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A Non-Comparative Prospective Pilot Study of Ketamine for Sedation in Adult Septic Shock

A Non-Comparative Prospective Pilot Study of Ketamine for Sedation in Adult Septic Shock Downloaded from https://academic.oup.com/milmed/article/183/11-12/e409/5003004 by DeepDyve user on 19 July 2022 MILITARY MEDICINE, 183, 11/12:e409, 2018 A Non-Comparative Prospective Pilot Study of Ketamine for Sedation in Adult Septic Shock MAJ Jason M. Reese, MC USA*; CPT Victoria Fernandes Sullivan, MC USA†; MAJ Nathan L. Boyer, MC USA‡; LTC Cristin A. Mount, MC USA* ABSTRACT Introduction: Sedation and analgesia in the intensive care unit (ICU) for patients with sepsis can be challenging. Opioids and benzodiazepines can lower blood pressure and decrease respiratory drive. Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist that provides both amnesia and analgesia without depressing respi- ratory drive or blood pressure. The purpose of this pilot study was to assess the effect of ketamine on the vasopressor requirement in adult patients with septic shock requiring mechanical ventilation. Materials and Methods: We conducted a two-phase study in a multi-disciplinary adult ICU at a tertiary medical center. The first phase was a retrospective chart review of patients admitted with septic shock between July 2010 and July 2011; 29 patients were identified for a historical control group. The second phase was a prospective, non-randomized, open-label pilot study. Patients were eligible for inclusion if they were 18–89 yr of age with a diagnosis of septic shock, who also required mechanical ven- tilation for at least 24 h, concomitant sedation, and vasopressor therapy. Pregnant patients, patients in the peri-operative timeframe, and patients with acute coronary syndrome were excluded. Patients enrolled in the phase two pilot study received ketamine as the primary sedative. Ketamine was administered as a 1–2 mg/kg IV bolus, then as a continuous infusion starting at 5 mcg/kg/min, titrated 2 mcg/kg/min every 30 min as needed to obtain a Richmond Agitation Sedation Scale (RASS) goal of −1to −2. If continuous sedation was still required after 48 h, patients were transitioned off ketamine and sedative strategy reverted to usual ICU sedation protocol. The primary outcome was the dose of vaso- pressor required at 24, 48, 72 and 96 h after enrollment. Secondary outcomes included cumulative ketamine dose, addi- tional sedative and analgesics used, cumulative sedative and analgesic dosing at all time periods, corticosteroid use, days of mechanical ventilation, ICU LOS, hospital LOS, and mortality. Contiguous data were analyzed with unpaired t-tests and categorical data were analyzed with two-tailed, Fisher’s exact test. This study was approved by our Institutional Review Board. Results: From January 2012 to April 2015, a total of 17 patients were enrolled. Patient characteristics were similar in the control and study group. Ketamine was discontinued in one patient due to agitation at 36 h. There was a trend towards decreased norepinephrine and vasopressin use in the study group at all time periods. Regarding secondary outcomes, the study group received less additional analgesia with fentanyl at 24 and 48 h (p < 0.001), and less additional sedation with lorazepam, midazolam or dexmedetomidine at 24 h (p = 0.015). Conclusion: This pilot study demonstrated a trend towards decreased vasopressor dose, and decreased benzodiazepine and opiate use when ketamine is used as the sole sedative. The limitations to our study include a small sample size and those inherent in using a retrospective control group. Our findings should be further explored in a large, randomized prospec- tive study. INTRODUCTION Ketamine is an N-methyl-D-aspartate (NMDA) receptor Sedation and analgesia in the intensive care unit (ICU) for antagonist, classified as a dissociative anesthetic, providing patients with sepsis and tenuous hemodynamics can be chal- both amnesia and analgesia. At therapeutic doses, the respi- lenging. Opioids and benzodiazepines can contribute to the ratory drive is preserved, with a chronotropic effect on the pathophysiology of shock by exacerbating poor tissue perfusion cardiovascular system, mediated by the sympathetic nervous through reduced cardiac contractility, and increased vasodilation system, inhibition of adenosine tri-phosphate-sensitive chan- 1,2 as well as reducing the respiratory drive. nels, direct inhibitory action on smooth muscle cells, and modulation of vascular tone through endothelial interac- 3–7 *Department of Medicine, Madigan Army Medical Center, 9040 tions. The rise in systolic and diastolic blood pressure Jackson Ave, Joint Base Lewis-McChord, WA 98431. occurs within minutes of administration, and can increase the †Department of Medicine, Walter Reed National Military Medical 8 blood pressure from 10-50% above the pre-anesthetic levels. Center, 8901 Rockville Pike, Bethesda, MD 20889. An intriguing aspect of ketamine is its potential anti- ‡Department of Medicine, Womack Army Medical Center, 2817 Reilly inflammatory properties. In some studies, ketamine has been Road, Fort Bragg, NC 28310. The views expressed are solely those of the authors and do