Ketamine for Sedation in the ICU

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           Ketamine for Sedation in the ICU
Ketamine is a versatile anesthetic agent that has been increasingly used for sedation in the intensive care unit setting. Its unique pharmacological properties, including its ability to maintain respiratory drive and cardiovascular stability, make it an attractive option for critically ill patients who require sedation.
Objectives
Mechanism & Adverse Effects
Describe the mechanism of action and adverse effects of Ketamine.
Beneficial Patient Populations
Identify the types of ICU patients that Ketamine infusions could be beneficial to outcomes.
Use Cases & Nursing Administration
Delineate the different patient situations where Ketamine could be used & identify key points regarding nursing administration.
Sedation Protocol Updates
Describe changes to the ICU ABCDEF bundle.
History
1
1962
Ketamine was first synthesized at Parke-Davis as an alternative to phencyclidine and was initially used in veterinary medicine.
2
1964
Ketamine was tested in prisoners.
3
1970
Ketamine was approved and first used in the Vietnam War.
4
Mid 1970s
Illicit use of ketamine, known as "Special K", was first reported in the literature.
5
1999
Ketamine became a controlled substance (Schedule III) in the United States.
Potter DE, Choudhury M. Drug Discovery Today 2014 http://dx.doi.org/10.1016/j.drudis.2014.08.017
Mechanism
Ketamine is a non-competitive antagonist of NMDA receptors, which contributes to its unique pharmacologic profile. At sub-anesthetic doses, it can provide analgesia for both nociceptive and neuropathic pain. However, at higher doses, it can also produce psychotomimetic effects. Ketamine also has sympathomimetic properties, decreasing catecholamine uptake, which can lead to its stimulant effects. Additionally, it has anti-inflammatory effects and can act as a bronchodilator, making it potentially useful in certain ICU settings.
Potter DE, Choudhury M. Drug Discovery Today 2014 http://dx.doi.org/10.1016/j.drudis.2014.08.017
Pharmacology
Potter DE, Choudhury M. Drug Discovery Today 2014 [http://dx.doi.org/10.1016/j.drudis.2014.08.017]
Pharmacokinetics
1
IV/IM
Onset 1-5 minutes
2
IV/IM
Duration 10-15 minutes
3
Sub Cutaneous
Onset 15-30 minutes
4
Sub Cutaneous
Duration 20-40 minutes
5
PO
Onset 30 minutes
6
PO
Duration 4-12 hours
 
Kronenberg RH et al. _J Pain Pall Care Pharmacotherapy_ 2002;16:27-35 Domino EF et al. _Clin Clin Pharmacol Ther_ 1965;6:279-91
What makes Ketamine different?
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Pharmacological Effects
Dosing and Effects:
Dosage and Administration: It's important for nurses to monitor and adjust dosages based on patient response and sedation goals.
High Dose (>1 mg/kg):
Induces cataleptic state
Sedative, dissociation where patients are insentient yet appear alert.
Sensory input is significantly diminished.
Low Dose (0.1 to 0.2 mg/kg):
Mild central nervous system effects.
Provides significant analgesia, ideal for pain management.
These opioid-sparing effects reduce the requirement for opioids and thereby minimize the risks associated with opioid use.
Advantages Over Other Anesthetics:
Maintains cardiovascular stability and does not suppress respiratory drive.
Maintains muscle tone in pharyngeal and laryngeal muscles.
Offers both analgesia and sedation, making it unique among anesthetic agents.
Monitoring 
Continuous monitoring is essential when administering ketamine, especially to observe for potential side effects such as increased blood pressure and heart rate. Nurses should also be vigilant about patients' sedation levels and overall comfort.
Patient Education
Nurses should educate patients and families about the effects of ketamine, particularly its potential to cause unusual sensory experiences or hallucinations, ensuring they understand these effects are typically transient.
Safety Profile
While ketamine is generally safe with a low incidence of serious adverse effects, it's crucial to use it cautiously in patients with a history of cardiovascular issues or those who are at risk of psychiatric disturbances.
Brown, K., & Tucker, C. (2020). Ketamine for acute pain management and sedation. Critical Care Nurse, 40(5), e26-e33. https://doi.org/10.4037/ccn2020419
Potter DE, Choudhury M. Drug Discovery Today 2014 http://dx.doi.org/10.1016/j.drudis.2014.08.017
Ketamine-Induced Adverse Effects
CNS:
hallucinations, delirium, vivid dreams, emergence phenomenon
Pulmonary:
laryngospasm, increased secretions
CV:
hypertension, tachyarrhythmias, negative inotrope in heart failure patients
GI/GU:
nausea/vomiting, hepatic damage (long term use), ulcerative cystitis (long term use)
Psychotomimetic Effects: Ketamine is known for its psychotomimetic properties, which are particularly evident when patients emerge from a dissociative state. These effects can manifest as transient increases in symptoms resembling schizophrenia (both positive and negative symptoms), dissociative symptoms, and manic behaviors. Typically, these symptoms appear during administration but resolve within 60 minutes.
