Icahn School of Medicine at Mount Sinai, New York, NY, USA
Clinical pharmacology
Context‐sensitive half‐time (CSHT) is defined as the duration of time required for plasma concentrations of a drug to decrease by 50% after discontinuing administration of the drug. ‘Context’ is meant to refer to the duration of time that an infusion has been running.
The CSHT is often different from the elimination half‐time and explains differences in duration of effect that exist based on how long an infusion is running versus the effect we see with a single bolus dose of a medication. As an example, if we were to believe that elimination half‐time determined the duration of effect of propofol, then a single bolus should leave our patient obtunded for several hours. Instead we know that a single bolus will wear off in a few minutes due to redistribution of the medication out of the central compartment into the periphery.
Likewise, the CSHT also explains why medications take longer for their effects to wear off after longer infusions. A simplified, if not perfectly scientific, explanation is that anesthetic drug effects wear off as medications redistribute from the central to the peripheral compartments. However, over time, the peripheral compartments can approach saturation, causing the central compartment to refill or maintain a steady state as its concentration decreases. Each drug has a different volume of periphery that it can fill at a different rate. Accordingly, we see that a medication like remifentanil which has virtually no CSHT will wear off in a few minutes regardless of the administration duration, while midazolam may take days after a sufficiently long infusion.
Monitoring
Sedation
Two methods have been well validated for monitoring sedation levels with equivalent results:
The Richmond Agitation‐Sedation Scale (Table 2.1) extends from –5 (unarousable) to +4 (combative) with zero representing a calm and alert patient. A typical goal is a light sedation of –1 to –2.
The Riker Sedation‐Agitation Scale (Table 2.2), extends from 1 (unarousable) to 7 (dangerous agitation), with 4 representing the calm and alert patient. A typical goal is a light sedation of 3.
Objective monitoring modalities such as EEG, bispectral index, or patient state index are not recommended by the Society of Critical Care Medicine guidelines as a regular monitoring tool. However, if the patient is paralyzed (through neuromuscular blockers or clinical condition), then use of an objective monitoring device is suggested.
Pulling at endotracheal tube, trying to remove catheters, striking staff
6
Very agitated
Does not calm down despite verbal instructions, requires physical restraints
5
Agitated
Anxious or mildly agitated, calms with verbal instructions
4
Calm and cooperative
Arouses easily and follows commands
3
Sedated
Does arouse to verbal or physical stimulus, able to follow simple commands
2
Very sedated
Does not follow commands but arouses to physical stimulation
1
Unarousable
Little or no response to noxious stimuli
Pain
Use of a validated pain scale is recommended for identifying treatment needs. Both verbal and non‐verbal scales should be used based on the patient’s condition.
A numeric ranking scale is a subjective method of ranking pain. A typical method is the visual analog scale which uses a line 10 cm long with every centimeter marked as a number. The patient is asked to rank their pain along this scale, with 10 being the worst possible pain. For patients who are cognitively unable to make this association, the faces pain scale is an option with a series of six faces with differing expressions of distress shown. The patient is asked to point to the face that most approximates their current state.
An objective pain scale can also be used as many patients are unable to actively participate in their own pain assessment due to intubation and sedation or cognitive problems. The two best validated methods are the behavioral pain scale (BPS) and the critical care pain observation tool (CPOT). Additionally, the CPOT has recently been shown to be valid in patients with traumatic brain injury.
The BPS is comprised of three domains: facial expression, upper limb movement, and compliance with ventilation, each scored from 1 through 4. A total score of 5 or less is considered acceptable pain control.
The CPOT is comprised of four domains: facial expression, body movements, compliance with the ventilator or vocalization, and muscle tension, each scored from 0 to 2 with a total possible score of 8.
Medications for sedation and analgesia
Recommended doses are from the Society of Critical Care Medicine (SCCM) 2013 Pain, Agitation, and Delirium Guidelines.
Opioids
Considered the first line analgesic by the SCCM guidelines for ICU patients.
As a class, they have some sedative properties when given in high enough doses, but have no amnestic effects.
Side effects are reasonably universal and include respiratory depression, hypotension, itching, nausea and vomiting, miosis, and decreased gastric motility.
Choice of opioid and dosage must be tailored to the individual patient. For example, a 24‐year‐old patient in a trauma ICU who was actively taking suboxone at the time of admission may require an order of magnitude more opioid for the first 24 hours than a 72‐year‐old patient with renal failure.
Fentanyl
Pharmacology:
Synthetic opioid with no active metabolites.
Broken down through the CYP3A4 pathway, with a potential for prolonged effect with certain chemotherapy agents.
Highly lipid soluble.
Onset of action 1–2 minutes, duration of effect ~40 minutes.
Elimination half‐life 2–4 hours.
CSHT is 200 minutes after a 6 hour infusion, and 300 minutes or greater after a 12 hour infusion (this can increase unpredictably in multiorgan failure).
Drug‐specific side effects:
Chest wall rigidity: a very uncommon side effect of synthetic opioids that can be complicated by glottic closure and trismus. Appears somewhat related to dosage, rapidity of administration, extremes of age, presence of critical illness, and use of antidepressant medications. Can render a patient unable to ventilate. Requires immediate reversal with naloxone and preparations for emergent intubation with a neuromuscular blocker. If no further complications are noted (e.g. negative pulmonary pressure edema due to closed glottis), extubation can be attempted within minutes of cessation of rigidity and neuromuscular blockade. This is not an allergic reaction and does not preclude the patient from receiving this analgesic agent in the future.
Onset of action 15–20 minutes, duration of effect 1–2 hours.
Elimination half‐life 3–11 hours.