not reflect shown to reduce IL-6 and TNF-alpha, reduce leukocyte the official policy or position of the Department of the Army, Department of recruitment, potentiate adenosine and increase myocardiac Defense, or the U.S. Government. cAMP levels, down regulate pro-inflammatory markers such doi: 10.1093/milmed/usy121 as iNOS and COX-2 and up regulate anti-inflammatory mar- Published by Oxford University Press on behalf of the Association of 9,10 kers such as heme oxygenase-1. Additionally, in rat mod- Military Surgeons of the United States 2018. This work is written by (a) US Government employee(s) and is in the public domain in the US. els exposed to sepsis, ketamine not only reduced the MILITARY MEDICINE, Vol. 183, November/December 2018 e409 Downloaded from https://academic.oup.com/milmed/article/183/11-12/e409/5003004 by DeepDyve user on 19 July 2022 production of inflammatory cytokines but also lead to known allergy to ketamine and patients with acute coronary 11,12 improved survival of the rats. syndrome were excluded. Ketamine is widely used in pediatrics for continuous and This study was approved by our Institutional Review procedural sedation, but is also gaining popularity in adult Board. All patients provided consent for inclusion via surro- patient populations. There is some evidence that ketamine gate medical decision maker, and were again contacted after has been used successfully for sedation in status asthmaticus, their ICU course to obtain consent to remain in the study. in burn patients undergoing multiple surgeries, and for anes- 13–17 thesia in coronary artery bypass graft surgery. Ketamine Study Procedures is also used more frequently in trauma populations and is Patients enrolled in the phase two pilot study received keta- now listed in the Military’s Tactical Combat Casualty care mine as the primary sedative for 48 h or less, if the indication (TCCC) guidelines for patients suffering from hemorrhagic for continuous sedation changed. Ketamine was administered shock. Currently, there are no published reports of the rou- as a 1–2 mg/kg IV bolus, then as a continuous infusion start- tine use of ketamine for primary sedation in an adult medical ing at 5 mcg/kg/min with a titration of 2 mcg/kg/min every ICU population in the setting of sepsis. Limited case reports 30 min as needed to obtain a Richmond Agitation Sedation have demonstrated the benefits of ketamine in the ICU environ- Scale (RASS) goal of 1 to −2. If continuous sedation was still 19,20 ment however this is tempered by non-randomized reports required after 48 h, patients were transitioned off ketamine 21,22 of adverse effects of ketamine in severely ill patients. and transitioned to usual ICU sedation protocol which favored The purpose of this pilot study was to assess the effect of benzodiazepine or dexmedetomidine infusion, fentanyl for ketamine on the vasopressor requirement in adult medical pain and a sedation goal of 1 to −2onthe RASS.Attending patients with septic shock requiring mechanical ventilation. physicians could discontinue ketamine or substitute additional sedative and analgesic agents at any point during the study as MATERIALS AND METHODS they deemed clinically necessary. The ketamine administra- tion protocol and usual sedation protocol are included in the Participants Supplementary material. We conducted a two-phase study in a multi-disciplinary The primary outcome was the dose of vasopressor adult ICU at a tertiary medical center. The first phase was a required at 24, 48, 72 and 96 h after enrollment. Secondary retrospective chart review of adult patients admitted with outcomes included cumulative ketamine dose, additional septic shock, requiring sedation, mechanical ventilation and sedative and analgesics used, cumulative sedative and anal- vasopressor therapy between July 2010 and July 2011. Age, gesic dosing at all time periods, corticosteroid use, days of gender, Acute Physiology and Chronic Health Evaluation mechanical ventilation, ICU LOS, hospital LOS, and (APACHE) II scores, type, dosing and duration of sedative, mortality. analgesic and vasopressor medications, use of systemic corti- costeroids, ventilator days, ICU length of stay (LOS) hospi- Statistical Analysis tal LOS and mortality were recorded. This was conducted in Contiguous data were analyzed with unpaired t-tests and cat- order to provide a historical control group. Twenty-nine egorical data were analyzed with two-tailed, Fisher’s exact patients were identified and included for analysis during this test. Given the lack of previously published data and the fact phase of the trial. Phase I was also used to estimate the vol- that this is a pilot study, we were unable to calculate power. ume of patients that would meet the proposed inclusion crite- The sample size required to demonstrate a statistically signif- ria and to better gauge the ability to provide an adequately icant trend, with an alpha level of 0.05, was determined in powered study. consultation with our Department of Clinical Investigation The second phase was a prospective, non-randomized, statistician. open-label pilot study during which sequential adult patients aged 18–89, with septic shock requiring sedation, mechani- cal ventilation and vasopressor