Optimizing the Administration Environment:
To minimize the occurrence of these adverse effects, it is beneficial to administer ketamine in a calm and quiet environment. Such measures have been shown to significantly reduce the incidence of distressing experiences in patients.
Dosage and Patient History Considerations:
Adverse effects on the central nervous system are more commonly observed in patients who:
Receive ketamine doses exceeding 2 mg/kg per dose.
Are administered ketamine at a high infusion rate (greater than 40 mg/min).
Have a preexisting psychiatric condition.
Psychological Effects:
Patients may also experience other psychological effects, including feelings of intoxication, confusion, lowered inhibition, and perceptual disturbances such as hallucinations and delusions.
Cardiovascular Risks and Special Precautions: Ketamine should be used with caution in patients with cardiovascular conditions such as cardiac ischemia, coronary artery disease, or acute cardiogenic shock. Ketamine can increase blood pressure, heart rate, and cardiac output, potentially worsening these conditions. Close monitoring and readiness to adjust the dosing are crucial in managing these risks.
Management of CNS Effects and Delirium: Nurses should be vigilant for signs of central nervous system disturbances, delirium, or severe agitation in patients receiving ketamine. Dose adjustments or the use of adjunctive medications may be necessary to manage these symptoms effectively. Additionally, if excessive secretions are noted, the use of anticholinergic medications may be warranted.
Emergence Phenomenon and Delirium Risks: A notable occurrence during ketamine administration is the 'emergence phenomenon'. Patients may report experiences such as feelings of floating, vivid dreams (both pleasant and distressing), and delirium. While there is controversy regarding the long-term neurological effects of ketamine, including its potential to increase the risk of delirium, current research, indicates that the incidence of delirium does not significantly differ between ketamine and placebo groups. However, patients receiving ketamine might experience increased hallucinations and nightmares. The concern for delirium remains significant in the ICU as it is associated with negative outcomes, but rates of delirium-free days are comparable between ketamine-based infusions and nonbenzodiazepine sedatives. Further research is necessary to fully understand these associations.
Summary: While ketamine is an effective anesthetic and analgesic, its use in the ICU must be carefully managed to mitigate its psychotomimetic, cardiovascular, and central nervous system effects. Awareness and understanding of these potential adverse effects are crucial for ICU nurses to ensure optimal patient care during and after ketamine administration.
Increased ICP
1970's – reports of elevated intracranial pressure
Large increases up to 1600 mmH20 accompanied by bradycardia, apnea
Branded ketamine with a contraindication
Misinterpretations in the early studies
Largest ICP elevations and all sequelae occurred in patients with preexisting hydrocephalus (ICP <20)
CPP is maintained or improved despite absolute increases in ICP
Many recent studies show no effect on ICP
Green SM et al. Ann Emerg Med 2014 pii: S0196-0644(14)01224-4 
Cohen L et al. Ann Emerg Med 2014 pii: S0196-0644(14)00529-0
Current Clinical Uses
Chronic/palliative analgesia
ICU sedation and analgesia
Intubation
Rapid Sequence Intubation
Delayed Sequence Intubation
Procedural sedation
Refractory status epilepticus
Potter DE, Choudhury M. Drug Discovery Today 2014 http://dx.doi.org/10.1016/j.drudis.2014.08.017
ICU Sedation and Analgesia
Mechanically Ventilated
Ketamine can be used for sedation and analgesia in mechanically ventilated patients in the ICU.
Opioid Tolerant
Ketamine can be beneficial for patients who are opioid tolerant, as it can reduce the need for other sedatives and analgesics.
Hemodynamic Instability
Ketamine can help increase mean arterial pressure (MAP) and decrease the use of vasopressors in patients with hemodynamic instability.
Bronchospasm
Ketamine can increase chest wall compliance, decrease airway resistance, reduce peak inspiratory pressures, increase PaO2, decrease PaCO2, and decrease wheezing and bronchodilator use in patients with bronchospasm.
