Advertisement

Early Sedation Depth and Clinical Outcomes in Mechanically Ventilated Patients in a Hospital: Retrospective Cohort Study

Open AccessPublished:December 30, 2022DOI:https://doi.org/10.1016/j.anr.2022.12.002

      sum mary

      Purpose

      This study aimed to identify the early sedation depth in the first 48 hours of mechanical ventilation and its relationship to clinical outcomes to promote the transition to light sedation.

      Methods

      This retrospective single-center cohort study was conducted in two medical intensive care units (MICUs) at a general tertiary hospital, using a standardized sedation protocol. To investigate the early sedation depth, the Sedation Index was used, which can indicate changes over the first 48 hours. Patients were divided into three groups based on tertiles of Sedation Index. The primary outcome was mortality at 30, 90, and 180 days. The secondary outcomes included length of stay in the ICU and ventilator-free days. Kaplan-Meier analysis and multivariable Cox regression were conducted to compare factors influencing mortality.

      Results

      This study included 394 patients. The deepest sedation group showed more severe illness, delirium, and deeper sedation at admission (p < .001). The survival curve decreased as sedation increased, even within the light sedation levels. In the deepest sedation group, 30-day mortality (hazard ratio [HR] 2.11, 95% confidence interval [CI] 1.33–3.34), 90-day mortality (HR 2.00, 95% CI 1.31–3.06), and 180-day mortality (HR 1.77, 95% CI 1.17–2.67) increased. The length of stay in the ICU and ventilator-free days did not show statistical differences.

      Conclusions

      These results indicate that early deep sedation is a modifiable factor that can potentially affect mortality. The protocol for inducing the transition into light sedation must comply with recommendations to improve clinical outcomes.