therapy received a continu- RESULTS ous infusion of ketamine as the primary sedative for the first From January 2012, through April 2015, a total of 19 48 h of their ICU course. Attending physicians were allowed patients were eligible. Two were excluded due to incomplete to add additional sedatives and analgesics as needed based consent and lack of a vasopressor requirement. Patient char- on their clinical judgment. acteristics were similar in the control and study group, to Patients were eligible for inclusion if they were 18–89 yr include age (67.8 vs. 69, p = 0.72) and gender (59% vs. of age with a diagnosis of septic shock, who also required 41% male, p = 0.36), with the exception of higher APACHE mechanical ventilation for at least 24 h with concomitant II scores in the ketamine group (23 ± 7 vs. 28 ± 7, p = 0.04) sedation and vasopressor therapy utilizing norepinephrine (Table I). Adherence to the ketamine protocol by clinicians and/or vasopressin, the most commonly used vasopressor was 94%, with early protocol cessation in only 1 patient due agents in our ICU. Pregnant patients, patients admitted with to agitation at 36 h. Mean (±SD) cumulative dose of keta- septic shock in the peri-operative timeframe, patients with a mine at 24 h was 1102 ± 615 mg and 2077 ± 1175 mg at e410 MILITARY MEDICINE, Vol. 183, November/December 2018 Downloaded from https://academic.oup.com/milmed/article/183/11-12/e409/5003004 by DeepDyve user on 19 July 2022 TABLE I. Patient Demographics, Primary and Secondary Outcomes for Control and Ketamine Groups. Control (N = 29) Ketamine (N = 17) p-Value Age 67.8 ± 13.7 69 ± 15 0.72 Gender 59% male (N = 17) 41% male (N = 7) 0.36 41% female (N = 12) 59% female (N = 10) APACHE II 23 ±728 ± 7 0.04 Norephinephrine days 2.2 ± 1.2 2.1 ± 1 0.59 Vasopressin use 62 % (N = 18) 35% (N = 6) 0.13 Ventilator days 6.8 ± 5.5 8.4 ± 6.9 0.39 ICU LOS 10 ± 7.6 11 ± 7.1 0.60 Hospital LOS 18.4 ± 11 15.9 ± 7 0.40 Hospital mortality 31% (N = 9) 41% (N = 7) 0.53 APACHE, Acute Physiology and Chronic Health Evaluation; ICU, Intensive Care Unit. Plus–minus values are means ± SD. 48 h. There was a trend towards decreased norepinephrine doses in the ketamine group at all time points. At 24 h, mean norepinephrine dose was 14 ± 13 mg in the control group and 9 ± 8mg (p = 0.14) in the ketamine group. At 48 h, the doses were 21 ± 22 mg and 11 ± 9mg (p = 0.08). At 72 and 96 h, the doses were 24 ± 29 mg and 12 ± 10 mg (p = 0.10), and 27 ± 37 mg and 12 ± 10 mg (p = 0.12) (Fig. 1). There was a trend towards decreased vasopressin use in the keta- mine group, with only 35% of ketamine patients vs. 62% control (p = 0.13) requiring vasopressin. Fentanyl was the only analgesic used in the control and study groups. The amount of fentanyl received in the control group was higher than in the ketamine group, with 41% (N = 7) and 29% (N = 5) of ketamine patients receiving no fentanyl at 24 and 48 H respectively. In the control group, the average total additional analgesia at 24 h was 1171 ± 731 mcg versus 175 ± 233 mcg in the ketamine group (p < 0.001). At 48 h, the average total dose was 2235 ± 1341 mcg in the control group, and 429 ± 599 mcg in the ketamine FIGURE 1. Total norepinephrine dose at all time periods. group (p < 0.001) (Fig. 2). Lorazepam, midazolam, and dexmedetomidine were used in both groups as additional sedating agents. The control group received higher doses of benzodiazepines, with 47% (N = 8) and 35% (N = 6) of ketamine patients received no additional sedative at 24 and 48 h. The average total benzo- diazepine given at 24 h was 42 ± 46 mg in the control group and 10 ± 30 mg in the ketamine group (p = 0.015). At 48 h, the average total dose of benzodiazepine was 75 ± 81 mg versus 26 ± 87 mg in the ketamine group (p = 0.063) (Fig. 3). Sixty-six percent of the control group required corti- costeroids for vasopressor refractory shock, compared with 41% of the ketamine group (p = 0.13) (Fig. 4). There was no difference in days on mechanical ventila- tion, ICU LOS, hospital LOS, or mortality between the two groups (Table I). There was one adverse event, severe agitation, in one patient at 36 h, and ketamine was FIGURE 2. Cumulative doses of fentanyl at 24 and 48 h for control and subsequently discontinued. ketamine groups. MILITARY MEDICINE, Vol. 183, November/December 2018 e411 Downloaded from https://academic.oup.com/milmed/article/183/11-12/e409/5003004 by DeepDyve user on 19 July 2022 may still be of clinical importance as patients in the ketamine group had significantly higher APACHE II scores. As the det- rimental effects of continuous analgesic and benzodiazepine infusions are now well documented, our finding that the keta- mine group received less continuous analgesia and less benzo- 26,27 diazepine to achieve target RASS may be important. There are limitations to our pilot study, including a sam- ple size smaller than the control group anticipated. This might reflect either a change in ICU census at our institution during the study vs. control period, or, potentially a selection bias in screening and determining eligibility. There are also limitations inherent in utilizing a retrospective control group, most notably, an inability to control for confounding vari- ables, such