To Determine The Antivasoplegic Effect Of Intravenous Ketamine In Septic Shock In ICU Patients: A Prospective Comparative Trial

BACKGROUND AND RATIONALE

Septic shock is a kind of distributive shock.Pathophysiology behind septic shock is vasodilation/pooling of blood due to vasoplegia.Organ dysfunction can be identified as an acute change in total SOFA score ≥2 points consequent to the infection. The baseline SOFA score can be assumed to be zero in patients not known to have pre-existing organ dysfunction.1

Septic shock is a potentially fatal medical condition that occurs when sepsis, which is organ injury or damage in response to infection, leads to dangerously low blood pressure and abnormalities in cellular metabolism. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) defines septic shock as a subset of sepsis in which particularly profound circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than with sepsis alone. Patients with septic shock can be clinically identified by requiring a vasopressor to maintain a mean arterial pressure of 65 mm Hg or greater and having serum lactate level greater than 2 mmol/L (>18 mg/dL) in the absence of hypovolemia.2

The pathophysiology of septic shock is not entirely understood, but it is known that a key role in the development of severe sepsis is played by an immune and coagulation response to an infection. Both pro-inflammatory and anti-inflammatory responses play a role in septic shock.3 Septic shock involves a widespread inflammatory response that produces a hypermetabolic effect. This is manifested by increased cellular respiration, protein catabolism, and metabolic acidosis with a compensatory respiratory alkalosis.3

Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist, classified as a dissociative anesthetic, providing both amnesia and analgesia.Ketamine provides a sympathomimetic response that may be beneficial to patients in shock. Ketamine, a potent analgesic and amnestic, is known to have IL-6-inhibiting properties. Ketamine comes in two forms: racemic (most commonly available), and S-ketamine (esketamine, Spravato®).4 The combination of anti-inflammatory and sympathomimetic properties of ketamine may play a role in reducing the risk of vasoplegia in high-risk cardiac surgery, such as left ventricular assist device (LVAD) to transplant.5

Interleukin 6 (IL-6) affects the immune system homeostatic processes with context-dependent pro- and anti-inflammatory properties that have become a prominent target for clinical intervention to improve disease outcome and patient wellbeing by focusing on how and when to block it. We sought to determine the incidence of adverse events of ketamine as a sedative agent in patients who require mechanical ventilation for greater than 24 hours.6

Shaked G  et al (2004) conducted a study that relationship between cytokines and survival following ketamine treatment is uncertain because no study has examined both cytokines and survival after E. coli inoculation. Rats were given E. coli (0.4 x 10(9) colony forming unit (CFU)) at time 0, followed by ketamine (50 mg/kg, n=30) or saline (n=30) at 5 min or 2 h. IL-6 and TNF were measured in serum at 6 h, and mortality was recorded for 7 days. Survival rate with ketamine was 57% (17/30) and was significantly increased compared to saline (27%, 8/30, P=0.01). IL-6 and TNF were lower with ketamine than saline (15,197 +/- 3444 versus 30,725 +/- 4623 pg/ml [mean +/- S.E.M.], P=0.013 and 38.5 +/- 9.5 versus 122.5 +/- 14.0 pg/ml, P=0.001, respectively). With ketamine, IL-6 (but not TNF) concentrations were lower in the survivors (10,900 +/- 776 pg/ml) as compared to the non-survivors (P=0.01). IL-6 in ketamine-treated survivors was not different from that in saline-treated survivors. Conclude that ketamine given 5 min or 2 h after induction of E. coli sepsis significantly improves survival, possibly by interfering with the inflammatory cascade (as evidenced by attenuation of cytokine production).

Lange M, et al (2006) studied that the beneficial effects are basically linked to stimulation of the sympathetic nervous system, inhibition of adenosine triphosphate-sensitive potassium channels and interactions with the nitric oxide pathway. Experimental and clinical studies have shown that ketamine exerts antiinflammatory properties by inhibiting the release of proinflammatory cytokines, such as tumor necrosis factor-alpha and interleukin-6. In addition, there is increasing evidence that early ketamine administration reduces mortality in experimental sepsis models. In this study ketamine appears to represent a beneficial therapeutic option for long-term sedation of patients with arterial hypotension resulting from sepsis and systemic inflammatory response syndrome (SIRS). However, it has to be taken into account that ketamine inhibits endothelial nitric oxide synthase, thereby potentially aggravating impaired (micro) regional blood flow in sepsis. Future studies are required to investigate the role of ketamine in the treatment of patients with sepsis and SIRS.