      Keywords

      Introduction

      Sedating a patient under mechanical ventilation is important for promoting stability and safety to aid in managing pain, agitation, and delirium, as well as preventing increased oxygen consumption due to desynchronization with mechanical ventilation [
      • Balzer F.
      • Weiss B.
      • Kumpf O.
      • Treskatsch S.
      • Spies C.
      • Wernecke K.D.
      • et al.
      Early deep sedation is associated with decreased in-hospital and two-year follow-up survival.
      ,
      • Lee J.M.
      • Lee S.H.
      • Kwak S.H.
      • Kang H.H.
      • Lee S.H.
      • Lim J.M.
      • et al.
      Comparison of morphine and remifentanil on the duration of weaning from mechanical ventilation.
      ,
      • Park C.S.
      The current state of sedation outside the operating room.
      ]. However, the appropriateness of sedation therapy is being questioned after reports of negative outcomes due to the prolonged application of mechanical ventilation under deep sedation [
      • Shehabi Y.
      • Bellomo R.
      • Reade M.C.
      • Bailey M.
      • Bass F.
      • Howe B.
      • et al.
      Early intensive care sedation predicts long-term mortality in ventilated critically ill patients.
      ,
      • Strom T.
      • Martinussen T.
      • Toft P.
      A protocol of no sedation for critically ill patients receiving mechanical ventilation: a randomised trial.
      ,
      • Treggiari M.M.
      • Romand J.A.
      • Yanez N.D.
      • Deem S.A.
      • Goldberg J.
      • Hudson L.
      • et al.
      Randomized trial of light versus deep sedation on mental health after critical illness.
      ]. Thus, the practice guidelines for sedation of critical patients under mechanical ventilation released by the U.S. Society of Critical Care Medicine advise maintaining light sedation, which is sufficient to facilitate treatment [
      • Barr J.
      • Fraser G.L.
      • Puntillo K.
      • Ely E.W.
      • Gelinas C.
      • Dasta J.F.
      • et al.
      Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit.
      ,
      • Devlin J.W.
      • Skrobik Y.
      • Gelinas C.
      • Needham D.M.
      • Slooter A.J.C.
      • Pandharipande P.P.
      • et al.
      Clinical practice guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the ICU.
      ].
      It has recently been reported that deep sedation within the first 48 hours of mechanical ventilation is a major factor that increases mortality in hospitals, even considering the patient's characteristics, such as severity of illness [
      • Balzer F.
      • Weiss B.
      • Kumpf O.
      • Treskatsch S.
      • Spies C.
      • Wernecke K.D.
      • et al.
      Early deep sedation is associated with decreased in-hospital and two-year follow-up survival.
      ,
      • Shehabi Y.
      • Bellomo R.
      • Kadiman S.
      • Ti L.K.
      • Howe B.
      • Reade M.C.
      • et al.
      Sedation intensity in the first 48 hours of mechanical ventilation and 180-day mortality: a multinational prospective longitudinal cohort study.
      ,
      • Stephens R.J.
      • Evans E.M.
      • Pajor M.J.
      • Pappal R.D.
      • Egan H.M.
      • Wei M.
      • et al.
      A dual-center cohort study on the association between early deep sedation and clinical outcomes in mechanically ventilated patients during the COVID-19 pandemic: the COVID-SED Study. Res Sq [Preprint].
      ,
      • Tanaka L.M.
      • Azevedo L.C.
      • Park M.
      • Schettino G.
      • Nassar A.P.
      • Rea-Neto A.
      • et al.
      Early sedation and clinical outcomes of mechanically ventilated patients: a prospective multicenter cohort study.
      ]. Furthermore, deeply sedated patients tend to experience less pain [
      • Balzer F.
      • Weiss B.
      • Kumpf O.
      • Treskatsch S.
      • Spies C.
      • Wernecke K.D.
      • et al.
      Early deep sedation is associated with decreased in-hospital and two-year follow-up survival.
      ], but more subsequent delirium [
      • Shehabi Y.
      • Bellomo R.
      • Kadiman S.
      • Ti L.K.
      • Howe B.
      • Reade M.C.
      • et al.
      Sedation intensity in the first 48 hours of mechanical ventilation and 180-day mortality: a multinational prospective longitudinal cohort study.
      ] and have an increased length of stay in the intensive care unit (ICU) [
      • Balzer F.
      • Weiss B.
      • Kumpf O.
      • Treskatsch S.
      • Spies C.
      • Wernecke K.D.
      • et al.
      Early deep sedation is associated with decreased in-hospital and two-year follow-up survival.
      ,
      • Stephens R.J.
      • Evans E.M.
      • Pajor M.J.
      • Pappal R.D.
      • Egan H.M.
      • Wei M.
      • et al.
      A dual-center cohort study on the association between early deep sedation and clinical outcomes in mechanically ventilated patients during the COVID-19 pandemic: the COVID-SED Study. Res Sq [Preprint].
      ] and longer ventilation times [
      • Balzer F.
      • Weiss B.
      • Kumpf O.
      • Treskatsch S.
      • Spies C.
      • Wernecke K.D.
      • et al.
      Early deep sedation is associated with decreased in-hospital and two-year follow-up survival.
      ,
      • Stephens R.J.
      • Evans E.M.
      • Pajor M.J.
      • Pappal R.D.
      • Egan H.M.
      • Wei M.
      • et al.
      A dual-center cohort study on the association between early deep sedation and clinical outcomes in mechanically ventilated patients during the COVID-19 pandemic: the COVID-SED Study. Res Sq [Preprint].
      ,
      • Tanaka L.M.
      • Azevedo L.C.
      • Park M.
      • Schettino G.
      • Nassar A.P.
      • Rea-Neto A.
      • et al.
      Early sedation and clinical outcomes of mechanically ventilated patients: a prospective multicenter cohort study.
      ]. Although this modifiable factor can improve clinical outcomes [
      • Balzer F.
      • Weiss B.
      • Kumpf O.
      • Treskatsch S.
      • Spies C.
      • Wernecke K.D.
      • et al.
      Early deep sedation is associated with decreased in-hospital and two-year follow-up survival.
      ], many patients still undergo deep sedation at the beginning of their treatment [
      • Fuller B.M.
      • Roberts B.W.
      • Mohr N.M.
      • Knight Iv W.A.
      • Adeoye O.
      • Pappal R.D.
      • et al.
      The ED-SED study: a multicenter, prospective cohort study of practice patterns and clinical outcomes associated with emergency department sedation for mechanically ventilated patients.
      ,
      • Stephens R.J.
      • Dettmer M.R.
      • Roberts B.W.
      • Ablordeppey E.
      • Fowler S.A.
      • Kollef M.H.
      • et al.
      Practice patterns and outcomes associated with early sedation depth in mechanically ventilated patients: a systematic review and meta-analysis.
      ]. In Korea, efforts have been made to comply with the sedation protocol [
      • Ko J.Y.
      • Park H.J.
      • In Y.W.
      • Lee Y.M.
      • Kim J.M.
      • Lee S.Y.
      Effect of pharmacist's intervention and management of pain and sedation protocol on clinical outcomes in medical ICU.
      ] and adjust medication use [
      • Kim H.H.
      • Choi S.C.
      • Ahn J.H.
      • Chae M.K.
      • Heo J.
      • Min Y.G.
      Analysis of trends in usage of analgesics and sedatives in intensive care units of South Korea: a retrospective nationwide population-based study.
      ,
      • Sim J.K.
      • Lee S.M.
      • Kang H.K.
      • Kim K.C.
      • Kim Y.S.
      • Kim Y.S.
      • et al.
      Change in management and outcome of mechanical ventilation in Korea: a prospective observational study.
      ] to transition to light sedation. Nevertheless, >50% of patients remain under deep sedation for the first 5 days under mechanical ventilation [
      • Sim J.K.
      • Lee S.M.
      • Kang H.K.
      • Kim K.C.
      • Kim Y.S.
      • Kim Y.S.
      • et al.
      Change in management and outcome of mechanical ventilation in Korea: a prospective observational study.
      ]. There is a lack of data on the association between sedation level and clinical outcomes such as early sedation depth and mortality.
      Deep sedation, as defined by the Richmond Agitation–Sedation Scale (RASS), an instrument for measuring sedation depth [
      • Sessler C.N.
      • Gosnell M.S.
      • Grap M.J.
      • Brophy G.M.
      • O'Neal P.V.
      • Keane K.A.
      • et al.
      The richmond agitation-sedation scale: validity and reliability in adult intensive care unit patients.
      ], is typically classified as a RASS score of ≤−3 points [
      • Stephens R.J.
      • Dettmer M.R.
      • Roberts B.W.
      • Ablordeppey E.
      • Fowler S.A.
      • Kollef M.H.
      • et al.
      Practice patterns and outcomes associated with early sedation depth in mechanically ventilated patients: a systematic review and meta-analysis.
      ]. However, the RASS score of the patient varies considerably over time [
      • Shehabi Y.
      • Bellomo R.
      • Reade M.C.
      • Bailey M.
      • Bass F.
      • Howe B.
      • et al.
      Early intensive care sedation predicts long-term mortality in ventilated critically ill patients.
      ] and has positive and negative values. Thus, calculating the sedation depth in the first 48 hours following mechanical ventilation is difficult [
      • Shehabi Y.
      • Bellomo R.
      • Kadiman S.
      • Ti L.K.
      • Howe B.
      • Reade M.C.
      • et al.
      Sedation intensity in the first 48 hours of mechanical ventilation and 180-day mortality: a multinational prospective longitudinal cohort study.
      ]. To deal with methodological problems, the Sedation Index was regarded as a representative value of early sedation depth to reflect changes over the first 48 hours of ventilation instead of a single point in time [
      • Shehabi Y.
      • Bellomo R.
      • Kadiman S.
      • Ti L.K.
      • Howe B.
      • Reade M.C.
      • et al.
      Sedation intensity in the first 48 hours of mechanical ventilation and 180-day mortality: a multinational prospective longitudinal cohort study.
      ]. To ascertain the current situation in this study, the Sedation Index was investigated in patients admitted to two medical ICUs (MICUs) at a general tertiary hospital in Korea that followed a standardized sedation protocol. In addition, the association of Sedation Index with clinical outcomes, including mortality, was analyzed. This study was aimed to examine the recent practice of sedating critically ill patients and provide basic data for transitioning to a light sedation protocol.