as the evolution of individual practice patterns over time. With respect to sedation, individual RASS scores were not recorded, therefore it is difficult to attribute the FIGURE 3. Cumulative benzodiazepine dose for control and ketamine reduction in vasopressor dose solely to ketamine, however, group at 48 h. if we assume that clinicians in both time periods targeted similar levels of sedation per protocol, it is reasonable to attribute some positive effect to ketamine. We conducted the study at a time when routine delirium screening utilizing CAM-ICU was not done, therefore, we do not have data regarding the potential effect of ketamine on the develop- ment of ICU delirium and its potential contributions to Post Intensive Care Syndrome. Lastly, there are multiple other variables that impact hemodynamics in septic shock and it is possible factors were not assessed that may have accounted for the differences seen in the two populations. To our knowledge, this is the first report of ketamine use for continuous sedation in adult non-surgical septic shock and mechanical ventilation patients. Our small pilot study demonstrated a trend towards decreased vasopressor dose, and decreased benzodiazepine and opiate use when ketamine FIGURE 4. Percent of patients in control and ketamine group with addi- is used as the primary sedative. This trend should be further tional corticosteroid therapy to support blood pressure goals. explored in a large, randomized prospective study, in order to determine what effects, if any can be contributed solely to CONCLUSION ketamine use. There is growing evidence in laboratory and clinical medi- cine supporting beneficial properties of ketamine. These SUPPLEMENTARY MATERIAL include neutral effects on respiratory drive, neutral or even Supplementary material is available at Military Medicine online. positive effects on heart rate and blood pressure, anti- inflammatory effects through reduced IL-6 and TNF-alpha as well as down regulation of iNOS and COX-2, mecha- PRESENTATION nisms thought to be linked to the pathophysiology of septic Presented in abstract format at the U.S. Army Chapter of the American shock. Although the initial data on goal-directed therapies College of Physicians Annual Meeting, virtual meeting, December 2014 and the National American College of Physicians Annual Session, Orlando, FL, was very promising subsequent studies have challenged April 2015. the benefits and raised concerns about the cost effective- ness. Current guidelines still focus on prompt recognition and treatment with early antibiotics and fluid resuscitation REFERENCES but have few recommendations about sedation in severe sep- 1. Patel S, Kress J: Sedation and analgesia in the mechanically ventilated tic shock requiring vasopressor support. This pilot study patient. Am J Respir Crit Care Med 2012; 185(5): 486–97. 2. Tobias J, Leder M: Procedural sedation: a review of sedative agents, demonstrated a non-significant trend in decreased vasopres- monitoring, and management of complications. Saudi J Anaesth 2011; sor dose when ketamine was used as the primary sedative. 5(4): 395–410. While there was no difference in mortality, ICU LOS, days 3. Westphal M, Traber DL: Ketamine in critical illness: Another no-NO of mechanical ventilation, or hospital LOS, we believe this agent? Crit Care Med 2005; 33(5): 1162–63. e412 MILITARY MEDICINE, Vol. 183, November/December 2018 Downloaded from https://academic.oup.com/milmed/article/183/11-12/e409/5003004 by DeepDyve user on 19 July 2022 4. Traber DL, Wilson RD, Priano LL: The effect of alpha-adrenergic attenuates pro-inflammatory cytokine response during and after cardio- blockade on the cardiopulmonary response to ketamine. Anesth Analg pulmonary bypass. Br J Anaesth 2011; 106(2): 172–9. 1971; 50: 737–42. 17. Miller AC, Jamin CT, Elamin EM: Continuous intravenous infusion of 5. Kawano T, Oshita S, Takahashi A, et al: Molecular mechanisms underly- ketamine for maintenance sedation. Minerva Anestesiol 2011; 77: 812–20. ing ketamine-mediated inhibition of sarcolemmal adenosine triphosphate- 18. Tactical Combat Casualty Care Guidelines. 2 June 2014. Available at sensitive potassium channels. Anesthesiology 2005; 102: 93–101. http://www.usaisr.amedd.army.mil/pdfs/TCCC_Guidelines_140602.pdf; 6. Akata T, Izumi K, Nakashima M: Mechanisms of direct inhibitory accessed January 26, 2001. action of ketamine on vascular smooth muscle in mesenteric resistance 19. De Pinto M, Jelacic J, Edwards WT: Very-low-dose ketamine for the arteries. Anesthesiology 2001; 95: 452–62. management of pain and sedation in the ICU. J Opioid Manag 2008; 7. Freedman JE, Loscalozo J: Endothelial dysfunction and atherothrombo- 4(1): 54–6. tic occlusive disease. Drugs 1997; 54: 41–9. 20. Adams HA, Biscoping J, Russ W, Bachmann B, Ratthey K, 8. Ketamine Hydrochloride [package insert]. Lake Forest, IL: Hospira Hempelmann G: Sedative-analgesic medication in intensive care Incorporated; 2013. patients needing ventilator treatment. Anaesthesist 1988; 37(4): 268–76. 9. Ward JL, Adams SD, Delano BA, et al: Ketamine suppresses LPS-induced 21. Waxman K, Shoemaker WC, Lippmann M: Cardiovascular effects of bile reflux and gastric bleeding in the rat. J Trauma 2010; 68: 69–75. anesthetic induction with ketamine. Anesth Analg 1980; 59: 355–8. 