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 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 respiratory 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 ventilation 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 −1 to −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 vasopressor required at 24, 48, 72 and 96 h after enrollment. Secondary outcomes included cumulative ketamine dose, additional 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 prospective study. INTRODUCTION Sedation and analgesia in the intensive care unit (ICU) for patients with sepsis and tenuous hemodynamics can be challenging. Opioids and benzodiazepines can contribute to the pathophysiology of shock by exacerbating poor tissue perfusion through reduced cardiac contractility, and increased vasodilation as well as reducing the respiratory drive.1,2 Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist, classified as a dissociative anesthetic, providing both amnesia and analgesia. At therapeutic doses, the respiratory drive is preserved, with a chronotropic effect on the cardiovascular system, mediated by the sympathetic nervous system, inhibition of adenosine tri-phosphate-sensitive channels, direct inhibitory action on smooth muscle cells, and modulation of vascular tone through endothelial interactions.3–7 The rise in systolic and diastolic blood pressure occurs within minutes of administration, and can increase the blood pressure from 10-50% above the pre-anesthetic levels.8 An intriguing aspect of ketamine is its potential anti-inflammatory properties. In some studies, ketamine has been shown to reduce IL-6 and TNF-alpha, reduce leukocyte recruitment, potentiate adenosine and increase myocardiac cAMP levels, down regulate pro-inflammatory markers such as iNOS and COX-2 and up regulate anti-inflammatory markers such as heme oxygenase-1.9,10 Additionally, in rat models exposed to sepsis, ketamine not only reduced the production of inflammatory cytokines but also lead to improved survival of the rats.11,12 Ketamine is widely used in pediatrics for continuous and procedural sedation, but is also gaining popularity in adult patient populations. There is some evidence that ketamine has been used successfully for sedation in status asthmaticus, in burn patients undergoing multiple surgeries, and for anesthesia in coronary artery bypass graft surgery.13–17 Ketamine is also used more frequently in trauma populations and is now listed in the Military’s Tactical Combat Casualty care (TCCC) guidelines for patients suffering from hemorrhagic shock.18 Currently, there are no published reports of the routine use of ketamine for primary sedation in an adult medical ICU population in the setting of sepsis. Limited case reports have demonstrated the benefits of ketamine in the ICU environment19,20 however this is tempered by non-randomized reports of adverse effects of ketamine in severely ill patients.21,22 The purpose of this pilot study was to assess the effect of ketamine on the vasopressor requirement in adult medical patients with septic shock requiring mechanical ventilation. MATERIALS AND METHODS Participants 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 adult patients admitted with septic shock, requiring sedation, mechanical ventilation and vasopressor therapy between July 2010 and July 2011. Age, gender, Acute Physiology and Chronic Health Evaluation (APACHE) II scores, type, dosing and duration of sedative, analgesic and vasopressor medications, use of systemic corticosteroids, ventilator days, ICU length of stay (LOS) hospital LOS and mortality were recorded. This was conducted in order to provide a historical control group. Twenty-nine patients were identified and included for analysis during this phase of the trial. Phase I was also used to estimate the volume of patients that would meet the proposed inclusion criteria and to better gauge the ability to provide an adequately powered study. The second phase was a prospective, non-randomized, open-label pilot study during which sequential adult patients aged 18–89, with septic shock requiring sedation, mechanical ventilation and vasopressor therapy received a continuous infusion of ketamine as the primary sedative for the first 48 h of their ICU course. Attending physicians were allowed to add additional sedatives and analgesics as needed based on their clinical judgment. Patients were eligible for inclusion if they were 18–89 yr of age with a diagnosis of septic shock, who also required mechanical ventilation for at least 24 h with concomitant sedation and vasopressor therapy utilizing norepinephrine and/or vasopressin, the most commonly used vasopressor agents in our ICU. Pregnant patients, patients admitted with septic shock in the peri-operative timeframe, patients with a known allergy to ketamine and patients with acute coronary syndrome were excluded. This study was approved by our Institutional Review Board. All patients provided consent for inclusion via surrogate medical