Umunna BP et al (2015) conducted a single-center retrospective study from September 2011 to March 2012 of patients who required sedation for greater than 24 hours, in whom ketamine was selected as the primary sedative agent. All patients greater than 18 years of age, regardless of admitting diagnosis, were eligible for inclusion. Patients that received ketamine for continuous infusion but died prior to receiving it for 24 hours were not included. Thirty patients received ketamine for continuous sedation. In four patients, ketamine was switched to another sedative agent due to possible adverse side effects. Of these, two patients had tachydysrhythmias, both with new onset atrial fibrillation and two patients had agitation believed to be caused by ketamine. The adverse event rate in our patient population was 13% (4/30). Among ICU patients receiving prolonged mechanical ventilation, the use of ketamine appeared to have a frequency of adverse events similar to more common sedative agents, like propofol and benzodiazepines.

LuggyaTS  et al (2017) conducted a randomized study that to receive pre-incision intravenous ketamine - 0.5mg/kg or 0.9% saline placebo in weighted dosing. Blood samples were collected and laboratory analyzed at baseline, post-operatively in PACU, 24 and 48 hours respectively. Total 39 patients of whom 18 were randomized to the ketamine arm and 21 in the placebo arm with follow up at 24 and 48 hours. Serum IL-6 and IL-1β levels were analyzed using ELIZA assay of pre-coated micro wells. Ketamine suppressed serum IL-6 at PACU with reduced increase at 24 hours. There was no reaction in 98% of IL-1β assayed. Low-dose ketamine attenuated early serum IL-6 levels due to surgical response with reduced 24 hour increase, but the difference was not statistically significant and we recommend more studies.

Reese JM  et al (2018) conducted a two-phase study in a multi-disciplinary adult ICU at a tertiary medical center 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. 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.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).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.

Amer, M  et al (2021) conducted a Pilot, active-controlled, open-label RCT was conducted at medical, surgical, and transplant ICUs at a large tertiary and quaternary care medical institution (King Faisal Specialist Hospital and Research Center, Saudi Arabia). Adult patients who were intubated within 24 h, expected to require MV for the next calendar day, and had institutional pain and sedation protocol initiated. Patients were randomized in a 1:1 ratio to adjunct ketamine infusion 1–2 μg/kg/min for 48 h or CG alone. Total 437 patients screened from September 2019 through November 2020, 83 (18.9%) patients were included (43 in CG and 40 in ketamine) and 352 (80.5%) were excluded. Consent and protocol adherence rates were adequate (89.24% and 76%, respectively). Demographics were balanced between groups. Median MV duration was 7 (interquartile range [IQR] 3–9.25 days) in ketamine and 5 (IQR 2–8 days) in CG. Median VFDs was 19 (IQR 0–24.75 days) in ketamine and 19 (IQR 0–24 days) in the CG (p = 0.70). More patients attained goal Richmond Agitation–Sedation Scale at 24 and 48 h in ketamine (67.5% and 73.5%, respectively) compared with CG (52.4% and 66.7%, respectively). Sedatives and vasopressors cumulative use, and hemodynamic changes were similar. ICU length-of-stay was 12.5 (IQR 6–21.2 days) in ketamine, compared with 12 (IQR 5.5–23 days) in CG. No serious adverse events were observed in either group. Ketamine as an adjunct analgosedative agent appeared to be feasible and safe with no negative impact on outcomes, including hemodynamics. This pilot RCT identified areas of improvement in study protocol before conducting a large, adequately powered, multicenter RCT which is likely justified to investigate ketamine association with patient-centered outcomes further.

Jung H  et al (2022) conducted a retrospective cohort study between March 2012 and June 2020 at an academy-affiliated tertiary hospital. Adult patients who received mechanical ventilation support for over 24 h and continuous ketamine infusion for at least 8 h were included. The primary outcome was immediate hemodynamic safety after continuous ketamine infusion. The secondary outcomes included immediate delirium, pain, and use of sedation.  Total 12,534 medical and cardiac ICU patients, 564 were eligible for the analysis. Ketamine was used for 33.3 (19.0-67.5) h and the median continuous infusion dose was 0.11 (0.06-0.23) mcg/kg/h. Of all patients, 469 (83.2%) received continuous ketamine infusion concomitant with analgosedation. Blood pressure and vasopressor inotropic scores did not change after continuous ketamine infusion. Heart rate decreased significantly from 106.9 (91.4-120.9) at 8 h before ketamine initiation to 99.8% (83.9-114.4) at 24 h after ketamine initiation. In addition, the respiratory rate decreased from 21.7 (18.6-25.4) at 8 h before ketamine initiation to 20.1 (17.0-23.0) at 24 h after ketamine initiation. Overall opioid usage was significantly reduced: 3.0 (0.0-6.0) mcg/kg/h as fentanyl equivalent dose at 8 h before ketamine initiation to 1.0 (0.0-4.1) mcg/kg/h as fentanyl equivalent dose at 24 h post-ketamine initiation. However, the use of sedatives and antipsychotic medications did not decrease. In addition, ketamine did not increase the incidence of delirium within 24 h after ketamine infusion. Ketamine may be a safe and feasible analgesic for medical and cardiac ICU patients who received mechanical ventilation support as an opioid-sparing agent without adverse hemodynamic effects.