10. Julia M, Boris R, Gad S, et al: Involvement of adenosine in the anti- 22. Gellisen HPMM, Epema AH, Henning RH, Krijnen HJ, Hennis PJ, den inflammatory action of ketamine. Anesthesiology 2005; 102: 1174–81. Hertog A: Inotropic effects of propofol, thiopental, midazolam, etomi- 11. Xiao H, Xu HW, Liu H, Zhang L: Effect of ketamine on endotoxin- date, and ketamine on isolated human atrial muscle. Anesthesiology induced septic shock in rats and its mechanism. Zhongguo Wei Zhong 1996; 84: 397–403. Bing Ji Jiu Yi Xue 2007; 19(5): 303–5. 23. Rivers E, Nguyen B, Havstad S, et al: Early goal-directed therapy in the 12. Yu M, Shao D, Yang R, et al: Effects of ketamine on pulmonary treatment of severe sepsis and septic shock. N Engl J Med 2001; 345: inflammatory responses and survival in rats exposed to polymicrobial 1368–77. sepsis. J Pharm Pharmaceut Sci 2007; 10(4): 434–2. 24. Mouncey PR, Osborn TM, Power GS, et al: Trial of early, goal-directed 13. Goyal S, Agrawal A: Ketamine in status asthmaticus: a review. Indian J resuscitation for septic shock. N Engl J Med 2015; 372: 1301–11. Crit Care Med 2013; 17(3): 154–61. 25. Dellinger RP, Levy MM, Rhodes A, et al: Surviving sepsis campaign: 14. McGhee L, Slater T, Garza T, et al: The relationship of early pain international guidelines for management of severe sepsis and septic scores and posttraumatic stress disorder in burned soldiers. J Burn Res shock. Crit Care Med 2012; 41(2): 580–637. 2011; 32(1): 46–51. 26. Barr J, Gilles LF, Puntillo K, et al: Clinical practice guidelines for the 15. Basagan-Mogol E, Goren S, Korfali G, Turker G, Nur Kaya F: management of pain, agitation, and delirium in adult patients in the Inducation of anesthesia in coronary artery bypass graft surgery: the intensive care unit. Crit Care Med 2013; 41(1): 263–306. hemodynamic and analgesic effects of ketamine. Clinics (Sao Paulo) 27. Skrupky LP, Drewry AM, Wessman B, et al: Clinical effectiveness of a 2010; 65(2): 133–8. sedation protocol minimizing benzodiazepine infusions and favoring 16. Welters ID, Feurer MK, Preiss V, et al: Continuous S–(+)-ketamine early dexmedetomidine: a before-after study. Crit Care 2015; 19(1): administration during elective coronary artery bypass graft surgery 136–48. MILITARY MEDICINE, Vol. 183, November/December 2018 e413 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Military Medicine Oxford University Press

A Non-Comparative Prospective Pilot Study of Ketamine for Sedation in Adult Septic Shock

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Oxford University Press
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Copyright © 2022 The Society of Federal Health Professionals
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0026-4075
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1930-613X
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10.1093/milmed/usy121
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Abstract

Downloaded from https://academic.oup.com/milmed/article/183/11-12/e409/5003004 by DeepDyve user on 19 July 2022 MILITARY MEDICINE, 183, 11/12:e409, 2018 A Non-Comparative Prospective Pilot Study of Ketamine for Sedation in Adult Septic Shock MAJ Jason M. Reese, MC USA*; CPT Victoria Fernandes Sullivan, MC USA†; MAJ Nathan L. Boyer, MC USA‡; LTC Cristin A. Mount, MC USA* ABSTRACT Introduction: Sedation and analgesia in the intensive care unit (ICU) for patients with sepsis can be challenging. Opioids and benzodiazepines can lower blood pressure and decrease respiratory drive. Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist that provides both amnesia and analgesia without depressing respi- ratory drive or blood pressure. The purpose of this pilot study was to assess the effect of ketamine on the vasopressor requirement in adult patients with septic shock requiring mechanical ventilation. Materials and Methods: We conducted a two-phase study in a multi-disciplinary adult ICU at a tertiary medical center. The first phase was a retrospective chart review of patients admitted with septic shock between July 2010 and July 2011; 29 patients were identified for a historical control group. The second phase was a prospective, non-randomized, open-label pilot study. Patients were eligible for inclusion if they were 18–89 yr of age with a diagnosis of septic shock, who also required mechanical ven- tilation for at least 24 h, concomitant sedation, and vasopressor therapy. Pregnant patients, patients in the peri-operative timeframe, and patients with acute coronary syndrome were excluded. Patients enrolled in the phase two pilot study received ketamine as the primary sedative. Ketamine was administered as a 1–2 mg/kg IV bolus, then as a continuous infusion starting at 5 mcg/kg/min, titrated 2 mcg/kg/min every 30 min as needed to obtain a Richmond Agitation Sedation Scale (RASS) goal of −1to −2. If continuous sedation was still required after 48 h, patients were transitioned off ketamine and sedative strategy reverted to usual ICU sedation protocol. The primary outcome was the dose of vaso- pressor required at 24, 48, 72 and 96 h after enrollment. Secondary outcomes included cumulative ketamine dose, addi- tional sedative and analgesics