Article
Low-Dose Ketamine in Chronic Critical Illness
Journal of Intensive Care Medicine 1-5 ª The Author(s) 2015 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0885066615587868 jic.sagepub.com
Vivek K. Moitra, MD1, Mona K. Patel, Pharm D2, Daniela Darrah, MD1, Alika Moitra, JD3, and Hannah Wunsch, MD, MSc4
Abstract We report a case series on the observed effects of low-dose ketamine infusions in 4 critically ill patients with varying complications related to prolonged critical illness. Doses of ketamine infusion ranged from 0.5 to 4 mg/kg/min. A low-dose ketamine infusion was used to reduce agitation in a patient requiring high doses of sedatives and analgesics. In a second patient, ketamine improved depression and anxiety symptoms. In a third patient, ketamine may have facilitated liberation from mechanical ventilation. In a fourth patient, ketamine was used for palliation to avoid lethargy. Ketamine may be considered to help decrease agitation, manage pain, facilitate opioid and benzodiazepine withdrawal, prevent respiratory depression, and potentially manage depression and anxiety in chronically critically ill patients. Keywords sedation, analgesia, ketamine, depression, chronic critical illness
Introduction Patients with chronic critical illness face a range of problems that are challenging to manage such as pain, anxiety, delirium, depression, opiate and benzodiazepine withdrawal, and ventilator weaning. Sedatives and analgesics are used to combat some of these problems. However, these medications are associated with unwanted side effects such as respiratory depression, lethargy, risk of subsequent withdrawal symptoms, delirium, and hyperalgesia. A little over 40 years ago, ketamine became popular for neuroleptanesthesia, a state of dissociative anesthesia in which the patient appears to be calm and nonreactive to pain, with maintained airway reflexes.1,2 But its popularity waned because of an undesirable side effect profile including hallucinations and delirium. Recent research, however, suggests that psychotomimetic effects are unlikely when subanesthetic or ‘‘low-dose’’ ketamine is administered.3-7 We describe 4 critically ill patients who received ‘‘low-dose’’ ketamine to manage common yet challenging problems faced by chronically critically ill patients.
Case Reports Patient 1 A 62-year-old male patient with a history of alcoholic cirrhosis and encephalopathy developed acute respiratory distress syndrome (ARDS) 9 days after orthotopic liver transplantation, requiring tracheostomy. During his prolonged mechanical ventilation, the patient attempted to pull out his central venous catheter line and monitoring devices. He required wrist restraints and
escalating doses of opioids, benzodiazepines, and antipsychotic medications to manage his severe delirium and agitation. Daily trials of awakening and ventilator weaning were unsuccessful. His altered mental status was thought to be due to a combination of underlying disease as well as dependence on opiates and benzodiazepines. Two days prior to initiation of ketamine, he was receiving 184 mg of intravenous morphine equivalents (fentanyl and methadone) and 450 mg of quetiapine daily in an attempt to manage his delirium and agitation (see Table 1). He was started on a subanesthetic dose of ketamine (4 mg/kg/min). After 24 hours, his medication requirements decreased substantially as his agitation improved (see Figure 1). Psychomimetic symptoms were not observed. Moreover, his quetiapine dose decreased from 100 to 150 mg/day and opioids
1
Department of Anesthesiology, College of Physicians & Surgeons, Columbia University, New York, NY, USA 2 Department of Pharmacy, New York Presbyterian Hospital, Columbia University, New York, NY, USA 3 Department of Pharmacy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, USA 4 Department of Anesthesia, University of Toronto, Toronto, Ontario, Canada
Received January 25, 2015, and in revised form April 15, 2015. Accepted for publication April 16, 2015. Corresponding Author: Vivek K. Moitra, Department of Anesthesiology, College of Physicians & Surgeons, Columbia University Medical Center, New York, NY 10032, USA. Email: [email protected]
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Table 1. Sedative, Analgesic, Antipsychotic Medication Administration Summary.