      Methods

      Study design

      This retrospective cohort study used data from the electronic medical records of an university-affiliated hospital Seoul, South Korea. To identify the effects of early deep sedation on the clinically important outcomes of patients under mechanical ventilation, all patients in the database were admitted to two MICUs and received mechanical ventilation from July 2018 to December 2019. This hospital follows a standardized sedation protocol (the Pain, Agitation, and Delirium [PAD] Protocol) [
      • Ko J.Y.
      • Park H.J.
      • In Y.W.
      • Lee Y.M.
      • Kim J.M.
      • Lee S.Y.
      Effect of pharmacist's intervention and management of pain and sedation protocol on clinical outcomes in medical ICU.
      ], with the nursing staff periodically measuring the patients’ sedation depth using the RASS [
      • Sessler C.N.
      • Gosnell M.S.
      • Grap M.J.
      • Brophy G.M.
      • O'Neal P.V.
      • Keane K.A.
      • et al.
      The richmond agitation-sedation scale: validity and reliability in adult intensive care unit patients.
      ].

      Participants

      Patients aged older than 18 years old who underwent endotracheal intubation followed by mechanical ventilation were included. Endotracheal intubation was performed in the emergency room, general ward, operating room, radiology room, or ICU of the study hospital. The criteria for initiation of mechanical ventilation were based on the actual time of intubation. The exclusion criteria were as follows: mechanical ventilation lasting less than 48 hours, not consenting to provide personal information, history of endotracheal intubation at another hospital, fewer than three RASS assessments during the first 48 hours under mechanical ventilation, reduced consciousness due to separate sedation or neurological injury from cardiovascular resuscitation, stroke, or other reasons; receiving extracorporeal membrane oxygenation (ECMO) for the heart or lungs; and history of ICU admission twice or more.

      Demographics and clinical characteristics

      Age, sex, admission route, patient diagnosis, and Simplified Acute Physiology Score (SAPS) III [
      • Moreno R.P.
      • Metnitz P.G.
      • Almeida E.
      • Jordan B.
      • Bauer P.
      • Campos R.A.
      • et al.
      SAPS 3--From evaluation of the patient to evaluation of the intensive care unit. part 2: development of a prognostic model for hospital mortality at ICU admission.
      ] were collected. The SAPS III is a validated scoring system for predicting hospital mortality that considers patient characteristics before ICU admission, reasons for ICU admission, and existence of physiologic derangement at ICU admission [
      • Moreno R.P.
      • Metnitz P.G.
      • Almeida E.
      • Jordan B.
      • Bauer P.
      • Campos R.A.
      • et al.
      SAPS 3--From evaluation of the patient to evaluation of the intensive care unit. part 2: development of a prognostic model for hospital mortality at ICU admission.
      ]. After admittance to the ICU, the doctor recorded the patient's unique SAPS III score.

      Sedation depth

      Early sedation depth refers to the Sedation Index in the first 48 hours of mechanical ventilation: the higher the Sedation Index, the deeper the early sedation depth. The Sedation Index is the sum of negative RASS scores divided by the total number of RASS measurements [
      • Shehabi Y.
      • Bellomo R.
      • Kadiman S.
      • Ti L.K.
      • Howe B.
      • Reade M.C.
      • et al.
      Sedation intensity in the first 48 hours of mechanical ventilation and 180-day mortality: a multinational prospective longitudinal cohort study.
      ]. The RASS is reliable instrument for assessing the quality and degree of sedation and agitation in adult ICU patients [
      • Barr J.
      • Fraser G.L.
      • Puntillo K.
      • Ely E.W.
      • Gelinas C.
      • Dasta J.F.
      • et al.
      Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit.
      ,
      • Sessler C.N.
      • Gosnell M.S.
      • Grap M.J.
      • Brophy G.M.
      • O'Neal P.V.
      • Keane K.A.
      • et al.
      The richmond agitation-sedation scale: validity and reliability in adult intensive care unit patients.
      ] and has a high quality of psychometric evidence such as interrater reliability, convergent or discriminant validation [
      • Barr J.
      • Fraser G.L.
      • Puntillo K.
      • Ely E.W.
      • Gelinas C.
      • Dasta J.F.
      • et al.
      Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit.
      ]. The individual RASS values, indicating the sedation depth at a specific time, were the data that the nurse measured every shift or, additionally, if changed. The participants were divided into three groups based on the tertiles of Sedation Index: the first tertile indicates the group with the lightest sedation level, whereas the third tertile indicates the group with the deepest sedation level. Under the central limit theorem, when the number of participants in each group was greater than 30, the normal approximation was regarded adequate [
      • Johnson R.A.
      • Bhattacharyya G.K.
      Statistics: principles and methods.
      ]. However, the individual RASS score at the point of admission could not be expressed by the Sedation Index; a single RASS of −3 or lower was categorically classified as deep sedation, from −2 to +1 as light sedation, and +2 and higher as agitation [
      • Riker R.R.
      • Shehabi Y.
      • Bokesch P.M.
      • Ceraso D.
      • Wisemandle W.
      • Koura F.
      • et al.
      Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial.
      ].