used, cumulative sedative and analgesic dosing at all time periods, corticosteroid use, days of mechanical ventilation, ICU LOS, hospital LOS, and mortality. Contiguous data were analyzed with unpaired t-tests and categorical data were analyzed with two-tailed, Fisher’s exact test. This study was approved by our Institutional Review Board. Results: From January 2012 to April 2015, a total of 17 patients were enrolled. Patient characteristics were similar in the control and study group. Ketamine was discontinued in one patient due to agitation at 36 h. There was a trend towards decreased norepinephrine and vasopressin use in the study group at all time periods. Regarding secondary outcomes, the study group received less additional analgesia with fentanyl at 24 and 48 h (p < 0.001), and less additional sedation with lorazepam, midazolam or dexmedetomidine at 24 h (p = 0.015). Conclusion: This pilot study demonstrated a trend towards decreased vasopressor dose, and decreased benzodiazepine and opiate use when ketamine is used as the sole sedative. The limitations to our study include a small sample size and those inherent in using a retrospective control group. Our findings should be further explored in a large, randomized prospec- tive study. INTRODUCTION Ketamine is an N-methyl-D-aspartate (NMDA) receptor Sedation and analgesia in the intensive care unit (ICU) for antagonist, classified as a dissociative anesthetic, providing patients with sepsis and tenuous hemodynamics can be chal- both amnesia and analgesia. At therapeutic doses, the respi- lenging. Opioids and benzodiazepines can contribute to the ratory drive is preserved, with a chronotropic effect on the pathophysiology of shock by exacerbating poor tissue perfusion cardiovascular system, mediated by the sympathetic nervous through reduced cardiac contractility, and increased vasodilation system, inhibition of adenosine tri-phosphate-sensitive chan- 1,2 as well as reducing the respiratory drive. nels, direct inhibitory action on smooth muscle cells, and modulation of vascular tone through endothelial interac- 3–7 *Department of Medicine, Madigan Army Medical Center, 9040 tions. The rise in systolic and diastolic blood pressure Jackson Ave, Joint Base Lewis-McChord, WA 98431. occurs within minutes of administration, and can increase the †Department of Medicine, Walter Reed National Military Medical 8 blood pressure from 10-50% above the pre-anesthetic levels. Center, 8901 Rockville Pike, Bethesda, MD 20889. An intriguing aspect of ketamine is its potential anti- ‡Department of Medicine, Womack Army Medical Center, 2817 Reilly inflammatory properties. In some studies, ketamine has been Road, Fort Bragg, NC 28310. The views expressed are solely those of the authors and do not reflect shown to reduce IL-6 and TNF-alpha, reduce leukocyte the official policy or position of the Department of the Army, Department of recruitment, potentiate adenosine and increase myocardiac Defense, or the U.S. Government. cAMP levels, down regulate pro-inflammatory markers such doi: 10.1093/milmed/usy121 as iNOS and COX-2 and up regulate anti-inflammatory mar- Published by Oxford University Press on behalf of the Association of 9,10 kers such as heme oxygenase-1. Additionally, in rat mod- Military Surgeons of the United States 2018. This work is written by (a) US Government employee(s) and is in the public domain in the US. els exposed to sepsis, ketamine not only reduced the MILITARY MEDICINE, Vol. 183, November/December 2018 e409 Downloaded from https://academic.oup.com/milmed/article/183/11-12/e409/5003004 by DeepDyve user on 19 July 2022 production of inflammatory cytokines but also lead to known allergy to ketamine and patients with acute coronary 11,12 improved survival of the rats. syndrome were excluded. Ketamine is widely used in pediatrics for continuous and This study was approved by our Institutional Review procedural sedation, but is also gaining popularity in adult Board. All patients provided consent for inclusion via surro- patient populations. There is some evidence that ketamine gate medical decision maker, and were again contacted after has been used successfully for sedation in status asthmaticus, their ICU course to obtain consent to remain in the study. in burn patients undergoing multiple surgeries, and for anes- 13–17 thesia in coronary artery bypass graft surgery. Ketamine Study Procedures is also used more frequently in trauma populations and is Patients enrolled in the phase two pilot study received keta- now listed in the Military’s Tactical Combat Casualty care mine as the primary sedative for 48 h or less, if the indication (TCCC) guidelines for patients suffering from hemorrhagic for continuous sedation changed. Ketamine was administered shock. Currently, there are no published reports of the rou- as a 1–2 mg/kg IV bolus, then as a continuous infusion start- tine use of ketamine for primary sedation in an adult medical ing at 5 mcg/kg/min with a titration of 2 mcg/kg/min every ICU population in the setting of sepsis. Limited case reports 30 min as needed to obtain a Richmond Agitation Sedation have demonstrated the benefits of ketamine in the ICU environ- Scale (RASS) goal of 1 to −2. If continuous sedation was