decision maker, and were again contacted after their ICU course to obtain consent to remain in the study. Study Procedures Patients enrolled in the phase two pilot study received ketamine as the primary sedative for 48 h or less, if the indication for continuous sedation changed. Ketamine was administered as a 1–2 mg/kg IV bolus, then as a continuous infusion starting at 5 mcg/kg/min with a titration of 2 mcg/kg/min every 30 min as needed to obtain a Richmond Agitation Sedation Scale (RASS) goal of 1 to −2. If continuous sedation was still required after 48 h, patients were transitioned off ketamine and transitioned to usual ICU sedation protocol which favored benzodiazepine or dexmedetomidine infusion, fentanyl for pain and a sedation goal of 1 to −2 on the RASS. Attending physicians could discontinue ketamine or substitute additional sedative and analgesic agents at any point during the study as they deemed clinically necessary. The ketamine administration protocol and usual sedation protocol are included in the Supplementary material. The primary outcome was the dose of vasopressor required at 24, 48, 72 and 96 h after enrollment. Secondary outcomes included cumulative ketamine dose, additional 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. Statistical Analysis Contiguous data were analyzed with unpaired t-tests and categorical data were analyzed with two-tailed, Fisher’s exact test. Given the lack of previously published data and the fact that this is a pilot study, we were unable to calculate power. The sample size required to demonstrate a statistically significant trend, with an alpha level of 0.05, was determined in consultation with our Department of Clinical Investigation statistician. RESULTS From January 2012, through April 2015, a total of 19 patients were eligible. Two were excluded due to incomplete consent and lack of a vasopressor requirement. Patient characteristics were similar in the control and study group, to include age (67.8 vs. 69, p = 0.72) and gender (59% vs. 41% male, p = 0.36), with the exception of higher APACHE II scores in the ketamine group (23 ± 7 vs. 28 ± 7, p = 0.04) (Table I). Adherence to the ketamine protocol by clinicians was 94%, with early protocol cessation in only 1 patient due to agitation at 36 h. Mean (±SD) cumulative dose of ketamine at 24 h was 1102 ± 615 mg and 2077 ± 1175 mg at 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 ± 8 mg (p = 0.14) in the ketamine group. At 48 h, the doses were 21 ± 22 mg and 11 ± 9 mg (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 ketamine group, with only 35% of ketamine patients vs. 62% control (p = 0.13) requiring vasopressin. 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 ± 7  28 ± 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    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 ± 7  28 ± 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. 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 ± 7  28 ± 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    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 ± 7  28 ± 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. FIGURE 1. View largeDownload slide Total norepinephrine dose at all time periods. FIGURE 1. View largeDownload slide Total norepinephrine dose at all time periods. 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 group (p < 0.001) (Fig. 2). Figure 2. View largeDownload slide Cumulative doses of fentanyl at 24 and 48 h for control and ketamine groups. Figure 2. View largeDownload slide Cumulative doses of fentanyl at 24 and 48 h for control and ketamine groups. 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 benzodiazepine 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). Figure 3. View largeDownload slide Cumulative benzodiazepine dose for control and ketamine group at 48 h. Figure 3. View largeDownload slide Cumulative benzodiazepine dose for control and ketamine group at 48 h. Sixty-six percent of the control group required corticosteroids for vasopressor refractory shock, compared with 41% of the ketamine group (p = 0.13) (Fig. 4). There was no difference in days on mechanical ventilation, 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 subsequently discontinued. Figure 4. View largeDownload slide Percent of patients in control and ketamine group with additional corticosteroid therapy to support blood pressure goals. Figure 4. View largeDownload slide Percent of patients in control and ketamine group with additional corticosteroid therapy to support blood pressure goals. CONCLUSION There is growing evidence in laboratory and clinical medicine supporting beneficial properties of ketamine. These include neutral effects on respiratory drive, neutral or even 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, mechanisms thought to be linked to the pathophysiology of septic shock. Although the initial data on goal-directed therapies was very promising23 subsequent studies have challenged the benefits and raised concerns