      Prevalence of pain and delirium

      During the first 48 hours of mechanical ventilation, the presence of pain and delirium was recorded. Pain and delirium in critically ill adults are recommended to measure by using reliable and valid assessment method [
      • Barr J.
      • Fraser G.L.
      • Puntillo K.
      • Ely E.W.
      • Gelinas C.
      • Dasta J.F.
      • et al.
      Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit.
      ,
      • Devlin J.W.
      • Skrobik Y.
      • Gelinas C.
      • Needham D.M.
      • Slooter A.J.C.
      • Pandharipande P.P.
      • et al.
      Clinical practice guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the ICU.
      ]. For patients who can express pain, the Numeric Rating Scale (NRS) is a valid and feasible pain scale [
      • Barr J.
      • Fraser G.L.
      • Puntillo K.
      • Ely E.W.
      • Gelinas C.
      • Dasta J.F.
      • et al.
      Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit.
      ,
      • Devlin J.W.
      • Skrobik Y.
      • Gelinas C.
      • Needham D.M.
      • Slooter A.J.C.
      • Pandharipande P.P.
      • et al.
      Clinical practice guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the ICU.
      ,
      • Puntillo K.
      • Pasero C.
      • Li D.
      • Mularski R.A.
      • Grap M.J.
      • Erstad B.L.
      • et al.
      Evaluation of pain in ICU patients.
      ]. For whom unable to report pain, the Critical Care Pain Observation Tool (CPOT) is useful because it has high interrater reliability and discriminant and criterion validity for all ICU adults except patients with brain injury [
      • Barr J.
      • Fraser G.L.
      • Puntillo K.
      • Ely E.W.
      • Gelinas C.
      • Dasta J.F.
      • et al.
      Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit.
      ,
      • Gélinas C.
      • Fillion L.
      • Puntillo K.A.
      • Viens C.
      • Fortier M.
      Validation of the critical-care pain observation tool in adult patients.
      ]. Pain was recorded as yes in the presence of the NRS score ≥4, or the CPOT score ≥3 at least once during the early phase of ventilation. Delirium was assessed using the Confusion Assessment Method-ICU (CAM-ICU), which has very good psychometric properties of validity and high interrater reliability [
      • Barr J.
      • Fraser G.L.
      • Puntillo K.
      • Ely E.W.
      • Gelinas C.
      • Dasta J.F.
      • et al.
      Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit.
      ]. The presence of at least one positive result was considered delirium during the first 48 hours of ventilation. But RASS scores of −4 or lower and +3 or higher were excluded because they could not be assessed in the CAM-ICU. Pain and delirium data were assessed by the bedside ICU nurse every shift or, additionally, if changed.

      Sedative variables

      Information on medications administered as analgesics and sedatives during the first 48 hours of ventilation was also collected. They were sorted by type (analgesics or sedatives) and infusion method (intermittent or continuous administration).

      Outcome

      Clinical outcomes related to early sedation depth included the following. The primary outcome was mortality over 30, 90, and 180 days. Patients were followed-up until hospital day 180 or death. Secondary outcomes included length of stay in the ICU and ventilator-free days [
      • Schoenfeld D.A.
      • Bernard G.R.
      Statistical evaluation of ventilator-free days as an efficacy measure in clinical trials of treatments for acute respiratory distress syndrome.
      ]. Length of stay in the ICU refers to the total period from admission to discharge from ICU. Ventilator-free days are defined as the number of days in which spontaneous breathing is possible continuously for more than 48 hours without mechanical ventilation assistance [
      • Schoenfeld D.A.
      • Bernard G.R.
      Statistical evaluation of ventilator-free days as an efficacy measure in clinical trials of treatments for acute respiratory distress syndrome.
      ]. If the patient is successfully weaned from mechanical ventilation within 28 days, ventilator-free days are calculated by subtracting the number of days applied to the mechanical ventilation from 28 days [
      • Schoenfeld D.A.
      • Bernard G.R.
      Statistical evaluation of ventilator-free days as an efficacy measure in clinical trials of treatments for acute respiratory distress syndrome.
      ]. If the patient died before 28 days or required mechanical ventilation for 28 days or more, ventilator-free days are zero [
      • Schoenfeld D.A.
      • Bernard G.R.
      Statistical evaluation of ventilator-free days as an efficacy measure in clinical trials of treatments for acute respiratory distress syndrome.
      ].

      Ethical consideration

      This study was approved by the Institutional Review Board of the Samsung Medical Center (Approval no. 2020-XX-099). The need for informed patient consent was waived because of the study's retrospective nature. This study was performed in accordance with the relevant guidelines and regulations of the IRB. One researcher then examined and collected electronic medical records.

      Statistical analysis

      The collected data were analyzed using SPSS WIN 25.0 (SPSS Inc., Chicago, IL, USA), with a significance level of .05, and a 95% confidence interval as follows: continuous variables were presented as average and standard deviation, and categorical variables as frequency and percentage. The patient demographics, clinical characteristics, sedative variables, and clinical outcomes according to the Sedation Index were analyzed using one-way analysis of variance, chi-squared test, or Fisher exact test. A post-hoc test was performed using Bonferroni correction. Kaplan–Meier analysis was conducted to compare the survival period according to the early sedation depth. To analyze the factors influencing mortality, a multivariable Cox regression analysis was conducted (backward likelihood ratio test was used to select variables). The confounding variables were age, sex, admission route, SAPS Ⅲ, patient diagnosis, RASS at admission, Sedation Index, prevalence of pain and delirium, and analgesics and sedatives with intermittent or continuous administration. To account for numerous confounding variables, multivariable Cox regression included covariates with a p value 0.05 in univariable Cox regression. Significant predictors were defined as covariates with a multivariable Cox regression p value 0.05.

      Results

      Demographics, clinical characteristics, and sedative variables according to Sedation Index