still 19,20 ment however this is tempered by non-randomized reports required after 48 h, patients were transitioned off ketamine 21,22 of adverse effects of ketamine in severely ill patients. and transitioned to usual ICU sedation protocol which favored The purpose of this pilot study was to assess the effect of benzodiazepine or dexmedetomidine infusion, fentanyl for ketamine on the vasopressor requirement in adult medical pain and a sedation goal of 1 to −2onthe RASS.Attending patients with septic shock requiring mechanical ventilation. physicians could discontinue ketamine or substitute additional sedative and analgesic agents at any point during the study as MATERIALS AND METHODS they deemed clinically necessary. The ketamine administra- tion protocol and usual sedation protocol are included in the Participants Supplementary material. We conducted a two-phase study in a multi-disciplinary The primary outcome was the dose of vasopressor adult ICU at a tertiary medical center. The first phase was a required at 24, 48, 72 and 96 h after enrollment. Secondary retrospective chart review of adult patients admitted with outcomes included cumulative ketamine dose, additional septic shock, requiring sedation, mechanical ventilation and sedative and analgesics used, cumulative sedative and anal- vasopressor therapy between July 2010 and July 2011. Age, gesic dosing at all time periods, corticosteroid use, days of gender, Acute Physiology and Chronic Health Evaluation mechanical ventilation, ICU LOS, hospital LOS, and (APACHE) II scores, type, dosing and duration of sedative, mortality. analgesic and vasopressor medications, use of systemic corti- costeroids, ventilator days, ICU length of stay (LOS) hospi- Statistical Analysis tal LOS and mortality were recorded. This was conducted in Contiguous data were analyzed with unpaired t-tests and cat- order to provide a historical control group. Twenty-nine egorical data were analyzed with two-tailed, Fisher’s exact patients were identified and included for analysis during this test. Given the lack of previously published data and the fact phase of the trial. Phase I was also used to estimate the vol- that this is a pilot study, we were unable to calculate power. ume of patients that would meet the proposed inclusion crite- The sample size required to demonstrate a statistically signif- ria and to better gauge the ability to provide an adequately icant trend, with an alpha level of 0.05, was determined in powered study. consultation with our Department of Clinical Investigation The second phase was a prospective, non-randomized, statistician. open-label pilot study during which sequential adult patients aged 18–89, with septic shock requiring sedation, mechani- cal ventilation and vasopressor therapy received a continu- RESULTS ous infusion of ketamine as the primary sedative for the first From January 2012, through April 2015, a total of 19 48 h of their ICU course. Attending physicians were allowed patients were eligible. Two were excluded due to incomplete to add additional sedatives and analgesics as needed based consent and lack of a vasopressor requirement. Patient char- on their clinical judgment. acteristics were similar in the control and study group, to Patients were eligible for inclusion if they were 18–89 yr include age (67.8 vs. 69, p = 0.72) and gender (59% vs. of age with a diagnosis of septic shock, who also required 41% male, p = 0.36), with the exception of higher APACHE mechanical ventilation for at least 24 h with concomitant II scores in the ketamine group (23 ± 7 vs. 28 ± 7, p = 0.04) sedation and vasopressor therapy utilizing norepinephrine (Table I). Adherence to the ketamine protocol by clinicians and/or vasopressin, the most commonly used vasopressor was 94%, with early protocol cessation in only 1 patient due agents in our ICU. Pregnant patients, patients admitted with to agitation at 36 h. Mean (±SD) cumulative dose of keta- septic shock in the peri-operative timeframe, patients with a mine at 24 h was 1102 ± 615 mg and 2077 ± 1175 mg at e410 MILITARY MEDICINE, Vol. 183, November/December 2018 Downloaded from https://academic.oup.com/milmed/article/183/11-12/e409/5003004 by DeepDyve user on 19 July 2022 TABLE I. Patient Demographics, Primary and Secondary Outcomes for Control and Ketamine Groups. Control (N = 29) Ketamine (N = 17) p-Value Age 67.8 ± 13.7 69 ± 15 0.72 Gender 59% male (N = 17) 41% male (N = 7) 0.36 41% female (N = 12) 59% female (N = 10) APACHE II 23 ±728 ± 7 0.04 Norephinephrine days 2.2 ± 1.2 2.1 ± 1 0.59 Vasopressin use 62 % (N = 18) 35% (N = 6) 0.13 Ventilator days 6.8 ± 5.5 8.4 ± 6.9 0.39 ICU LOS 10 ± 7.6 11 ± 7.1 0.60 Hospital LOS 18.4 ± 11 15.9 ± 7 0.40 Hospital mortality 31% (N = 9) 41% (N = 7) 0.53 APACHE, Acute Physiology and Chronic Health Evaluation; ICU, Intensive Care Unit. Plus–minus values are means ± SD. 48 h. There was a trend towards decreased norepinephrine doses in the ketamine group at all time points. At 24 h, mean norepinephrine dose was 14 ± 13 mg in the control group and 9 ± 8mg (p = 0.14) in the ketamine group. At 48 h, the doses were 21 ± 22 mg and 11 ± 9mg (p = 0.08). At 72 and 96 h, the doses were 24 ± 29 mg and 12 ± 10 mg (p = 0.10), and 27 ± 37 mg and 12 ± 10 mg (p = 0.12) (Fig. 1). There was a trend towards decreased vasopressin use in the keta- mine group, with only 35% of ketamine patients vs. 62% control (p = 0.13) requiring vasopressin. Fentanyl was the only analgesic used in the control and study groups. The amount of fentanyl received in the control group was higher than in the ketamine group, with 41% (N = 7) and 29% (N = 5) of ketamine patients receiving no fentanyl at 24 and 48 H respectively. In the control group, the average total additional analgesia at 24 h was 1171 ± 731 mcg versus 175 ± 233 mcg in the ketamine group (p < 0.001). At 48 h, the average total dose was 2235 ± 1341 mcg in the control group, and 429 ± 599 mcg in the ketamine FIGURE 1. Total norepinephrine dose at all time periods. group (p < 0.001) (Fig. 2). Lorazepam, midazolam, and dexmedetomidine were used in both groups as additional sedating agents. The control group received higher doses of benzodiazepines, with 47% (N = 8) and 35% (N = 6) of ketamine patients received no additional sedative at 24 and 48 h. The average total benzo- diazepine given at 24 h was 42 ± 46 mg in the control group and 10 ± 30 mg in the ketamine group (p = 0.015). At 48 h, the average total dose of benzodiazepine was 75 ± 81 mg versus 26 ± 87 mg in the ketamine group (p = 0.063) (Fig. 3). Sixty-six percent of the control group required corti- costeroids for vasopressor refractory shock, compared with 41% of the ketamine group (p = 0.13) (Fig. 4). There was no difference in days on mechanical ventila- tion, ICU LOS, hospital LOS, or mortality between the two groups (Table I). There was one adverse event, severe agitation, in one patient at 36 h, and ketamine was FIGURE 2. Cumulative doses of fentanyl at 24 and 48 h for control and subsequently discontinued. ketamine groups. MILITARY MEDICINE, Vol. 183, November/December 2018 e411 Downloaded from https://academic.oup.com/milmed/article/183/11-12/e409/5003004 by DeepDyve user on 19 July 2022 may still be of clinical importance as patients in the ketamine group had significantly higher APACHE II scores. As the det- rimental effects of continuous analgesic and benzodiazepine infusions are now well documented, our finding that the keta- mine group received less continuous analgesia and less benzo- 26,27 diazepine to achieve target RASS may be important. There are limitations to our pilot study, including a sam- ple size smaller than the control group anticipated. This might reflect either a change in ICU census at our institution during the study vs. control period, or, potentially a selection bias in screening and determining eligibility. There are also limitations inherent in utilizing a retrospective control group, most notably, an inability to control for confounding vari- ables, such as the evolution of individual practice patterns over time. With respect to sedation, individual RASS scores were not recorded, therefore it is difficult to attribute the FIGURE 3. Cumulative benzodiazepine dose for control and ketamine reduction in vasopressor dose solely to ketamine, however, group at 48 h. if we assume that clinicians in both time periods targeted similar levels of sedation per protocol, it is reasonable to attribute some positive effect to ketamine. We conducted the study at a time when routine delirium screening utilizing CAM-ICU was not done, therefore, we do not have data regarding the potential effect of ketamine on the develop- ment of ICU delirium and its potential contributions to Post Intensive Care Syndrome. Lastly, there are multiple other variables that impact hemodynamics in septic shock and it is possible factors were not assessed that may have accounted for the differences seen in the two populations. To our knowledge, this is the first report of ketamine use for continuous sedation in adult non-surgical septic shock and mechanical ventilation patients. Our small pilot study demonstrated a trend towards decreased vasopressor dose, and decreased benzodiazepine and opiate use when ketamine FIGURE 4. Percent of patients in control and ketamine group with addi- is used as the primary sedative. This trend should be further tional corticosteroid therapy to support blood pressure goals. explored in a large, randomized prospective study, in order to determine what effects, if any can be contributed solely to CONCLUSION ketamine use. There is growing evidence in laboratory and clinical medi- cine supporting beneficial properties of ketamine. These SUPPLEMENTARY MATERIAL include neutral effects on respiratory drive, neutral or even Supplementary material is available at Military Medicine online. positive effects on heart rate and blood pressure, anti- inflammatory effects through reduced IL-6 and TNF-alpha as well as down regulation of iNOS and COX-2, mecha- PRESENTATION nisms thought to be linked to the pathophysiology of septic Presented in abstract format at the U.S. Army Chapter of the American shock. 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Journal

Military MedicineOxford University Press

Published: Nov 5, 2018

Keywords: vasoconstrictor agents; septic shock; adult; ketamine; sedation procedure; sepsis; intensive care unit; sedatives; mechanical ventilation

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