about the cost effectiveness.24 Current guidelines still focus on prompt recognition and treatment with early antibiotics and fluid resuscitation but have few recommendations about sedation in severe septic shock requiring vasopressor support.25 This pilot study demonstrated a non-significant trend in decreased vasopressor dose when ketamine was used as the primary sedative. While there was no difference in mortality, ICU LOS, days of mechanical ventilation, or hospital LOS, we believe this may still be of clinical importance as patients in the ketamine group had significantly higher APACHE II scores. As the detrimental effects of continuous analgesic and benzodiazepine infusions are now well documented, our finding that the ketamine group received less continuous analgesia and less benzodiazepine to achieve target RASS may be important.26,27 There are limitations to our pilot study, including a sample 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 variables, 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 reduction in vasopressor dose solely to ketamine, however, 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 development 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 is used as the primary sedative. This trend should be further explored in a large, randomized prospective study, in order to determine what effects, if any can be contributed solely to ketamine use. Supplementary Material Supplementary material is available at Military Medicine online. Presentation Presented in abstract format at the U.S. Army Chapter of the American College of Physicians Annual Meeting, virtual meeting, December 2014 and the National American College of Physicians Annual Session, Orlando, FL, April 2015. REFERENCES 1 Patel S, Kress J: Sedation and analgesia in the mechanically ventilated patient. Am J Respir Crit Care Med  2012; 185( 5): 486– 97. Google Scholar CrossRef Search ADS PubMed  2 Tobias J, Leder M: Procedural sedation: a review of sedative agents, monitoring, and management of complications. Saudi J Anaesth  2011; 5( 4): 395– 410. Google Scholar CrossRef Search ADS PubMed  3 Westphal M, Traber DL: Ketamine in critical illness: Another no-NO agent? Crit Care Med  2005; 33( 5): 1162– 63. Google Scholar CrossRef Search ADS PubMed  4 Traber DL, Wilson RD, Priano LL: The effect of alpha-adrenergic blockade on the cardiopulmonary response to ketamine. Anesth Analg  1971; 50: 737– 42. Google Scholar CrossRef Search ADS PubMed  5 Kawano T, Oshita S, Takahashi A, et al.  : Molecular mechanisms underlying ketamine-mediated inhibition of sarcolemmal adenosine triphosphate-sensitive potassium channels. Anesthesiology  2005; 102: 93– 101. Google Scholar CrossRef Search ADS PubMed  6 Akata T, Izumi K, Nakashima M: Mechanisms of direct inhibitory action of ketamine on vascular smooth muscle in mesenteric resistance arteries. Anesthesiology  2001; 95: 452– 62. Google Scholar CrossRef Search ADS PubMed  7 Freedman JE, Loscalozo J: Endothelial dysfunction and atherothrombotic occlusive disease. Drugs  1997; 54: 41– 9. Google Scholar CrossRef Search ADS PubMed  8 Ketamine Hydrochloride [package insert]. Lake Forest, IL: Hospira Incorporated; 2013. 9 Ward JL, Adams SD, Delano BA, et al.  : Ketamine suppresses LPS-induced bile reflux and gastric bleeding in the rat. J Trauma  2010; 68: 69– 75. Google Scholar CrossRef Search ADS PubMed  10 Julia M, Boris R, Gad S, et al.  : Involvement of adenosine in the anti-inflammatory action of ketamine. Anesthesiology  2005; 102: 1174– 81. Google Scholar CrossRef Search ADS PubMed  11 Xiao H, Xu HW, Liu H, Zhang L: Effect of ketamine on endotoxin-induced septic shock in rats and its mechanism. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue  2007; 19( 5): 303– 5. Google Scholar PubMed  12 Yu M, Shao D, Yang R, et al: Effects of ketamine on pulmonary inflammatory responses and survival in rats exposed to polymicrobial sepsis. J Pharm Pharmaceut Sci  2007; 10( 4): 434– 2. Google Scholar CrossRef Search ADS   13 Goyal S, Agrawal A: Ketamine in status asthmaticus: a review. Indian J Crit Care Med  2013; 17( 3): 154– 61. Google Scholar CrossRef Search ADS PubMed  14 McGhee L, Slater T, Garza T, et al.  : The relationship of early pain scores and posttraumatic stress disorder in burned soldiers. J Burn Res  2011; 32( 1): 46– 51. Google Scholar CrossRef Search ADS   15 Basagan-Mogol E, Goren S, Korfali G, Turker G, Nur Kaya F: Inducation of anesthesia in coronary artery bypass graft surgery: the hemodynamic and analgesic effects of ketamine. Clinics (Sao Paulo)  2010; 65( 2): 133– 8. Google Scholar CrossRef Search ADS PubMed  16 Welters ID, Feurer MK, Preiss V, et al.  : Continuous S–(+)-ketamine administration during elective coronary artery bypass graft surgery attenuates pro-inflammatory cytokine response during and after cardiopulmonary bypass. Br J Anaesth  2011; 106( 2): 172– 9. Google Scholar CrossRef Search ADS PubMed  17 Miller AC, Jamin CT, Elamin EM: Continuous intravenous infusion of ketamine for maintenance sedation. Minerva Anestesiol  2011; 77: 812– 20. Google Scholar PubMed  18 Tactical Combat Casualty Care Guidelines. 