AIM AND OBJECTIVES

·         Aim of this study is to determine anti vasoplegic effect of intravenous ketamine in septic shock

Primary Objectives: To study the effect of ketamine on antivasoplegic effect by measuring interleukin 6 level

Secondary Objectives:

Ø  Total vasopressor requirement

Ø  Duration of vasopressor use[days]

Ø  ICU length of stay

Ø  28days mortality

Ø  Effect on SOFAscore

MATERIAL AND METHODS

Study settings:

The study will be conducted in Department of Anesthesiology,  King George’s Medical University, Lucknow.

Study duration: One and half year

Study design: Randomized controlled trial

Sample Size:

n= Z2P(1-P)/d2

 Where,

●        n = sample size,

●        Z = Z statistic for a level of confidence, for the level of confidence of 95%, which is conventional, Z value is 1.96.

●        P = prevalence based on previous study or proportion  (in proportion of one; if 57%, P = 0.57),

●        d = precision (in proportion of one; if 10%, d = 0.1).

**n=**1.96x1.96x0.57x0.43/0.12

=96.08

The minimum sample size required n=96 (approx.=100)

**Reference:**Shaked G, Czeiger D, Dukhno O, Levy I, Artru AA, Shapira Y, Douvdevani A. Ketamine improves survival and suppresses IL-6 and TNFalpha production in a model of Gram-negative bacterial sepsis in rats. Resuscitation. 2004 Aug;62(2):237-42. doi: 10.1016/j.resuscitation.2004.02.015. PMID: 15294410.

Inclusion criteria:

·         20-50 years old patients admitted in ICU with septic shock.

Exclusion criteria:

·         presence of shock other than septic shock

·         Pregnancy

·         Allergic to ketamine

·         Increased ICP

·         APACHE

25

·         Patient expired in 24hrs

Study Protocol:

The study will be conducted after getting approval from ethics committee of King George’s Medical University, Lucknow. A computer generated system will be used for randomization by creating a list of number each number referred to a patient

All enrolled patients who full fill the inclusion criteria will be randomly allocated with two groups

–      Group A: All standard ICU protocol with infusion of placebo in form of NS

–      Group B: All standard ICU protocol with infusion of  ketamine in low dose (0.5 mg/kg/hr.)

We will enroll all icu admitted patient who are in septic shock or develop during icustay. Septic shock is diagnosed by clinical feature, counts and correlate PCT level other possible shock should be excluded

We will calculate the vasopressor dose{noradrenaline,dopamine,vasopression}by its concentration and flow rate whole duration in hrsof its administration

Beside some taking another inotrope/vasopressor will not be included

Baseline characteristics obtained will be age, gender, weight (kilograms), race (White/Caucasian, Black/African American, others), and primary diagnoses. Height and weight were collected to calculate body mass index (BMI).

All enrolled patients will be given standard treatment as per ICU protocol of either group.In the group A normal saline will be given through infusion pump as placebo and in group B low dose ketamine[0.5mg/kg/hr] will be given as intervention.

we will take blood sample on day 1,3,5 for assessing IL-6 level and vasopressor requirements. We will follow-up the patient and noted total no days of ICU stay and mortality ,if any with in 28 days.

APACHE   score on day of admission and SOFA score daily till the follow up patient.

Data will be collected on multiple variables, including demographics, adverse events, ventilator days, ICU days, and mortality. Patient demographic data included patient name, age, medical record number, date of admit, and diagnosis.

End point of study:

• patient expired within 28 days

-patient completely cured

-patient shock got resolved

Outcome measuresStatistical Analysis

The SPSS (Version 23.0) program will be used for statistical analysis. Descriptive statistics will be presented as mean, standard deviation, median, minimum, maximum, frequency and ratios. Categorical data will be analysed using the chi-square test, and continuous data will be analysed using the student t-test. Descriptive statistics will be used to analyze and report our data. Specifically, we report means and ranges of ketamine doses and duration of sedation, point estimates of adverse event rates, and confidence intervals using the exact method. Significance will be evaluated at a p-value <0.05.

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