  Propofol has a rapid onset of approximately 60 seconds with 3 to 10 minutes of duration of effect and is fast-on, fast-off when used for short periods of time.  Propofol is notorious for cardiovascular depression; hypotension and shock frequently preclude its use, but it’s depressant effects have an additional positive side effect profile of decreased cerebral metabolism and cerebral blood flow.  For this, it is often a definitive medication (after intubation) for recalcitrant status epilepticus.  Further side effects and limitations to its use in the ED include hypertriglyceridemia, myocardial depression, and PRIS.  PRIS (Propofol Related Infusion Syndrome) is a poorly understood consequence of high doses (above 4 mg/hour) or long continuous infusion (greater than 48 hours) that manifests with bradycardia, profound metabolic acidosis, cardiovascular collapse, rhabdomyolysis, renal failure, hyperlipidemia, and hepatopathy.  

Ketamine is an NMDA antagonist that induces glutamate expression and CNS inhibition to produce a unique combination of sedation, hypnosis, analgesia, and dissociation, at varying doses.  Ketamine is used at subdissociative doses for sedation and analgesia with a continuous infusion rate of 0.05-0.4 mg/kg/hour (3.5 to 30 mg/hour for a 70 kg patient).  It lasts for approximately 5-15 minutes once discontinued, but may accumulate in renal or hepatic disease due to CYP system metabolism.  Ketamine adds an often favorable catecholamine surge that is known to produce increased blood pressure and transient tachycardia.  It was once unpopular due to increased ICP when used, however this effect has not demonstrated worsened clinical outcomes in those with TBI. (Zeiler et al., 2014).  

Finally, Dexmedetomidine arrives to the emergency department vernacular.  It is infrequently used in emergency medicine, primarily due to its cost on hospital formularies, but is an emerging sedative of choice.  Dexmedetomidine (brand: Precedex, much easier to pronounce) is an alpha2-agonist, analgesic, and sympatholytic that induces CNS sedation easily interrupted by external stimuli. Dexmedetomidine is a desired sedative for ICU patients because it produces intubated patients who sleep comfortably but awaken to verbal stimuli with minimal risk of over-sedation.  Dexmedetomidine is delivered as a continuous IV infusion of 0.2 to 0.7 mcg/kg/hour (15-50 mcg/hour) with 15 minutes of onset and 60-120 minutes of duration.  It has earned itself a name in ICUs across the country for desirable sedation for mechanical ventilation, but has also demonstrated success in treatment of EtOH withdrawal as well as mild sedation for NIPPV.  Hypotension and bradycardia may rarely be seen as side effects, worryingly, they may not resolve with cessation of infusion.   

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Selecting Post-Intubation Comfort Regimens

Consider presenting to the emergency department in respiratory distress or extremis.  In the course of your care, while likely already delirious due to critical illness, you are told you are “going to be put to sleep so we can put a tube down your throat and breath for you.”  Sounds reasonable, all things considered. 

But now, think of waking up minutes to hours to days later with said large plastic tube gagging you, being forced air instead of taking your own breaths, exhaling through a glorified straw, and having no idea where or when you are… 

This is the experience of being sedated for critical care once intubated.  It does not address the significant discomfort of an ETT and further adds medications that promote delirium within a critically ill patient who knows not where or when they exist behind the off-white walls of their ED or ICU room.

It shouldn’t surprise you that it has been demonstrated that pain-first management of intubated patients demonstrates better patient outcomes when compared to titrate-as-you-go sedation-only counterparts. 

This school of thought was first demonstrated in Denmark ICUs. 140 critically-ill, intubated patients were enrolled into a prospective randomized but unblinded clinical trial of sedation versus no sedation. The control group received 48 hours of continuous propofol followed by continuous midazolam infusion until deceased or extubated.  The variable group received neither.  Both cohorts were given IVP 4 mg Morphine aliquots as needed.  After exclusion of the deceased patients and those extubated within 48 hours, the variable arm demonstrated a statistically and clinically significant reduction in continuous days of mechanical ventilation (Strom, Martinussen, and Toft, 2010). Extrapolating from this, in a study of 414 ED patients post-intubation, randomized to propofol, midazolam, or fentanyl treatment groups, those with deeper objective sedation scores demonstrated increased admission mortality when compared to those treated with pain control (Stephens et al, 2017).  This effect is further seen when sedation is provided within 48 hours of intubation and acts independently as a risk factor for all-cause mortality and prolonged ICU stays (Shebabi et al., 2012).  

From the aforementioned research, it is the collective expert consensus with emergency medicine that patients should be kept comfortable immediately post-RSI and intubation and kept comfortable first with targeted pain control, followed by sedation if needed. 

In small retrospective survey studies, up to half of intubated patients remember pain and discomfort during intubation and even after appropriate RSI-doses (Weingart et al., 2013).  Patients intubated in the ED need immediate comfort as many will have prolonged paralysis (and may regain awareness without indication) while awaiting ICU bed placement. 