      Among the 1,287 patients who were aged more than 18 years and received mechanical ventilation via endotracheal intubation, 970 received mechanical ventilation for ≥48 hours. Of these, 28 patients refused to provide their personal information, 84 had undergone endotracheal intubation in other hospitals, 2 had fewer than three RASS assessments during the first 48 hours under mechanical ventilation, 124 had reduced consciousness due to separate sedation or neurological injury from seizures, cardiovascular resuscitation, stroke, or other reasons, 43 were under ECMO for the heart or lung, and 295 patients had been admitted to the ICU for two or more reasons. After excluding these 576 patients, data from 394 patients were used for analysis. The mean early sedation depth in the entire cohort was 1.35. Dividing this into three groups based on tertiles, the Sedation Index of the first tertile with the lightest sedation ranged from 0.00 to 0.83, with 130 patients (0.54 ± 0.23); the second tertile's Sedation Index ranged from 0.84 to 1.50, with 136 patients (1.13 ± 0.20); and the Sedation Index of the third tertile with the deepest sedation ranged from 1.51 to 5.00, with 128 patients (2.40 ± 0.77) (Figure 1).
      Figure 1
      Figure 1Patient Inclusion Flow Diagram. Note: RASS = Richmond Agitation Sedation Scale; ECMO = extracorporeal membrane oxygenation; SI=Sedation Index.
      The demographics, clinical characteristics, and sedative variables of the patients in the early phase of ventilation in terms of Sedation Index are shown in Table 1. Age, sex (male), ICU admission route, and patient diagnosis did not differ significantly between the groups. More than 50% of patients admitted to ICU had cancer, followed by respiratory, neurological, and digestive system diseases. The SAPS Ⅲ was 58.64 ± 14.62 points in the first tertile, 62.13 ± 15.53 points in the second tertile, and 68.25 ± 15.94 points in the third tertile, increasing as the sedation deepened; there were significant differences between the third tertile and first and second tertile groups (p < .001); 73.8% of the first tertile group was lightly sedated at admission, and only 17.7% were deeply sedated. On the other hand, 50.8% of the third tertile group showed light sedation at admission, and 43.8% showed deep sedation (p < .001).
      Table 1Demographics, Clinical Characteristics and Sedative Variables of Patients in the First 48 Hours of Ventilation according to Sedation Index (N = 394).
      VariableSI 1st tertilea (n = 130)SI 2nd tertileb (n = 136)SI 3rd tertilec (n = 128)X2 or FpPost-hoc
      N (%)/M±SDN (%)/M±SDN (%)/M±SD
      Age(y)63.61 ± 14.1963.67 ± 15.9065.50 ± 14.220.68.506
      Gender, Men87 (66.9)92 (67.6)85 (66.4)0.05.977
      Admission route
       ER53 (40.8)56 (41.2)52 (40.6)4.18.375
      Fisher exact test.
       Ward71 (54.6)78 (57.4)75 (58.6)
       Other6 (4.6)2 (1.5)1 (0.8)
       SAPS Ⅲ (n = 354)58.64 ± 14.6262.13 ± 15.5368.25 ± 15.9411.54<.001∗∗a,b < c
      Patient diagnosis
       Respiratory19 (14.6)19 (14.0)13 (10.2)6.91.547
       Cancer73 (56.2)73 (53.7)76 (59.4)
       Neurology7 (5.4)8 (5.9)13 (10.2)
       Gastrointestinal6 (4.6)8 (5.9)9 (7.0)
       Other25 (19.2)28 (20.6)17 (13.3)
      RASS at admission
       Light sedation96 (73.8)83 (61.0)65 (50.8)20.57<.001∗∗
       Deep sedation23 (17.7)43 (31.6)56 (43.8)
       Agitation11 (8.5)10 (7.4)7 (5.5)
       Pain prevalence
      Pain was recorded as yes in the presence of the Numeric Rating Scale (NRS) score ≥4, or the Critical Care Pain Observation Tool (CPOT) score ≥3 at least once.
      40 (30.8)45 (33.1)24 (18.8)7.71.021
       Delirium prevalence
      Delirium was recorded as yes when at least one Confusion Assessment Method-ICU (CAM-ICU) was positive.
      85 (65.4)114 (83.8)115 (89.8)26.03<.001∗∗
      Analgesic, intermittent114 (87.7)126 (92.6)105 (82.0)6.83.033
       Fentanyl114 (87.7)126 (91.9)103 (80.5)7.67.022
       Morphine5 (3.8)5 (3.7)5 (3.9)1.000
       Pethidine4 (3.1)6 (4.4)2 (1.6).442
       Hydromorphone1 (0.8)0 (0.0)1 (0.8).547
      Analgesic, continuous118 (90.8)120 (88.2)108 (84.4)2.50.287
       Remifentanil110 (84.6)112 (82.4)94 (73.4)5.68.058
       Fentanyl21 (16.2)21 (15.4)21 (16.4)0.05.976
       Hydromorphone6 (4.6)11 (8.1)21 (16.4)10.87.004∗∗
      Sedative, intermittent89 (68.5)85 (62.5)86 (67.2)1.17.556
       Ketamine85 (65.4)79 (58.1)70 (54.7)3.21.201
       Propofol3 (2.3)2 (1.5)3 (2.3).824
       Midazolam1 (0.8)0 (0.0)5 (3.9).011
      Sedative, continuous50 (38.5)53 (39.0)77 (60.2)16.01<.001∗∗
       Ketamine30 (23.1)30 (22.1)50 (39.1)11.73.003∗∗
       Dexmedetomidine24 (18.5)28 (20.6)22 (17.2)0.51.774
       Propofol4 (3.1)2 (1.5)25 (19.5)35.82<.001∗∗
       Midazolam0 (0.0)0 (0.0)5 (3.9).003∗∗
      Note: ER = emergency room; RASS = Richmond Agitation–Sedation Scale; SAPS III = Simplified Acute Physiology Score III; SI = Sedation Index.
      ∗ p < .01.
      ∗∗ p < .001.
      a SI 1st tertile group.
      b SI 2nd tertile group.
      c SI 3rd tertile group
      Fisher exact test.
      Pain was recorded as yes in the presence of the Numeric Rating Scale (NRS) score ≥4, or the Critical Care Pain Observation Tool (CPOT) score ≥3 at least once.
      § Delirium was recorded as yes when at least one Confusion Assessment Method-ICU (CAM-ICU) was positive.
      Pain prevalence decreased from the first to the third tertile (30.8 vs. 18.8%, p = .021). Delirium prevalence was 65.4% in the first tertile, 83.8% in the second tertile, and 89.8% in the third tertile, increasing as sedation deepened, showing significant differences (p < .001).
      Intermittent analgesics were most frequently used in the second tertile (92.6%, p = .033). Fentanyl was used the most in all groups and showed significant differences among the three groups (p = .022). Continuous analgesic prescribed most was remifentanil in all three groups, but statistically significant difference between groups was only shown in hydromorphone among continuous analgesics (p = .004). No significant differences were found between the three groups in the use of intermittent sedatives, and ketamine was used the most. The use of midazolam showed significant differences among the three groups (p = .011). Continuous sedatives were used by 60.2% of the third tertile, with a significantly higher usage rate than the first tertile (38.5%) and the second tertile (39.0%) (p < .001). Although the continuous infusion of midazolam, ketamine, and propofol showed significant differences among the groups per medication, there were no significant differences in the use of dexmedetomidine among the three groups.