Drug‐specific side effects:
Typical solutions contain propylene glycol that can cause metabolic acidosis and acute kidney injury when run as an infusion. A serum osmolar gap greater than 10–12 mOsm/L suggests propylene glycol toxicity.
Recommended doses:
Bolus: 0.02–0.04 mg/kg (maximum dose 2 mg) every 2–6 hours as required.
Infusion (generally not recommended): 0.01–0.1 mg/kg/h (maximum dose <10 mg/h).
Diazepam
Pharmacology:
Active metabolites.
Onset of action 2–5 minutes IV, peak effect 1‐2 hours, duration of effect variable but typically 4–6 hours.
Can be given per rectum for seizure treatment if no intravenous access.
Elimination half‐life 20+ hours due to active metabolites.
Drug‐specific side effects:
Respiratory depression.
Phlebitis.
Uses propylene glycol as solvent.
Accumulation of metabolites in renal failure.
Recommended doses:
Bolus: 5–10 mg IV.
PRN dosing: 0.03–0.1 mg/kg every 0.5–6 hours.
Rectal dose for seizures: 0.2 mg/kg seizures, every 4–12 hours as required, status epilepticus 0.5 mg/kg bolus and 0.25 mg/kg every 10 minutes as required.
Other sedatives
Propofol
Pharmacology:
Predominantly agonist at GABA receptor.
Hypnotic, antiemetic, and anticonvulsant.
No analgesic properties.
98% protein bound.
No active metabolites.
Onset of action 1–2 minutes, duration of effect 5–10 minutes.
Propofol is delivered in a fat emulsion that provides 1.1 kcal/mL. This should be considered when adjusting enteral and parenteral nutritional requirements.
Side effects:
Vasodilation and hypotension.
Myocardial depression.
Respiratory depression.
Pancreatitis.
Propofol infusion syndrome:
A potentially lethal syndrome marked by metabolic acidosis, hypertriglyceridemia, and hypotension refractory to vasopressors.
Believed due to mitochondrial dysfunction.
Treatment is cessation of infusion and supportive.
Associated with prolonged infusions of greater than 70 μg/kg/min.
Incidence of propofol infusion syndrome 1%, mortality 33%.
Recommended doses:
Bolus: 0.1–0.3 mg/kg slowly.
Infusion: 5–50 μg/kg/min.
Dexmedetomidine
Pharmacology:
Alpha‐2 receptor agonist.
Minimal respiratory depression.
Hypnotic and analgesic properties.
No active metabolites.
Onset of action after loading dose 5–10 minutes.
Side effects:
Hypertension: often associated with loading doses.
Hypotension: often associated with loading doses.
Bradycardia.
Recommended doses:
Loading dose: 1 μg/kg over 10 minutes.
Infusion: FDA approved for 0.2–0.7 μg/kg/h for up to 24 hours; reports have shown safety with maximum infusion 1.5 μg/kg/h for up to 1 month.
Miscellaneous:
No proven benefit to delirium.
Ketamine
Pharmacology:
NMDA antagonist.
Hypnotic and analgesic.
Active metabolite norketamine.
There should be no expectation of decreased opioid use or rates of delirium after a single intraoperative dose of ketamine.
Onset of action 30–40 seconds.
Elimination half‐life 2–3 hours.
Side effects:
Increased salivation.
Potential for increased intracranial pressure (ICP)
Potential for sympathetic discharge.
Hallucinations: can be attenuated by simultaneous administration of benzodiazepine.
Negative inotropy: may be harmful in heart failure patients; further research is warranted.
Recommended doses:
Bolus: 0.1–0.5 mg/kg IV.
Infusion: 0.05–0.4 mg/kg/h.
Reading list
Barr J, et al. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med 2013; 41(1):263–306.
Devlin JW, et al. Clinical practice guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the ICU. Crit Care Med 2018; 46:e825–73.
Joffe AM, McNulty B, Boitor M, Marsh R, Gélinas C. Validation of the critical‐care pain observation tool in brain‐injured critically ill adults. J Crit Care 2016; 36:76–80.
Khan BA, et al. Comparison and agreement between the Richmond Agitation‐Sedation Scale and the Riker Sedation‐Agitation Scale in evaluating patients’ eligibility for delirium assessment in the ICU. Chest 2012; 142(1):48–54.
Kotifs K, Zegan‐Baranska M, Szydlowski L, Zukowski M, Ely EW. Methods of pain assessment in adult intensive care unit patients – Polish version of CPOT (Critical Care Pain Observation Tool) and BPS (Behavioral Pain Scale). Anaesthesiol Intensive Ther 2017; 49(1):66–72.
Parker AM, Sricharoenchai T, Raparla S, Schneck KW, Bienvenu OJ, Needham DM. Posttraumatic stress disorder in critical illness survivors. Crit Care Med 2015; 43(5):1121–9.
Patanwala AE, Martin JR, Erstad BL. Ketamine for analgosedation in the intensive care unit: a systematic review. J Intensive Care Med 2017; 32(6):387–95.
Payen J, et al. Assessing pain in critically ill sedated patients by using a behavioral pain scale. Crit Care Med 2001; 29(12):2258–63.
Reade MC, et al. for the DahLIA Investigators and the Australian and New Zealand Intensive Care Society Clinical Trials Group. Effect of dexmedetomidine added to standard care on ventilator‐free time in patients with agitated delirium: a randomized clinical trial. JAMA 2016; 315(14):1460–8.
Turunen H, et al. Dexmedetomidine versus standard care sedation with propofol or midazolam in intensive care: an economic evaluation. Crit Care 2015; 19(1):67.
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