2 June 2014. Available at http://www.usaisr.amedd.army.mil/pdfs/TCCC_Guidelines_140602.pdf; accessed January 26, 2001. 19 De Pinto M, Jelacic J, Edwards WT: Very-low-dose ketamine for the management of pain and sedation in the ICU. J Opioid Manag  2008; 4( 1): 54– 6. Google Scholar CrossRef Search ADS PubMed  20 Adams HA, Biscoping J, Russ W, Bachmann B, Ratthey K, Hempelmann G: Sedative-analgesic medication in intensive care patients needing ventilator treatment. Anaesthesist  1988; 37( 4): 268– 76. Google Scholar PubMed  21 Waxman K, Shoemaker WC, Lippmann M: Cardiovascular effects of anesthetic induction with ketamine. Anesth Analg  1980; 59: 355– 8. Google Scholar CrossRef Search ADS PubMed  22 Gellisen HPMM, Epema AH, Henning RH, Krijnen HJ, Hennis PJ, den Hertog A: Inotropic effects of propofol, thiopental, midazolam, etomidate, and ketamine on isolated human atrial muscle. Anesthesiology  1996; 84: 397– 403. Google Scholar CrossRef Search ADS PubMed  23 Rivers E, Nguyen B, Havstad S, et al.  : Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med  2001; 345: 1368– 77. Google Scholar CrossRef Search ADS PubMed  24 Mouncey PR, Osborn TM, Power GS, et al.  : Trial of early, goal-directed resuscitation for septic shock. N Engl J Med  2015; 372: 1301– 11. Google Scholar CrossRef Search ADS PubMed  25 Dellinger RP, Levy MM, Rhodes A, et al.  : Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock. Crit Care Med  2012; 41( 2): 580– 637. Google Scholar CrossRef Search ADS   26 Barr J, Gilles LF, 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. Google Scholar CrossRef Search ADS PubMed  27 Skrupky LP, Drewry AM, Wessman B, et al.  : Clinical effectiveness of a sedation protocol minimizing benzodiazepine infusions and favoring early dexmedetomidine: a before-after study. Crit Care  2015; 19( 1): 136– 48. Google Scholar CrossRef Search ADS PubMed  Author notes The views expressed are solely those of the authors and do not reflect the official policy or position of the Department of the Army, Department of Defense, or the U.S. Government Published by Oxford University Press on behalf of the Association of 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. 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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Abstract

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 respiratory 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 ventilation 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 −1 to −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 vasopressor required at 24, 48, 72 and 96 h after enrollment. Secondary outcomes included cumulative ketamine dose, additional 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 prospective study. INTRODUCTION Sedation and analgesia in the intensive care unit (ICU) for patients with sepsis and tenuous hemodynamics can be challenging. Opioids and benzodiazepines can contribute to the pathophysiology of shock by exacerbating poor tissue perfusion through reduced cardiac contractility, and increased vasodilation as well as reducing the respiratory drive.1,2 Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist, classified as a dissociative anesthetic, providing both amnesia and analgesia. At therapeutic doses, the respiratory drive is preserved, with a chronotropic effect on the cardiovascular system, mediated by the sympathetic nervous system, inhibition of adenosine tri-phosphate-sensitive channels, direct inhibitory action on smooth muscle cells, and modulation of vascular tone through endothelial interactions.3–7 The rise in systolic and diastolic blood pressure occurs within minutes of administration, and can increase the blood pressure from 10-50% above the pre-anesthetic levels.8 An intriguing aspect of ketamine is its potential anti-inflammatory properties. In some studies, ketamine has been shown to reduce IL-6 and TNF-alpha, reduce leukocyte recruitment, potentiate adenosine and increase myocardiac cAMP levels, down regulate pro-inflammatory markers such as iNOS and COX-2 and up regulate anti-inflammatory markers such as heme oxygenase-1.9,10 Additionally, in rat models exposed to sepsis, ketamine not only reduced the production of inflammatory cytokines but also lead to improved survival of the rats.11,12 Ketamine is widely used in pediatrics for continuous and procedural sedation, but is also gaining popularity in adult patient populations. There is some evidence that ketamine has been used successfully for sedation in status asthmaticus, in burn patients undergoing multiple surgeries, and for anesthesia in coronary artery bypass graft surgery.13–17 Ketamine is also used more frequently in trauma populations and is now listed in the Military’s Tactical Combat Casualty care (TCCC) guidelines for patients suffering from hemorrhagic shock.18 Currently, there are no published reports