      Clinical outcomes according to Sedation Index

      The clinical outcomes of patients in the first 48 hours of ventilation in accordance with the Sedation Index are shown in Table 2. The primary outcome was the mortality rate. The 30-day mortality (p < .001), 90-day mortality (p = .004), and 180-day mortality (p = .013) increased as sedation deepened, indicating statistical differences. The results of the Kaplan–Meier analysis of 30-, 90-, and 180-day mortality are shown in Figure 2. Throughout all periods, the survival curve indicated a significant difference between the first tertile and the second and third tertiles, and the survival curve between the second and third tertiles was not statistically significant. The secondary outcome was length of stay in the ICU and ventilator-free days, neither of which revealed statistically significant differences within the groups (Table 2).
      Table 2Clinical Outcomes of Patients in the First 48 Hours of Ventilation according to Sedation Index (N = 394).
      VariableSI 1st tertile (n = 130)SI 2nd tertile (n = 136)SI 3rd tertile (n = 128)X2 or Fp
      N (%)/M±SDN (%)/M±SDN (%)/M±SD
      Mortality
       30-day mortality32 (24.6)58 (42.6)67 (52.3)21.37<.001∗∗
       90-day mortality48 (36.9)70 (51.5)73 (57.0)11.19.004∗∗
       180-day mortality56 (43.1)75 (55.1)78 (60.9)8.63.013
      Length of stay, ICU11.65 ± 9.6813.58 ± 13.6312.42 ± 8.691.06.349
      Ventilator-free days19.59 ± 7.7518.72 ± 7.6318.59 ± 6.990.68.507
      Note: SI = Sedation Index.
      ∗ p < .01.
      ∗∗ p < .001.
      Figure 2
      Figure 2Tertiles of Sedation Index Kaplan–Meier 30-, 90-, and 180-day survival curve. Note: The log rank p values of comparing with groups are values applied with Bonferroni correction.

      Relationship between factors influencing mortality

      To analyze the factors influencing mortality and how the Sedation Index predicted mortality, multivariable Cox regression was performed, and the results are shown in Table 3. Multivariable Cox regression incorporated factors with a p value of 0.05 in univariable Cox regression to account for various confounding variables of age, sex, admission route, SAPS Ⅲ, patient diagnosis, RASS at admission, Sedation Index, prevalence of pain and delirium, and analgesics and sedatives with intermittent or continuous administration. The admission route, SAPS III, use of intermittent morphine, delirium prevalence, and Sedation Index were the variables associated with 30-day mortality in univariable Cox regression. Addition to variables above, patient's diagnosis and use of intermittent ketamine were plus added for predicting the 90- and 180-day periods, and use of continuous fentanyl for the 180-day mortality in univariable Cox regression. Significant predictors were determined to be variables with a multivariable Cox regression p value of 0.05. Delirium prevalence and use of continuous fentanyl among the initial covariates in the univariable cox analysis were excluded from the final model to predict all period of mortality.
      Table 3Multivariable Cox Regression Analysis of Relationship Between Factors Influencing 30-, 90-, and 180-day Mortality (N = 354).
      Variable30-day90-day180-day
      HR95% CIpHR95% CIpHR95% CIp
      Sedation Index
       1st tertile (=Ref)1.01.01.0
       2nd tertile1.731.10–2.72.0181.611.08–2.39.020∗1.461.00–2.14.052
       3rd tertile2.111.33–3.34.001∗∗2.001.31–3.06.001∗∗1.771.17–2.67.007∗∗
       SAPS Ⅲ1.021.01–1.03<.001∗∗1.021.00–1.03.006∗∗1.021.01–1.03.004∗∗
      Admission route
       ER (=Ref)1.01.0
       Ward1.531.09–2.16.0151.611.16–2.24.005∗∗
       Other1.970.70–5.59.2011.730.61–4.88.302
      Patient diagnosis
       Respiratory (=Ref)1.01.0
       Cancer1.240.75–2.07.4031.120.70–1.81.631
       Neurology0.350.13–0.95.0390.280.10–0.74.010
       Gastrointestinal0.880.38–2.03.7620.710.31–1.61.411
       Other0.810.43–1.51.4990.690.39–1.25.226
      Morphine, intermittent2.371.14–4.89.0202.171.09–4.31.0282.281.19–4.40.013
      Ketamine, intermittent1.471.05–2.05.0251.350.99–1.85.062
      Delirium prevalence1.400.94–2.08.100
      Note: CI = confidence interval; ER = emergency room; HR = hazard ratio; Ref = reference.
      Multivariable Cox regression incorporated factors with a p value of 0.05 in univariable Cox regression of 30, 90, and 180 days to account for various confounding variables of age, sex, admission route, SAPS Ⅲ, patient diagnosis, RASS at admission, Sedation Index, prevalence of pain and delirium, and analgesics and sedatives with intermittent or continuous administration.
      ∗ p < .01.
      ∗∗ p < .001.
      The Sedation Index tertiles were identified as independent predictors of mortality. In the second tertile group, compared to the first one, the risk of death increased by 1.73 times at 30 days (p = .018), 1.61 times at 90 days (p = .020), and 1.46 times at 180 days (p = .052). In the third tertile group, mortality was 2.11 times higher than the first tertile at 30 days, 2.00 times at 90 days, and 1.77 times at 180 days (p < .01). As the SAPS III increased, all types of mortality increased (p < .01). While intermittent ketamine usage only increased the risk of death by 1.47 times at 90 days, intermittent morphine usage more than doubled the mortality rate across all time periods. When patient was admitted to the intensive care unit via the general ward compared to the emergency room, mortality at 90 and 180 days increased higher by 1.53 times (p < .05) and 1.61 times (p < .01), respectively. The risk of death at 90 and 180 days decreased, however, when the patient had a neurological diagnosis compared to a respiratory diagnostic by 0.35 times and 0.28 times, respectively (p < .05).