Patient
Ketamine Dose, mg/kg/min
Ketamine Duration, h
Total Daily Dose of Medications Prior to Ketamine Infusion
Total Daily Dose of Medications Total Daily Dose of Medications During Ketamine Infusion After Ketamine Infusion
1
Day 1: 4 Day 2: 1
49
Day 3: Quetiapine 450 mg orally Haloperidol 12.5 mg IV ME 154 mg IV Day 2: Quetiapine 450 mg orally Haloperidol 15 mg IV ME 184 mg IV Day 1: Quetiapine 450 mg orally Haloperidol 0 mg ME 109 mg IV
Day 1: Quetiapine 450 mg orally Haloperidol 30 mg IV ME 80 mg IV Day 2: Quetiapine 450 mg orally Haloperidol 25 mg IV ME 45 mg IV
Day þ1: Quetiapine 450 mg orally Haloperidol 5 mg IV ME 0 mg IV Day þ2: Quetiapine 450 mg orally Haloperidol 10 mg IV ME 0 mg IV Day þ3: Quetiapine 150 mg orally Haloperidol 5 mg IV ME 0 mg IV
2
Day 1: 3 Day 2: 2 Day 3: 2
70
Day 3: None Day 2: None Day 1: Lorazepam 0.5 mg IV
Day 1: None Day 2: Lorazepam 0.5 mg IV Day 3: None
Days þ1 to þ3: None
3
Days 1-4: 2 Day 5: 0.5 Day 6: 1
142
Days 3 to 1: None
Day 1: None Days 2-6: Paroxetine 20 mg orallya
Days þ1 to þ3: Paroxetine 20 mg orallya
4
Days 1-6: 1
141
Day 3: DEX 94 mg IV ME 21 mg IV Day 2: DEX 540 mg IV ME 20 mg IV Day 1: DEX 1035 mg ME 19 mg IV
Days 1-6: DEX 0 mg IV ME 0 mg IV
Days þ1 to þ3: DEX 0 mg IV ME 0 mg IV
Abbreviations: ME, morphine equivalents; DEX, dexmedetomidine; IV, intravenous. a Outpatient regimen.
Patient 2
Figure 1. Effect of low-dose ketamine on RASS (Richmond Agitation Sedation Scale).
were discontinued 3 days after initiating the ketamine infusion. The ketamine infusion was discontinued 49 hours after initiation, and the patient was discharged from the intensive care unit (ICU) 60 days after admission.
A 55-year-old man was hospitalized with ARDS secondary to influenza requiring extra corporeal membrane oxygenation and developed chronic critical illness. After liberation from the ventilator, he complained of severe anxiety and feelings of hopelessness, despite administration of lorazepam (see Table 1). We administered the Hospital Anxiety and Depression Scale (HADS) to assess the severity of mood symptoms.8 He scored 21 (maximal) on the anxiety domain (HADS-A) and 12 for depression (HADS-D; above the threshold of 11 for symptoms consistent with depression). He was started on an infusion of ketamine at 3 mg/kg/min. After 24 hours of ketamine, his HADS-A score decreased to 15 and his HADS-D score to 9 (see Figure 2). On the third day of ketamine infusion, the patient’s wife commented that his mood was the best it had been for many weeks. He did not report any psychotomimetic effects during the infusion. Twenty-four hours after the infusion was stopped, he scored 18 on the anxiety domain
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Moitra et al
3 up to 4 mg of intravenous hydromorphone daily (30 mg of intravenous morphine equivalents; see Table 1). The family, however, was concerned by the lethargy that was associated with her analgesic regimen and expressed their wish to be able to have more meaningful interactions with the patient. Hydromorphone was stopped for 2 days, but the alternative of substantial pain was ultimately deemed unacceptable. We initiated a low-dose ketamine infusion (1 mg/kg/min), with substantial improvement in her pain control accompanied by minimal lethargy. The family expressed satisfaction with their ability to interact with the patient in a meaningful way without the emotional distress associated with seeing her in pain. The patient ultimately died in the ICU.
Discussion Figure 2. Effect of low-dose ketamine on depression and anxiety.
and 8 on the depression domain, representing a 21% decrease from the baseline.
Patient 3 A 64-year-old woman with a history of emphysema and recent pneumonia, major depressive disorder, and generalized anxiety with panic symptoms underwent lung volume reduction surgery. She failed extubation twice and received a tracheostomy 7 days after surgery. Ventilator weaning was difficult because of the patient’s anxiety and sensitivity to sedation, with resultant hypercarbia. The patient was evaluated daily for liberation from mechanical ventilation via a tracheostomy collar. Trials of ventilator liberation were unsuccessful because of cycles of tachypnea, anxiety, wheezing, and agitation, followed by hypercapnia and apnea after any attempt at pharmacologic treatment (including benzodiazepines, dexmedetomidine, and antipsychotic agents). We initiated a low-dose ketamine (2 mg/ kg/min) infusion to manage the patient’s anxiety and minimize the respiratory depression (see Table 1). Two and a half days after initiation of the ketamine infusion, the patient’s mood improved, wheezing decreased, and the patient was liberated from the ventilator. Psychomimetic symptoms were not observed. The ketamine infusion was discontinued after the completion of ventilator weaning.