of the routine use of ketamine for primary sedation in an adult medical ICU population in the setting of sepsis. Limited case reports have demonstrated the benefits of ketamine in the ICU environment19,20 however this is tempered by non-randomized reports of adverse effects of ketamine in severely ill patients.21,22 The purpose of this pilot study was to assess the effect of ketamine on the vasopressor requirement in adult medical patients with septic shock requiring mechanical ventilation. MATERIALS AND METHODS Participants 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 adult patients admitted with septic shock, requiring sedation, mechanical ventilation and vasopressor therapy between July 2010 and July 2011. Age, gender, Acute Physiology and Chronic Health Evaluation (APACHE) II scores, type, dosing and duration of sedative, analgesic and vasopressor medications, use of systemic corticosteroids, ventilator days, ICU length of stay (LOS) hospital LOS and mortality were recorded. This was conducted in order to provide a historical control group. Twenty-nine patients were identified and included for analysis during this phase of the trial. Phase I was also used to estimate the volume of patients that would meet the proposed inclusion criteria and to better gauge the ability to provide an adequately powered study. The second phase was a prospective, non-randomized, open-label pilot study during which sequential adult patients aged 18–89, with septic shock requiring sedation, mechanical ventilation and vasopressor therapy received a continuous infusion of ketamine as the primary sedative for the first 48 h of their ICU course. Attending physicians were allowed to add additional sedatives and analgesics as needed based on their clinical judgment. Patients were eligible for inclusion if they were 18–89 yr of age with a diagnosis of septic shock, who also required mechanical ventilation for at least 24 h with concomitant sedation and vasopressor therapy utilizing norepinephrine and/or vasopressin, the most commonly used vasopressor agents in our ICU. Pregnant patients, patients admitted with septic shock in the peri-operative timeframe, patients with a known allergy to ketamine and patients with acute coronary syndrome were excluded. This study was approved by our Institutional Review Board. All patients provided consent for inclusion via surrogate medical decision maker, and were again contacted after their ICU course to obtain consent to remain in the study. Study Procedures Patients enrolled in the phase two pilot study received ketamine as the primary sedative for 48 h or less, if the indication for continuous sedation changed. Ketamine was administered as a 1–2 mg/kg IV bolus, then as a continuous infusion starting at 5 mcg/kg/min with a titration of 2 mcg/kg/min every 30 min as needed to obtain a Richmond Agitation Sedation Scale (RASS) goal of 1 to −2. If continuous sedation was still required after 48 h, patients were transitioned off ketamine and transitioned to usual ICU sedation protocol which favored benzodiazepine or dexmedetomidine infusion, fentanyl for pain and a sedation goal of 1 to −2 on the RASS. Attending physicians could discontinue ketamine or substitute additional sedative and analgesic agents at any point during the study as they deemed clinically necessary. The ketamine administration protocol and usual sedation protocol are included in the Supplementary material. The primary outcome was the dose of vasopressor required at 24, 48, 72 and 96 h after enrollment. Secondary outcomes included cumulative ketamine dose, additional 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. Statistical Analysis Contiguous data were analyzed with unpaired t-tests and categorical data were analyzed with two-tailed, Fisher’s exact test. Given the lack of previously published data and the fact that this is a pilot study, we were unable to calculate power. The sample size required to demonstrate a statistically significant trend, with an alpha level of 0.05, was determined in consultation with our Department of Clinical Investigation statistician. RESULTS From January 2012, through April 2015, a total of 19 patients were eligible. Two were excluded due to incomplete consent and lack of a vasopressor requirement. Patient characteristics were similar in the control and study group, to include age (67.8 vs. 69, p = 0.72) and gender (59% vs. 41% male, p = 0.36), with the exception of higher APACHE II scores in the ketamine group (23 ± 7 vs. 28 ± 7, p = 0.04) (Table I). Adherence to the ketamine protocol by clinicians was 94%, with early protocol cessation in only 1 patient due to agitation at 36 h. Mean (±SD) cumulative dose of ketamine at 24 h was 1102 ± 615 mg and 2077 ± 1175 mg at 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 ± 8 mg (p = 0.14) in the ketamine group. At 48 h, the doses were 21 ± 22 mg and 11 ± 9 mg (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 ketamine group, with only 35% of ketamine patients vs. 62% control (p = 0.13) requiring vasopressin. 