      Discussion

      This retrospective cohort study attempted to improve early sedation strategies in critical patients by analyzing early sedation depth, which has been reported to be related to mortality in patients under mechanical ventilation.
      The average Sedation Index of the entire patient cohort was 1.35 points, with two-thirds of the participants scoring 0.00–1.50 points. The patients in this study maintained a lighter sedation depth overall compared with the results of other study where the average Sedation Index was 2.42 points and the distribution of two-thirds of the participants ranged from 0.00 to 3.25 [
      • Shehabi Y.
      • Bellomo R.
      • Kadiman S.
      • Ti L.K.
      • Howe B.
      • Reade M.C.
      • et al.
      Sedation intensity in the first 48 hours of mechanical ventilation and 180-day mortality: a multinational prospective longitudinal cohort study.
      ].
      Also, the participants in this study showed less pain prevalence, about 30% or less. According to previous studies, 40–70% of patients admitted to ICU are known to experience moderate to severe pain [
      • Desbiens N.A.
      • Wu A.W.
      Pain and suffering in seriously ill hospitalized patients.
      ,
      • Li D.T.
      • Puntillo K.
      A pilot study on coexisting symptoms in intensive care patients.
      ]. More than 30% of patients complained of pain even during rest, and this number was more than 50% during various nursing treatments [
      • Chanques G.
      • Sebbane M.
      • Barbotte E.
      • Viel E.
      • Eledjam J.J.
      • Jaber S.
      A prospective study of pain at rest: incidence and characteristics of an unrecognized symptom in surgical and trauma versus medical intensive care unit patients.
      ]. The use of the standardized sedation protocol (PAD Protocol) is cited as the reason for maintaining light sedation while controlling pain properly. It is estimated that pain in mechanically ventilated patients was properly controlled by assessing pain every shift and administering analgesic first. In all groups, intermittent analgesic fentanyl was used in at least 80% of cases. The benefit of fentanyl-based analgosedation is that it is known to help the transition to light sedation by reducing pain and unnecessary use of sedatives [
      • Faust A.C.
      • Rajan P.
      • Sheperd L.A.
      • Alvarez C.A.
      • McCorstin P.
      • Doebele R.L.
      Impact of an analgesia-based sedation protocol on mechanically ventilated patients in a medical intensive care unit.
      ]. The continuous analgesic remifentanil is chiefly used, which is also effective for maintaining light sedation [
      • Aoki Y.
      • Niwa T.
      • Shiko Y.
      • Kawasaki Y.
      • Mimuro S.
      • Doi M.
      • et al.
      Remifentanil provides an increased proportion of time under light sedation than fentanyl when combined with dexmedetomidine for mechanical ventilation.
      ]. The frequent use of ketamine, a sedative with analgesic effects, could have led to lower pain as the sedation deepened, even though the analgesic dosage decreased [
      • Chan K.
      • Burry L.D.
      • Tse C.
      • Wunsch H.
      • De Castro C.
      • Williamson D.R.
      Impact of ketamine on analgosedative consumption in critically ill patients: a systematic review and meta-analysis.
      ,
      • Patanwala A.E.
      • Martin J.R.
      • Erstad B.L.
      Ketamine for analgosedation in the intensive care unit: a systematic review.
      ]. In particular, benzodiazepine midazolam usage was substantially lower in all groups, regardless of Sedation Index. This low use could have influenced the fact that there was no difference in the length of stay in the ICU and ventilator-free days among the three groups in this study [
      • Riker R.R.
      • Shehabi Y.
      • Bokesch P.M.
      • Ceraso D.
      • Wisemandle W.
      • Koura F.
      • et al.
      Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial.
      ,
      • Wang H.
      • Wang C.
      • Wang Y.
      • Tong H.
      • Feng Y.
      • Li M.
      • et al.
      Sedative drugs used for mechanically ventilated patients in intensive care units: a systematic review and network meta-analysis.
      ].
      However, despite the low use of benzodiazepine, delirium occurred frequently in this study's patients, even in the first tertile, with the lowest occurrence (65.4%) compared with 38.8% in previous study [
      • Shehabi Y.
      • Bellomo R.
      • Kadiman S.
      • Ti L.K.
      • Howe B.
      • Reade M.C.
      • et al.
      Sedation intensity in the first 48 hours of mechanical ventilation and 180-day mortality: a multinational prospective longitudinal cohort study.
      ], and it was the highest in the deepest sedation (third tertile). Delirium is assumed to occur due to various risk factors, including the use of mechanical ventilation, age, emergency room admission, and medical history of dementia [
      • Devlin J.W.
      • Skrobik Y.
      • Gelinas C.
      • Needham D.M.
      • Slooter A.J.C.
      • Pandharipande P.P.
      • et al.
      Clinical practice guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the ICU.
      ]. The risk of delirium increased 6.27 times when under mechanical ventilation [
      • Choi S.J.
      • Cho Y.A.
      Prevalence and related risk factors of delirium in intensive care units as detected by the CAM-ICU.
      ]. This study targeted only patients undergoing mechanical ventilation. In contrast with the previous study [
      • Shehabi Y.
      • Bellomo R.
      • Kadiman S.
      • Ti L.K.
      • Howe B.
      • Reade M.C.
      • et al.
      Sedation intensity in the first 48 hours of mechanical ventilation and 180-day mortality: a multinational prospective longitudinal cohort study.
      ], the admission rate in the emergency rooms and the average age in this study showed higher, 40.0% vs. 27.9% and 64.0 vs. 58.4 years, respectively, and could thus represent risk factors for the occurrence of delirium. Moreover, unlike a previous study that only investigated a patient's delirium between −2 and + 1 of RASS [
      • Shehabi Y.
      • Bellomo R.
      • Kadiman S.
      • Ti L.K.
      • Howe B.
      • Reade M.C.
      • et al.
      Sedation intensity in the first 48 hours of mechanical ventilation and 180-day mortality: a multinational prospective longitudinal cohort study.
      ], this study included all patients between −3 and +2 of RASS. It is assumed that this inclusion reflects hypoactive delirium, the primary subtype of delirium occurring in the ICU [
      • Pun B.T.
      • Ely E.W.
      The importance of diagnosing and managing ICU delirium.
      ,
      • Krewulak K.D.
      • Stelfox H.T.
      • Leigh J.P.
      • Ely E.W.
      • Fiest K.M.