Patient 4 A 62-year-old female patient with adenocarcinoma of the bladder and cirrhosis underwent a cystectomy. Her postoperative course was complicated by the development of abdominal abscesses, multisystem organ failure, and candidemia. She was not intubated, and, after consultation with the family, her goals of care were changed to comfort measures only. The patient had a significant amount of abdominal pain and was receiving
We propose that intravenous infusion of ketamine at a low dose has unique analgesic and sedative properties that should be considered in critically ill patients, particularly those with chronic critical illness to allay a variety of problems, including agitation, pain, opioid and benzodiazepine withdrawal, respiratory depression associated with sedatives, and to potentially mitigate anxiety and depression. At these low doses, the plasma concentrations are lower than the plasma concentrations that are known to produce psychomimetic side effects.4-7 Agitated, delirious, and anxious patients with prolonged stays in the ICU, such as patients 1, 2, and 3, are at risk of complications such as device pulling, increased oxygen consumption, failure to participate in therapeutic interventions (ie, physical therapy and ventilator weaning), and ultimately dependence on sedative medications, which may then worsen the cycle of agitation and sedation. Although data on the use of ketamine in critically ill patients are limited, current sedation guidelines suggest that administration of nonbenzodiazepines such as dexmedetomidine may reduce the duration of delirium and improve clinical outcomes.9 The initiation of a low dose of ketamine may have improved patient 1’s agitation for several reasons. First, surgical patients and patients with trauma and patients who undergo painful procedures in the ICU experience prolonged noxious stimuli that can cause central sensitization (the ‘‘windup’’ phenomenon) and lead to a chronic pain syndrome. By antagonizing the N-methyl-D-aspartate (NMDA) receptor, a gate of pain perception, ketamine blocks NMDAmediated nociceptive impulses, inhibits the brain’s response to noxious stimuli, reducing ‘‘windup’’ pain and central hyperexcitability, and may prevent the development of chronic pain.10-13 Second, ketamine decreases the incidence of opioidinduced hyperalgesia.14-19 Although the incidence of hyperalgesia in critically ill patients is unknown and difficult to measure, short-term opioid administration can induce hyperalgesia and allodynia which can increase anxiety, agitation, and delirium. Third, the NMDA receptor has been implicated in the development of tolerance to opioids, and after initiation of ketamine, the most potent inhibitor of the NMDA receptor available, we were able to quickly decrease other medications
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(ie, methadone, fentanyl, and quetiapine) that may have been contributing to the agitation.19 Depression and anxiety are common among critically ill patients. Several recent randomized controlled trials and case series have found that a single infusion of a subanesthetic dose of ketamine can rapidly improve symptoms in patients with treatment refractory major depressive disorder.20,21 After 24 hours of ketamine, patient 2 had an improvement in his symptoms of depression and anxiety. Although subanesthetic ketamine is commonly used during the perioperative period, its role as an antidepressant and anxiolytic among critically ill patients warrants further exploration. Liberating anxious patients from mechanical ventilation is challenging because they can be caught in a cycle of anxiety, pharmacologic treatment, and subsequent sedation that does not allow for safe weaning. In patient 3, low doses of lorazepam and dexmedetomidine caused unacceptable lethargy. In critically ill patients, the respiratory response to ketamine may facilitate ventilator weaning. Ketamine causes bronchodilation and has been used to manage patients with status asthmaticus.22-25 Ketamine also preserves functional residual capacity, minute ventilation, and tidal volume and enhances thoracic compliance.26-28 Low doses of ketamine may have a role in allowing patients to feel more relaxed and cooperative with ventilator changes while remaining alert with a normal respiratory drive. In spite of a systematic