|Year : 2020 | Volume
| Issue : 1 | Page : 5-8
Adjunctive continuous ketamine infusion to conventional sedation in mechanically ventilated patients: It is time for a randomized trial
Mohammed Bawazeer1, Marwa Amer2, Khalid Maghrabi3, Kamel Al-Sheikh3, Rashid Amin2, Muhammad Rizwan3, Mohammad Shaban3, Malak Altewerki4, Fawziah Alkhaldi5, Sanaa Alenazi5, Mehreen Bao5, Edward De Vol6, Mohammed Hijazi3
1 Department of Critical Care Medicine (MBC 94), King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
2 Pharmaceutical Care Division, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
3 Department of Critical Care Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
4 Department of Neurosciences, Residency Training Program, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
5 Department of Oncology Liver Nursing, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
6 Department of Biostatistics and Epidemiology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
|Date of Submission||05-Feb-2020|
|Date of Decision||09-Feb-2020|
|Date of Acceptance||13-Mar-2020|
|Date of Web Publication||30-Apr-2020|
Department of Critical Care Medicine (MBC 94), King Faisal Specialist Hospital and Research Centre, P. O. Box 3354, Riyadh 11211
Source of Support: None, Conflict of Interest: None
Managing sedative and analgesic medications is an essential part of critical care medicine. There is a shift toward favoring the use of nonbenzodiazepine agents because of their side effects. There is an increasing interest in using ketamine as an analgo-sedative in the intensive care unit because of its unique pharmacologic properties. A comprehensive literature search was performed to capture all the studies involving ketamine use in critical care. We searched PubMed, EMBASE, and Cochrane databases. We also extracted the references from major review articles and recent guidelines. In this review, we present the most up-to-date studies done on this topic. We also present the proposal for a future multicenter randomized trial through the Saudi Critical Care Trials Group.
Keywords: Analgo-sedation, critical care, ketamine, mechanical ventilation
|How to cite this article:|
Bawazeer M, Amer M, Maghrabi K, Al-Sheikh K, Amin R, Rizwan M, Shaban M, Altewerki M, Alkhaldi F, Alenazi S, Bao M, De Vol E, Hijazi M. Adjunctive continuous ketamine infusion to conventional sedation in mechanically ventilated patients: It is time for a randomized trial. Saudi Crit Care J 2020;4:5-8
|How to cite this URL:|
Bawazeer M, Amer M, Maghrabi K, Al-Sheikh K, Amin R, Rizwan M, Shaban M, Altewerki M, Alkhaldi F, Alenazi S, Bao M, De Vol E, Hijazi M. Adjunctive continuous ketamine infusion to conventional sedation in mechanically ventilated patients: It is time for a randomized trial. Saudi Crit Care J [serial online] 2020 [cited 2020 Jun 1];4:5-8. Available from: http://www.sccj-sa.org/text.asp?2020/4/1/5/283644
Managing sedative and analgesic medications is an essential part of critical care medicine. Although benzodiazepines have been the sedative of choice for many years in critically ill patients, their use has declined recently, with favoring nonbenzodiazepines, such as propofol and dexmedetomidine. This change in practice is based on studies demonstrating the association between benzodiazepines and increased mechanical ventilation (MV) duration, intensive care unit (ICU) length of stay (LOS), and development of delirium. A paradigm shift has, therefore, occurred in the choice of sedative medications in critical care. Maintenance of light sedation in adult critically ill patients has been recommended to improve the patient clinical outcomes, such as shorter duration of MV and shorter ICU LOS.