ICU Sedation in Mechanically Ventilated Patients
- Dose: 
0.5-1 mg/kg bolus, can be given IVP by a nurse in mechanically ventilated patients
0.1-4.5 mg/kg/hr given via IV pump (Alaris soft max: 2 mg/kg/hr) 
- Titration (can be titrated by a nurse in mechanically ventilated patients):
 - Initiate infusion at ordered starting dose
- Titrate to SAS of 3-4 - If sedation scale > ordered goal increase infusion by 0.1 to 0.5 mg/kg/hr every 30 minutes (titration dose will be chosen by provider on order) 
- If SAS score at goal for 12 hours at same infusion rate or if SAS < goal, decrease infusion by 0.1-0.5 mg/kg/hr (titration dose chosen by provider on order) 
- Notify provider if dose exceeds 2 mg/kg/hr or if hemodynamically unstable or for significant secretions or worsening delirium
ICU Sedation and Analgesia in Mechanically Ventilated Patients
Two RNs verify order and program pump
Monitoring:
Increased secretions
Increases in HR and BP
Delirium screening with CAM-ICU
Eyes may remain open, however patient may not be conscious
ICU Pain and Sedation Guidelines
This guideline refers to the use of ketamine as an adjunctive sedative/analgesic agent in MECHANICALLY VENTILATED patients for ICU sedation.
Use of ketamine for the treatment of intractable pain in NON-INTUBATED patients is outside of our current scope
Clinical situations where ketamine may be appropriate:
Opioid tolerance due to its analgesic effects as well as its ability to reduce central sensitization
Status asthmaticus/COPD due to its bronchodilation effects
Hemodynamic instability due to its sympathomimetic effects
Produces a cataleptic state where eyes may remain open
ICU Pain and Sedation Guidelines
USE WITH CAUTION:
Patients with hypertension and/or tachycardia, decompensated heart failure, pulmonary hypertension
Patients with or at risk for delirium/psychiatric illness, may exacerbate or cause delirium
Patients with increased intraocular pressure
Usual dose for sedation/analgesia in MECHANICALLY VENTILATED patients:
Bolus: 0.5-1 mg/kg can be given prior to starting the infusion
Start infusion: 0.5-1 mg/kg/hr with the usual range being 0.1-4.5 mg/kg/hr (Alaris soft max: 2 mg/kg/hr)
Please note this dose range is much higher than what is used for the treatment of intractable pain in NON- INTUBATED patients
Opioid sparing doses are typically 0.05-0.5 mg/kg/hr
Dose can be increased by 0.25-0.5 mg/kg/hr every 30 minutes to achieve a SAS of 4 or NVPS ≤ 3
Consider slower titration of 0.1 mg/kg/hr if using lower doses (0.05-0.5 mg/kg/hr)
Bolus dose and titration can be performed by a nurse who has completed the required education in MECHANICALLY VENTILATED patients.
Monitor for increased secretions, hypertension, tachycardia, hypotension (catecholamine depleted), emergence reaction (dreams, hallucinations, delirium), withdrawal with prolonged use (taper to off)
NYS Regulations for Nursing Administration in Setting of Sedation/Analgesia for Mechanically Ventilated Patients
NYS memorandum on IV anesthetic agents and recommendations from board of nursing state these agents should only be administered by an anesthesia trained provider or nurse who is deemed competent through education.
A nurse can administer and titrate a continuous infusion of ketamine for the purpose of sedation and analgesia in a MECHANICALLY VENTILATED patient after completing competency and education.
Status Epilepticus (SE)
Benefits
Apparent correlation between ketamine and cessation of SE
Unique mechanism may be useful in refractory SE due to resistance seen with traditional anti-epileptics
Very few adverse effects – especially compared to anti-epileptics
Limitations
Limited data indicating a benefit (56% effective)
Part of multidrug regimen
Wide array of doses/routes of administration
Unsure of best time to start it
Usual Dose
3 to 5 mg/kg/hr
Two RNs should verify dose and program the pump
NYS Regulations for Nursing Administration in Setting of Status Epilepticus
Specific recommendations do not exist. A nurse can administer a continuous infusion of ketamine for the purpose of treating status epilepticus in a MECHANICALLY VENTILATED patient after completing competency and education. However, a nurse can NOT titrate a continuous infusion of ketamine for this indication. An order for all dose changes must be placed by a provider.
Alaris Programming
Two RNs should verify dose and program pump
Wild card option with dose limits:
Occasionally a non-standard concentration of 10 mg/ml may be required to reduce fluid volume in patients with increased weight or dose requirements
Always double check the concentration on the bag with the order and the Alaris profile
Conclusions
Ketamine is a dissociative anesthetic and analgesic with a very complex pharmacologic profile. Historically, it has not been used due to risks for psychological effects, but its use is increasing as we become more familiar with its pharmacologic effects. Ketamine has clinical utility for ICU patients, particularly for intubation of septic or hemodynamically unstable patients, as well as for sedation of opioid-tolerant patients, those with bronchospasm, and those with hemodynamic instability.