review which found insufficient evidence to evaluate ketamine’s effectiveness as an adjuvant to opioid treatment in cancer pain, reports of ketamine’s potential to relieve end-of-life cancer and neuropathic pain with minimal side effects have been published.29-31 Ketamine has been used as an analgesic and as an antidepressant in the palliative care setting.32,33 Moreover, data from studies of comprehensive end-of-life care demonstrate that both patients and families endorse the importance of mental awareness and lucidity.34 Achieving patient and family satisfaction goals, without sacrificing pain control because of concerns about hastening death through medications that depress respiratory drive and cause hypercarbia in nonintubated patients, remains a struggle for most clinicians. Low-dose ketamine in patient 4 did not cause the lethargy or respiratory depression that would have been observed with opioid therapy. The patient was responsive, with an acceptable level of pain control. Our case series has several limitations. We did not assess for psychomimetic symptoms in any systematic way. Further study is warranted to investigate potential psychomimetic symptoms that may develop after initiation of subanesthetic ketamine in critically ill patients. Concerns about using ketamine in the ICU stemmed from its association with hallucinations and unpleasant emergence recall, which could itself create anxiety and potentially lead to long-term distress. However, low doses of ketamine are not known to cause these effects. Moreover, data to support long-term psychological sequelae with ketamine are sparse. Our initial experiences suggest that ketamine may have a role in the management of chronically critically ill patients with anxiety, pain, and depression. In all 4 patients, significant effects were noted within 24 hours. It is rare that an ‘‘old’’ drug
is revisited in the midst of the development of new pharmaceutical agents as pharmaceutical companies advocate using the latest on-patent medications. As the number of patients with chronic critical illness continue to increase, we propose that ketamine, a novel ‘‘old’’ therapeutic agent, may be useful in the management of many of these patients and warrants further investigation. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
References 1. Domino EF, Chodoff P, Corssen G. Pharmacologic effects of Ci-581, a new dissociative anesthetic, in Man. Clin Pharmacol Ther. 1965;6:279-291. 2. Malchow RJ, Black IH. The evolution of pain management in the critically ill trauma patient: emerging concepts from the global war on terrorism. Crit Care Med. 2008;36(suppl 7):S346-S357. 3. Bell RF, Dahl JB, Moore RA, Kalso E. Perioperative ketamine for acute postoperative pain. Cochrane Database Syst Rev. 2006;(1): CD004603. 4. Himmelseher S, Durieux ME. Ketamine for perioperative pain management. Anesthesiology. 2005;102(1):211-220. 5. Bowdle TA, Radant AD, Cowley DS, Kharasch ED, Strassman RJ, Roy-Byrne PP. Psychedelic effects of ketamine in healthy volunteers: relationship to steady-state plasma concentrations. Anesthesiology. 1998;88(1):82-88. 6. Hartvig P, Valtysson J, Lindner KJ, et al. Central nervous system effects of subdissociative doses of (S)-ketamine are related to plasma and brain concentrations measured with positron emission tomography in healthy volunteers. Clin Pharmacol Ther. 1995; 58(2):165-173. 7. Tucker AP, Kim YI, Nadeson R, Goodchild CS. Investigation of the potentiation of the analgesic effects of fentanyl by ketamine in humans: a double-blinded, randomised, placebo controlled, crossover study of experimental pain [ISRCTN83088383]. BMC Anesthesiol. 2005;5(1):2. 8. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand. 1983;67(6):361-370. 9. Barr J, Fraser GL, Puntillo K, 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. 10. Wang C, Sadovova N, Patterson TA, et al. Protective effects of 7-nitroindazole on ketamine-induced neurotoxicity in rat forebrain culture. Neurotoxicology. 2008;29(4):613-620. 11. Li J, Simone DA, Larson AA. Windup leads to characteristics of central sensitization. Pain. 1999;79(1):75-82. 12. Guirimand F, Dupont X, Brasseur L, Chauvin M, Bouhassira D. The effects of ketamine on the temporal summation (wind-up) of the R(III) nociceptive flexion reflex and pain in humans. Anesth Analg. 2000;90(2):408-414.