Due to an increased focus on ensuring that pain is adequately controlled before using sedative medications (also known as the analgo-sedation approach), ketamine has gained attention for its unique pharmacologic properties that could address both the analgesic and sedative requirements. Ketamine could result in a decreased duration of MV while providing optimal levels of sedation. Similar to dexmedetomidine, ketamine has a non-GABAergic mechanism of action. It induces rapid sedation and analgesia through dual mechanisms mediated by inhibition of the N-methyl-D-aspartate receptor and activation of the opioid u and ƙ receptors. Ketamine has favorable characteristics, including bronchodilation, preservation of cardiac output, increase in blood pressure, minimal effects on bowel motility, and maintains respiratory rate and airway reflexes during weaning from MV; this makes it an excellent option where there is respiratory and hemodynamic instability.,
In a double-blind, randomized controlled trial (RCT) done in one center included 93 ICU postabdominal surgery patients; adjunctive ketamine was associated with the reduced intake of morphine. However, there were no differences in patients' self-reported pain intensity. Ketamine was administered as 0.5 mg/kg IV bolus. Then, an infusion of 2 μg/kg/min for 24 h, and then 1 μg/kg/min for 24 h was administered. The incidence of adverse effects did not differ between the ketamine and opioid-alone groups.
Although commonly used sedatives are effective, they have side effects. This includes delirium due to benzodiazepines, constipation due to opioids, and negative hemodynamic effects caused by propofol and dexmedetomidine.,, The most frequent side effects associated with ketamine use include tachycardia (6.7%), hypertension (6%), paradoxical agitation (up to 20%), and hypersalivation (12%). Risk factors for delirium with ketamine include prior history of psychiatric disorders, dementia, and the use of a high dose in procedural sedation. However, ketamine-based analgo-sedation administered as subanesthetic/subdissociative/low dose has similar rates of days without delirium or coma to nonketamine-based regimens as shown in a retrospective cohort study conducted by Shurtleff et al. at a teaching hospital. Ketamine infusion in this study was administered at a rate of 5 μg/kg/min. The infusion was increased by 5 μg/kg/min increments every 5 min up to a maximum of 25 μg/kg/min. Delirium- and coma-free days were 6 days (interquartile range [IQR]: 2–9 days) in the ketamine group and 4 days (IQR: 3–7 days) in the nonketamine group (P = 0.351). In the ketamine group, 29 patients out of 39 (74%) developed delirium, while in the nonketamine group, delirium occurred in 34 patients out of the 40 (85%), (P = 0.274). Similarly, the study showed that the incidence of adverse effects did not differ between the ketamine and opioid-alone groups.
The 2018 Pain, Analgesia, Delirium, Immobility, and Sedation Guidelines recommended the use of ketamine conditionally, owing to the limited high level of evidence. Most studies listed in [Table 1] are performed in surgical ICU settings and are either retrospective in nature, or RCTs focused on comparing ketamine to placebo or to a single agent (e.g., ketamine vs. opioid). However, most critically ill patients are not sedated with a single agent rather than with combinations. Moreover, most studies had a limited focus on clinical outcomes as the primary outcome, such as the duration of MV or ICU LOS.,,,,,,,, To help further delineate ketamine's role as a maintenance analgo-sedation agent in the ICU, further RCT needs to be conducted to compare the effects of ketamine to other analgesics and sedatives on reducing the duration of MV, ICU LOS, and delirium occurrence. Recently, there was a prospective, double-blinded, multicenter RCT (KeMiMof) in critically ill patients >12 years old and requiring sedation for >24 h in the ICU, in Uganda. The trial was terminated for unknown reasons on August 28, 2019, with pending results. Limitations of this trial are using premixed syringes (ketamine-midazolam or morphine-midazolam), which is not typically used in adult ICU sedation practice and focused on comparing two study drugs (ketamine vs. morphine).
The lack of strong and clear evidence from RCTs has been reflected in the wide variation in the utility of ketamine as a sedative medication in ICU. Therefore, we are now conducting a randomized trial in our ICU. The trial is prospective in nature, actively controlled, open-label, pilot, and feasibility study. It is aimed to assess the efficacy and safety of Analgosedative adjuncT keTAmine Infusion iN Mechanically vENTilated ICU patients (ATTAINMENT trial) compared to the standard of care alone. The primary objective is to study the effect of adjunct low-dose ketamine infusion on MV duration compared to the standard of care alone. The secondary objectives include the cumulative dose of pain and sedative medications, the incidence of dexmedetomidine uses postrandomization, the number of patients are in Richmond Agitation and Sedation Scale and pain score goal, vasopressor therapy requirements, ICU and hospital LOS, tracheostomy, unplanned extubation, and re-intubation rates, the incidence of delirium and rate of positive CAM-ICU, the rate of antipsychotic use for ICU-acquired delirium, and the rate of using physical restraint and mortality rate at 28 days.