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 ± 7  28 ± 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    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 ± 7  28 ± 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. 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 ± 7  28 ± 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    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 ± 7  28 ± 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. FIGURE 1. View largeDownload slide Total norepinephrine dose at all time periods. FIGURE 1. View largeDownload slide Total norepinephrine dose at all time periods. 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 group (p < 0.001) (Fig. 2). Figure 2. View largeDownload slide Cumulative doses of fentanyl at 24 and 48 h for control and ketamine groups. Figure 2. View largeDownload slide Cumulative doses of fentanyl at 24 and 48 h for control and ketamine groups. 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 benzodiazepine 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). Figure 3. View largeDownload slide Cumulative benzodiazepine dose for control and ketamine group at 48 h. Figure 3. View largeDownload slide Cumulative benzodiazepine dose for control and ketamine group at 48 h. Sixty-six percent of the control group required corticosteroids for vasopressor refractory shock, compared with 41% of the ketamine group (p = 0.13) (Fig. 4). There was no difference in days on mechanical ventilation, 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 subsequently discontinued. Figure 4. View largeDownload slide Percent of patients in control and ketamine group with additional corticosteroid therapy to support blood pressure goals. Figure 4. View largeDownload slide Percent of patients in control and ketamine group with additional corticosteroid therapy to support blood pressure goals. CONCLUSION There is growing evidence in laboratory and clinical medicine supporting beneficial properties of ketamine. These include neutral effects on respiratory drive, neutral or even 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, mechanisms thought to be linked to the pathophysiology of septic shock. Although the initial data on goal-directed therapies was very promising23 subsequent studies have challenged the benefits and raised concerns about the cost effectiveness.24 Current guidelines still focus on prompt recognition and treatment with early antibiotics and fluid resuscitation but have few recommendations about sedation in severe septic shock requiring vasopressor support.25 This pilot study demonstrated a non-significant trend in decreased vasopressor dose when ketamine was used as the primary sedative. While there was no difference in mortality, ICU LOS, days of mechanical ventilation, or hospital LOS, we believe this may still be of clinical importance as patients in the ketamine group had significantly higher APACHE II scores. As the detrimental effects of continuous analgesic and benzodiazepine infusions are now well documented, our finding that the ketamine group received less continuous analgesia and less benzodiazepine to achieve target RASS may be important.26,27 There are limitations to our pilot study, including a sample 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 variables, 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 reduction in vasopressor dose solely to ketamine, however, 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 development 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 is used as the primary sedative. This trend should be further explored in a large, randomized prospective study, in order to determine what effects, if any can be contributed solely to ketamine use. Supplementary Material Supplementary material is available at Military Medicine online. Presentation Presented in abstract format at the U.S. Army Chapter of the American College of Physicians Annual Meeting, virtual meeting, December 2014 and the National American College of Physicians Annual Session, Orlando, FL, April 2015. REFERENCES 1 Patel S, Kress J: Sedation and analgesia in the mechanically ventilated patient. Am J Respir Crit Care Med  2012; 185( 5): 486– 97. Google Scholar CrossRef Search ADS PubMed  2 Tobias J, Leder M: Procedural sedation: a review of sedative agents, monitoring, and management of complications. 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Google Scholar CrossRef Search ADS PubMed  Author notes The views expressed are solely those of the authors and do not reflect the official policy or position of the Department of the Army, Department of Defense, or the U.S. Government Published by Oxford University Press on behalf of the Association of 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.

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Military MedicineOxford University Press

Published: May 24, 2018

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