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13. Latremoliere A, Woolf CJ. Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J Pain. 2009; 10(9):895-926. 14. Mao J, Price DD, Mayer DJ. Mechanisms of hyperalgesia and morphine tolerance: a current view of their possible interactions. Pain. 1995;62(3):259-274. 15. Angst MS, Clark JD. Opioid-induced hyperalgesia: a qualitative systematic review. Anesthesiology. 2006;104(3):570-587. 16. Stubhaug A, Breivik H, Eide PK, Kreunen M, Foss A. Mapping of punctuate hyperalgesia around a surgical incision demonstrates that ketamine is a powerful suppressor of central sensitization to pain following surgery. Acta Anaesthesiol Scand. 1997;41(9): 1124-1132. 17. Celerier E, Rivat C, Jun Y, et al. Long-lasting hyperalgesia induced by fentanyl in rats: preventive effect of ketamine. Anesthesiology. 2000;92(2):465-472. 18. Joly V, Richebe P, Guignard B, et al. Remifentanil-induced postoperative hyperalgesia and its prevention with small-dose ketamine. Anesthesiology. 2005;103(1):147-155. 19. Kissin I, Bright CA, Bradley EL, Jr. The effect of ketamine on opioid-induced acute tolerance: can it explain reduction of opioid consumption with ketamine-opioid analgesic combinations? Anesth Analg. 2000;91(6):1483-1488. 20. Rasmussen KG, Lineberry TW, Galardy CW, et al. Serial infusions of low-dose ketamine for major depression. J Psychopharmacol. 2013;27(5):444-450. 21. Zarate CA Jr, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63(8):856-864. 22. Park GR, Manara AR, Mendel L, Bateman PE. Ketamine infusion. Its use as a sedative, inotrope and bronchodilator in a critically ill patient. Anaesthesia. 1987;42(9):980-983. 23. Sarma VJ. Use of ketamine in acute severe asthma. Acta Anaesthesiol Scand. 1992;36(1):106-107.
24. Youssef-Ahmed MZ, Silver P, Nimkoff L, Sagy M. Continuous infusion of ketamine in mechanically ventilated children with refractory bronchospasm. Intensive Care Med. 1996;22(9):972-976. 25. Hemming A, MacKenzie I, Finfer S. Response to ketamine in status asthmaticus resistant to maximal medical treatment. Thorax. 1994;49(1):90-91. 26. Shulman D, Beardsmore CS, Aronson HB, Godfrey S. The effect of ketamine on the functional residual capacity in young children. Anesthesiology. 1985;62(5):551-556. 27. Tokics L, Strandberg A, Brismar B, Lundquist H, Hedenstierna G. Computerized tomography of the chest and gas exchange measurements during ketamine anaesthesia. Acta Anaesthesiol Scand. 1987;31(8):684-692. 28. Mankikian B, Cantineau JP, Sartene R, Clergue F, Viars P. Ventilatory pattern and chest wall mechanics during ketamine anesthesia in humans. Anesthesiology. 1986;65(5):492-499. 29. Prommer EE. Ketamine for pain: an update of uses in palliative care. J Palliat Med. 2012;15(4):474-483. 30. Taylor M, Jakacki R, May C, Howrie D, Maurer S. Ketamine PCA for treatment of end-of-life neuropathic pain in pediatrics [published online July 15, 2014]. Am J Hosp Palliat Care. 2014. 31. Bell RF, Eccleston C, Kalso EA. Ketamine as an adjuvant to opioids for cancer pain. Cochrane Database Syst Rev. 2012;11: CD003351. 32. Kerr C, Holahan T, Milch R. The use of ketamine in severe cases of refractory pain syndromes in the palliative care setting: a case series. J Palliat Med. 2011;14(9):1074-1077. 33. Legge J, Ball N, Elliott DP. The potential role of ketamine in hospice analgesia: a literature review. Consult Pharm. 2006;21(1): 51-57. 34. Steinhauser KE, Christakis NA, Clipp EC, McNeilly M, McIntyre L, Tulsky JA. Factors considered important at the end of life by patients, family, physicians, and other care providers. JAMA. 2000;284(19):2476-2482.
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Low-Dose Ketamine in Chronic Critical Illness
Journal of Intensive Care Medicine 1-5 ª The Author(s) 2015 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0885066615587868 jic.sagepub.com
Vivek K. Moitra, MD1, Mona K. Patel, Pharm D2, Daniela Darrah, MD1, Alika Moitra, JD3, and Hannah Wunsch, MD, MSc4
Abstract We report a case series on the observed effects of low-dose ketamine infusions in 4 critically ill patients with varying complications related to prolonged critical illness. Doses of ketamine infusion ranged from 0.5 to 4 mg/kg/min. A low-dose ketamine infusion was used to reduce agitation in a patient requiring high doses of sedatives and analgesics. In a second patient, ketamine improved depression and anxiety symptoms. In a third patient, ketamine may have facilitated liberation from mechanical ventilation. In a fourth patient, ketamine was used for palliation to avoid lethargy. Ketamine may be considered to help decrease agitation, manage pain, facilitate opioid and benzodiazepine withdrawal, prevent respiratory depression, and potentially manage depression and anxiety in chronically critically ill patients. Keywords sedation, analgesia, ketamine, depression, chronic critical illness
Introduction Patients with chronic critical illness face a range of problems that are challenging to manage such as pain, anxiety, delirium, depression, opiate and benzodiazepine withdrawal, and ventilator weaning. Sedatives and analgesics are used to combat some of these problems. However, these medications are associated with unwanted side effects such as respiratory depression, lethargy, risk of subsequent withdrawal symptoms, delirium, and hyperalgesia. A little over 40 years ago, ketamine became popular for neuroleptanesthesia, a state of dissociative anesthesia in which the patient appears to be calm and nonreactive to pain, with maintained airway reflexes.1,2 But its popularity waned because of an undesirable side effect profile including hallucinations and delirium. Recent research, however, suggests that psychotomimetic effects are unlikely when subanesthetic or ‘‘low-dose’’ ketamine is administered.3-7 We describe 4 critically ill patients who received ‘‘low-dose’’ ketamine to manage common yet challenging problems faced by chronically critically ill patients.