In conclusion, the findings of this pilot trial will contribute to a better understanding of the adjunct low-dose ketamine infusion as an analgo-sedative agent and test the feasibility for a larger multicenter, randomized trial that can be done through the Saudi Critical Care Trial Group. The trial will be a double-blinded and placebo-controlled one with adequate power to determine the effect of ketamine infusion as analgo-sedative agent on primary clinical outcomes such as ventilator-free days and mirror other major sedation-related RCTs.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Devlin JW, Skrobik Y, Gélinas C, Needham DM, Slooter AJ, Pandharipande PP, 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.
Patanwala AE, Martin JR, Erstad BL. Ketamine for analgosedation in the intensive care unit: A systematic review. J Intensive Care Med 2017;32:387-95.
Wieruszewski PM, Leung JG, Nelson S. Ketamine use in the intensive care unit. AACN Adv Crit Care 2018;29:101-6.
Guillou N, Tanguy M, Seguin P, Branger B, Campion JP, Mallédant Y. The effects of small-dose ketamine on morphine consumption in surgical intensive care unit patients after major abdominal surgery. Anesth Analg 2003;97:843-7.
Shehabi Y, Howe BD, Bellomo R, Arabi YM, Bailey M, Bass FE, et al
. Early sedation with dexmedetomidine in critically ill patients. N Engl J Med 2019;380:2506-17.
Strayer RJ, Nelson LS. Adverse events associated with ketamine for procedural sedation in adults. Am J Emerg Med 2008;26:985-1028.
Shurtleff V, Radosevich JJ, Patanwala AE. Comparison of ketamine- versus nonketamine-based sedation on delirium and coma in the intensive care unit. J Intensive Care Med 2018. doi: 10.1177/0885066618767619.
Whitman CB, Rhodes H, Tellor BR, Hampton NB. Continuous infusion ketamine for adjunctive sedation in medical intensive care unit patients: A case series. J Anesthesiol Crit Care Med 2015;2:1-5.
Moitra VK, Patel MK, Darrah D, Moitra A, Wunsch H. Low-dose ketamine in chronic critical illness. J Intensive Care Med 2016;31:216-20.
Garber PM, Droege CA, Carter KE, Harger NJ, Mueller EW. Continuous infusion ketamine for adjunctive analgosedation in mechanically ventilated, critically ill patients. Pharmacotherapy 2019;39:288-96.
Pruskowski KA, Harbourt K, Pajoumand M, Chui SJ, Reynolds HN. Impact of ketamine use on adjunctive analgesic and sedative medications in critically ill trauma patients. Pharmacotherapy 2017;37:1537-44.
Buchheit JL, Yeh DD, Eikermann M, Lin H. Impact of low-dose ketamine on the usage of continuous opioid infusion for the treatment of pain in adult mechanically ventilated patients in surgical intensive care units. J Intensive Care Med 2019;34:646-51.
Perbet S, Verdonk F, Godet T, Jabaudon M, Chartier C, Cayot S, et al
. Low doses of ketamine reduce delirium but not opiate consumption in mechanically ventilated and sedated ICU patients: A randomised double-blind control trial. Anaesth Crit Care Pain Med 2018;37:589-95.
Groetzinger LM, Rivosecchi RM, Bain W, Bahr M, Chin K, McVerry BJ, et al
. Ketamine infusion for adjunct sedation in mechanically ventilated adults. Pharmacotherapy 2018;38:181-8.
NCT03407404 Comparing Clinical Outcomes Between Ketamine-midazolam and Morphine-midazolam for Continuous Sedation in ICU Patients. Available from: http://Clinicaltrials. Gov
. [Last accessed on 2019 Sep 25].