• Target pain control first, choose opioids as regimented above to treat patient discomfort, or ketamine. 
• Should patients receive appropriate weight-based doses with reduction in autonomic surrogates of pain such as agitation, tachycardia, and hypertension but remain physically labile, add the lowest possible dose of sedation to their regimen. 
• Propofol is an excellent choice if tolerated, midazolam is easily titrated. 
• Treat pain first and foremost! 
• If patients require pain control and sedative agents that compromise their hemodynamics, maintain what is most compassionate and consider providing vasopressors. 
• Choose your post-intubation comfort measures to best match both patient needs and hemodynamic profiles. 

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RASS (Richmond Agitation-Sedation Score)

Sedation should be standardized when used in addition to analgesia regimens.  Standardizing sedation goals and anticipated level of effect help maintain goal-directed orientation of the patient and prevents unrecognized periods of deep sedation with risk for ICU delirium once admitted.  The most popular sedation score is the Richmond Agitation-Sedation Score that is graded from full obtundation (-5) to full awareness and agitation (=4). Its stratified scores are as follows:

• RASS +4: Overly agitated, violent, and combative, immediate threat to self 
• RASS +3: Very agitated, attempts to remove IV lines and ETT
• RASS +2: Agitated, frequent non-purposeful movement or ventilator dyssynchrony
• RASS +1: Anxious, but no aggressive or dangerous movements
• RASS 0: Alert and Calm, redirects and follows commands
• RASS -1: Drowsy, awakens for at least 10 seconds, tracks examiner’s voice
• RASS -2: Light sedation, awakens to voice but for less than 10 seconds
• RASS -3: Moderate sedation, moes to verbal stimuli but does not open eyes
• RASS -4: Deep sedation, moves to physical stimuli, no response to voice
• RASS -5: Obtunded, responds to no stimuli 

The ideal post-intubation RASS should target a score between 0 and -2 at any time.   

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Dosing Regimens

Agent	Bolus Dose	Drip Dose	Positives	Negatives	Metabolism
Morphine	0.1mg/kg	N/A	Readily available	Hypotension	Glucuronidation
Hydromorphone	0.5-2 mg	0.5-3mg/hr	Long duration	Excitotoxic	Glucuronidation
Fentanyl	1-2 mcg/kg(25-100 mcg)	0.7-10 mcg/kg/hour(50-700 mcg/hr)	Minimal vasodilation	CYP interactions	Hepatic CYP enzymes
Midazolam	1-2 mg	0.02-0.1 mg/kg/hr	Rapid onset, no propylene glycol	Accumulates with long drips	Hepatic CYP
Lorazepam	2-4 mg	0.02-0.06 mg/kg/hr	No CYP interactions	Long-acting, easily overdosed	Hepatic Glucuronidation
Diazepam	N/A	0.03-0.1 mg/kg/hour	Rapid onset	Long-acting metabolites	Hepatic CYP
Propofol	1-2 mcg/kg	5-50 mcg/kg/hour	Decreased cerebral metabolism, seizure abortion	Hypotension, PRIS, hyperlipidemia	Hepatic CYP
Ketamine	0.25-0.5 mg/kg	0.05-0.4 mg/kg/hr	Catecholamine surge	Dissociation	Hepatic CYP
Dexmedetomidine	N/A	0.2-0.7 mcg/kg/hour(15-50 mcg/hr)	Sedation with ideal RASS	Expensive, hard to find	Hepatic CYP

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Further Resources

UpToDate Critical Care Analgesia and Sedation

EMCrit Post-Intubation Sedation

EMCrit P A D

EMRA Post-Intubation Analgesia and Sedation

Canadian Journal of EM – Ketamine Safe for Induction in TBI

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References

Shehabi Y, Bellomo R, Reade MC, et al. Early intensive care sedation predicts long-term mortality in ventilated critically ill patients. Am J Respir Crit Care Med. 2012;186(8):724-731. doi:10.1164/rccm.201203-0522OC

Stephens RJ, Ablordeppey E, Drewry AM, et al. Analgosedation Practices and the Impact of Sedation Depth on Clinical Outcomes Among Patients Requiring Mechanical Ventilation in the ED: A Cohort Study. Chest. 2017;152(5):963-971. doi:10.1016/j.chest.2017.05.041

Strøm T, Martinussen T, Toft P. A protocol of no sedation for critically ill patients receiving mechanical ventilation: a randomised trial. Lancet. 2010;375(9713):475-480. doi:10.1016/S0140-6736(09)62072-9

Weingart GS, Carlson JN, Callaway CW, Frank R, Wang HE. Estimates of sedation in patients undergoing endotracheal intubation in US EDs. Am J Emerg Med. 2013;31(1):222-226. doi:10.1016/j.ajem.2012.05.015

Zeiler FA, Teitelbaum J, West M, Gillman LM. The ketamine effect on ICP in traumatic brain injury. Neurocrit Care. 2014;21(1):163-173. doi:10.1007/s12028-013-9950-y