Case Reports Patient 1 A 62-year-old male patient with a history of alcoholic cirrhosis and encephalopathy developed acute respiratory distress syndrome (ARDS) 9 days after orthotopic liver transplantation, requiring tracheostomy. During his prolonged mechanical ventilation, the patient attempted to pull out his central venous catheter line and monitoring devices. He required wrist restraints and
escalating doses of opioids, benzodiazepines, and antipsychotic medications to manage his severe delirium and agitation. Daily trials of awakening and ventilator weaning were unsuccessful. His altered mental status was thought to be due to a combination of underlying disease as well as dependence on opiates and benzodiazepines. Two days prior to initiation of ketamine, he was receiving 184 mg of intravenous morphine equivalents (fentanyl and methadone) and 450 mg of quetiapine daily in an attempt to manage his delirium and agitation (see Table 1). He was started on a subanesthetic dose of ketamine (4 mg/kg/min). After 24 hours, his medication requirements decreased substantially as his agitation improved (see Figure 1). Psychomimetic symptoms were not observed. Moreover, his quetiapine dose decreased from 100 to 150 mg/day and opioids
1
Department of Anesthesiology, College of Physicians & Surgeons, Columbia University, New York, NY, USA 2 Department of Pharmacy, New York Presbyterian Hospital, Columbia University, New York, NY, USA 3 Department of Pharmacy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, USA 4 Department of Anesthesia, University of Toronto, Toronto, Ontario, Canada
Received January 25, 2015, and in revised form April 15, 2015. Accepted for publication April 16, 2015. Corresponding Author: Vivek K. Moitra, Department of Anesthesiology, College of Physicians & Surgeons, Columbia University Medical Center, New York, NY 10032, USA. Email: [email protected]
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Table 1. Sedative, Analgesic, Antipsychotic Medication Administration Summary.
Patient
Ketamine Dose, mg/kg/min
Ketamine Duration, h
Total Daily Dose of Medications Prior to Ketamine Infusion
Total Daily Dose of Medications Total Daily Dose of Medications During Ketamine Infusion After Ketamine Infusion
1
Day 1: 4 Day 2: 1
49
Day 3: Quetiapine 450 mg orally Haloperidol 12.5 mg IV ME 154 mg IV Day 2: Quetiapine 450 mg orally Haloperidol 15 mg IV ME 184 mg IV Day 1: Quetiapine 450 mg orally Haloperidol 0 mg ME 109 mg IV
Day 1: Quetiapine 450 mg orally Haloperidol 30 mg IV ME 80 mg IV Day 2: Quetiapine 450 mg orally Haloperidol 25 mg IV ME 45 mg IV
Day þ1: Quetiapine 450 mg orally Haloperidol 5 mg IV ME 0 mg IV Day þ2: Quetiapine 450 mg orally Haloperidol 10 mg IV ME 0 mg IV Day þ3: Quetiapine 150 mg orally Haloperidol 5 mg IV ME 0 mg IV
2
Day 1: 3 Day 2: 2 Day 3: 2
70
Day 3: None Day 2: None Day 1: Lorazepam 0.5 mg IV
Day 1: None Day 2: Lorazepam 0.5 mg IV Day 3: None
Days þ1 to þ3: None
3
Days 1-4: 2 Day 5: 0.5 Day 6: 1
142
Days 3 to 1: None
Day 1: None Days 2-6: Paroxetine 20 mg orallya
Days þ1 to þ3: Paroxetine 20 mg orallya
4
Days 1-6: 1
141
Day 3: DEX 94 mg IV ME 21 mg IV Day 2: DEX 540 mg IV ME 20 mg IV Day 1: DEX 1035 mg ME 19 mg IV
Days 1-6: DEX 0 mg IV ME 0 mg IV
Days þ1 to þ3: DEX 0 mg IV ME 0 mg IV
Abbreviations: ME, morphine equivalents; DEX, dexmedetomidine; IV, intravenous. a Outpatient regimen.
Patient 2
Figure 1. Effect of low-dose ketamine on RASS (Richmond Agitation Sedation Scale).
were discontinued 3 days after initiating the ketamine infusion. The ketamine infusion was discontinued 49 hours after initiation, and the patient was discharged from the intensive care unit (ICU) 60 days after admission.
A 55-year-old man was hospitalized with ARDS secondary to influenza requiring extra corporeal membrane oxygenation and developed chronic critical illness. After liberation from the ventilator, he complained of severe anxiety and feelings of hopelessness, despite administration of lorazepam (see Table 1). We administered the Hospital Anxiety and Depression Scale (HADS) to assess the severity of mood symptoms.8 He scored 21 (maximal) on the anxiety domain (HADS-A) and 12 for depression (HADS-D; above the threshold of 11 for symptoms consistent with depression). He was started on an infusion of ketamine at 3 mg/kg/min. After 24 hours of ketamine, his HADS-A score decreased to 15 and his HADS-D score to 9 (see Figure 2). On the third day of ketamine infusion, the patient’s wife commented that his mood was the best it had been for many weeks. He did not report any psychotomimetic effects during the infusion. Twenty-four hours after the infusion was stopped, he scored 18 on the anxiety domain
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Moitra et al
3 up to 4 mg of intravenous hydromorphone daily (30 mg of intravenous morphine equivalents; see Table 1). The family, however, was concerned by the lethargy that was associated with her analgesic regimen and expressed their wish to be able to have more meaningful interactions with the patient. Hydromorphone was stopped for 2 days, but the alternative of substantial pain was ultimately deemed unacceptable. We initiated a low-dose ketamine infusion (1 mg/kg/min), with substantial improvement in her pain control accompanied by minimal lethargy. The family expressed satisfaction with their ability to interact with the patient in a meaningful way without the emotional distress associated with seeing her in pain. The patient ultimately died in the ICU.
Discussion Figure 2. Effect of low-dose ketamine on depression and anxiety.
and 8 on the depression domain, representing a 21% decrease from the baseline.
Patient 3 A 64-year-old woman with a history of emphysema and recent pneumonia, major depressive disorder, and generalized anxiety with panic symptoms underwent lung volume reduction surgery. She failed extubation twice and received a tracheostomy 7 days after surgery. Ventilator weaning was difficult because of the patient’s anxiety and sensitivity to sedation, with resultant hypercarbia. The patient was evaluated daily for liberation from mechanical ventilation via a tracheostomy collar. Trials of ventilator liberation were unsuccessful because of cycles of tachypnea, anxiety, wheezing, and agitation, followed by hypercapnia and apnea after any attempt at pharmacologic treatment (including benzodiazepines, dexmedetomidine, and antipsychotic agents). We initiated a low-dose ketamine (2 mg/ kg/min) infusion to manage the patient’s anxiety and minimize the respiratory depression (see Table 1). Two and a half days after initiation of the ketamine infusion, the patient’s mood improved, wheezing decreased, and the patient was liberated from the ventilator. Psychomimetic symptoms were not observed. The ketamine infusion was discontinued after the completion of ventilator weaning.
Patient 4 A 62-year-old female patient with adenocarcinoma of the bladder and cirrhosis underwent a cystectomy. Her postoperative course was complicated by the development of abdominal abscesses, multisystem organ failure, and candidemia. She was not intubated, and, after consultation with the family, her goals of care were changed to comfort measures only. The patient had a significant amount of abdominal pain and was receiving
We propose that intravenous infusion of ketamine at a low dose has unique analgesic and sedative properties that should be considered in critically ill patients, particularly those with chronic critical illness to allay a variety of problems, including agitation, pain, opioid and benzodiazepine withdrawal, respiratory depression associated with sedatives, and to potentially mitigate anxiety and depression. At these low doses, the plasma concentrations are lower than the plasma concentrations that are known to produce psychomimetic side effects.4-7 Agitated, delirious, and anxious patients with prolonged stays in the ICU, such as patients 1, 2, and 3, are at risk of complications such as device pulling, increased oxygen consumption, failure to participate in therapeutic interventions (ie, physical therapy and ventilator weaning), and ultimately dependence on sedative medications, which may then worsen the cycle of agitation and sedation. Although data on the use of ketamine in critically ill patients are limited, current sedation guidelines suggest that administration of nonbenzodiazepines such as dexmedetomidine may reduce the duration of delirium and improve clinical outcomes.9 The initiation of a low dose of ketamine may have improved patient 1’s agitation for several reasons. First, surgical patients and patients with trauma and patients who undergo painful procedures in the ICU experience prolonged noxious stimuli that can cause central sensitization (the ‘‘windup’’ phenomenon) and lead to a chronic pain syndrome. By antagonizing the N-methyl-D-aspartate (NMDA) receptor, a gate of pain perception, ketamine blocks NMDAmediated nociceptive impulses, inhibits the brain’s response to noxious stimuli, reducing ‘‘windup’’ pain and central hyperexcitability, and may prevent the development of chronic pain.10-13 Second, ketamine decreases the incidence of opioidinduced hyperalgesia.14-19 Although the incidence of hyperalgesia in critically ill patients is unknown and difficult to measure, short-term opioid administration can induce hyperalgesia and allodynia which can increase anxiety, agitation, and delirium. Third, the NMDA receptor has been implicated in the development of tolerance to opioids, and after initiation of ketamine, the most potent inhibitor of the NMDA receptor available, we were able to quickly decrease other medications
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Journal of Intensive Care Medicine
(ie, methadone, fentanyl, and quetiapine) that may have been contributing to the agitation.19 Depression and anxiety are common among critically ill patients. Several recent randomized controlled trials and case series have found that a single infusion of a subanesthetic dose of ketamine can rapidly improve symptoms in patients with treatment refractory major depressive disorder.20,21 After 24 hours of ketamine, patient 2 had an improvement in his symptoms of depression and anxiety. Although subanesthetic ketamine is commonly used during the perioperative period, its role as an antidepressant and anxiolytic among critically ill patients warrants further exploration. Liberating anxious patients from mechanical ventilation is challenging because they can be caught in a cycle of anxiety, pharmacologic treatment, and subsequent sedation that does not allow for safe weaning. In patient 3, low doses of lorazepam and dexmedetomidine caused unacceptable lethargy. In critically ill patients, the respiratory response to ketamine may facilitate ventilator weaning. Ketamine causes bronchodilation and has been used to manage patients with status asthmaticus.22-25 Ketamine also preserves functional residual capacity, minute ventilation, and tidal volume and enhances thoracic compliance.26-28 Low doses of ketamine may have a role in allowing patients to feel more relaxed and cooperative with ventilator changes while remaining alert with a normal respiratory drive. In spite of a systematic review which found insufficient evidence to evaluate ketamine’s effectiveness as an adjuvant to opioid treatment in cancer pain, reports of ketamine’s potential to relieve end-of-life cancer and neuropathic pain with minimal side effects have been published.29-31 Ketamine has been used as an analgesic and as an antidepressant in the palliative care setting.32,33 Moreover, data from studies of comprehensive end-of-life care demonstrate that both patients and families endorse the importance of mental awareness and lucidity.34 Achieving patient and family satisfaction goals, without sacrificing pain control because of concerns about hastening death through medications that depress respiratory drive and cause hypercarbia in nonintubated patients, remains a struggle for most clinicians. Low-dose ketamine in patient 4 did not cause the lethargy or respiratory depression that would have been observed with opioid therapy. The patient was responsive, with an acceptable level of pain control. Our case series has several limitations. We did not assess for psychomimetic symptoms in any systematic way. Further study is warranted to investigate potential psychomimetic symptoms that may develop after initiation of subanesthetic ketamine in critically ill patients. Concerns about using ketamine in the ICU stemmed from its association with hallucinations and unpleasant emergence recall, which could itself create anxiety and potentially lead to long-term distress. However, low doses of ketamine are not known to cause these effects. Moreover, data to support long-term psychological sequelae with ketamine are sparse. Our initial experiences suggest that ketamine may have a role in the management of chronically critically ill patients with anxiety, pain, and depression. In all 4 patients, significant effects were noted within 24 hours. It is rare that an ‘‘old’’ drug
is revisited in the midst of the development of new pharmaceutical agents as pharmaceutical companies advocate using the latest on-patent medications. As the number of patients with chronic critical illness continue to increase, we propose that ketamine, a novel ‘‘old’’ therapeutic agent, may be useful in the management of many of these patients and warrants further investigation. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
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