      Incidence and prevalence of delirium subtypes in an adult ICU: a systematic review and meta-analysis.
      ]. According to a systematic literature review of subtypes of delirium [
      • Krewulak K.D.
      • Stelfox H.T.
      • Leigh J.P.
      • Ely E.W.
      • Fiest K.M.
      Incidence and prevalence of delirium subtypes in an adult ICU: a systematic review and meta-analysis.
      ], the prevalence of hypoactive delirium is high in groups with increased severity of disease or mechanical ventilation. Considering that patients in the third tertile group had high severity of illness with a ventilator, it is estimated that the incidence of delirium was the highest since hypoactive type delirium was reflected more than the others.
      Although RASS at admission did not affect mortality, it showed a tendency to affect early sedation depth during the first 48 hours. Patients with deep sedation in early phase of mechanical ventilation were more subsequently deeply sedated during the first 2 ICU days [
      • Fuller B.M.
      • Roberts B.W.
      • Mohr N.M.
      • Knight Iv W.A.
      • Adeoye O.
      • Pappal R.D.
      • et al.
      The ED-SED study: a multicenter, prospective cohort study of practice patterns and clinical outcomes associated with emergency department sedation for mechanically ventilated patients.
      ]. Hence, medical staff must accurately assess and constantly monitor early sedation depth to prevent unnecessary deep sedation. Admission route was not associated with the Sedation Index, but, in line with previous research [
      • Shehabi Y.
      • Bellomo R.
      • Kadiman S.
      • Ti L.K.
      • Howe B.
      • Reade M.C.
      • et al.
      Sedation intensity in the first 48 hours of mechanical ventilation and 180-day mortality: a multinational prospective longitudinal cohort study.
      ,
      • Motzkus C.A.
      • Chrysanthopoulou S.A.
      • Luckmann R.
      • Rincon T.A.
      • Lapane K.L.
      • Lilly C.M.
      ICU admission source as a predictor of mortality for patients with sepsis.
      ], the patients in this study also showed increased 90- and 180-day mortality when admitted from a ward compared to emergency room. Patients who remained in the ward for a longer period may have an opportunity to be exposed to infection, nutritional deficiencies, and other conditions [
      • Motzkus C.A.
      • Chrysanthopoulou S.A.
      • Luckmann R.
      • Rincon T.A.
      • Lapane K.L.
      • Lilly C.M.
      ICU admission source as a predictor of mortality for patients with sepsis.
      ]. Therefore, it is necessary to consider the possibility that patient characteristics may vary depending on the source of admission, which may have an impact on mortality. Even though patient's diagnosis was mainly cancer and morphine administration was less observed in this study, there was association between morphine use and morality in all period. Morphine can increase mortality for patients with acute heart failure [
      • Caspi O.
      • Naami R.
      • Halfin E.
      • Aronson D.
      Adverse dose-dependent effects of morphine therapy in acute heart failure.
      ] or ARDS [
      • Hu A.M.
      • Shan Z.M.
      • Zhang Z.J.
      • Li H.P.
      Comparative efficacy of fentanyl and morphine in patients with or at risk for acute respiratory distress syndrome: a propensity score-matched cohort study.
      ], and its evidence remains controversial [
      • Caspi O.
      • Naami R.
      • Halfin E.
      • Aronson D.
      Adverse dose-dependent effects of morphine therapy in acute heart failure.
      ,
      • Hu A.M.
      • Shan Z.M.
      • Zhang Z.J.
      • Li H.P.
      Comparative efficacy of fentanyl and morphine in patients with or at risk for acute respiratory distress syndrome: a propensity score-matched cohort study.
      ]. Thus, it is necessary to use morphine carefully in consideration of each patient's disease.
      The 30-, 90-, and 180-day mortality rates tended to significantly increase as the sedation deepened, and this tendency was identical to a previous study [
      • Shehabi Y.
      • Bellomo R.
      • Kadiman S.
      • Ti L.K.
      • Howe B.
      • Reade M.C.
      • et al.
      Sedation intensity in the first 48 hours of mechanical ventilation and 180-day mortality: a multinational prospective longitudinal cohort study.
      ]. However, the participants in this study differed in that there was a decrease in the survival curve even in the first and second tertile groups with light sedation although the difference in SAPS III that affected the mortality between the two groups was not statistically significant. In the current circumstances, in which the definition of light sedation and deep sedation is not clear [
      • Devlin J.W.
      • Skrobik Y.
      • Gelinas C.
      • Needham D.M.
      • Slooter A.J.C.
      • Pandharipande P.P.
      • et al.
      Clinical practice guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the ICU.
      ] unless deep sedation is required for therapeutic purposes, it suggests that maintaining the patient in a lighter sedation may play a role in improving mortality of patients with mechanical ventilation. However, no statistical significance was confirmed in the survival curve between the second and third tertile. This lack of significance could have been due to a difference in SAPS III scores, strongly affecting mortality between the two groups.
      A limitation of this study is that there could be other factors that influenced the clinical outcomes during the early phase of ventilation. For example, there were no data on the reason for mechanical ventilation at the time of hospitalization or the setting value of the ventilator. In addition, the medication administration dosages were not considered and medication administration during intubation was not excluded from total medication usage during the first 48 hours of ventilation. Furthermore, it is difficult to state that this research is representative of treatment in Korea, given that it was conducted in only one tertiary general hospital that already had a standardized sedation protocol. The details of protocols may vary from hospital to hospital, and inconsistent protocols may affect the transition of the patient to light sedation, which may be another bias in evaluating the effect of sedation status on clinical outcomes. Therefore, a study was conducted in a single hospital where standardized sedation protocols were applied. In the future, it will be necessary to conduct the study in multiple institutions with a uniform sedation protocol.
      Despite these limitations, the results from this study are consistent with the previous study [
      • Shehabi Y.
      • Bellomo R.
      • Kadiman S.
      • Ti L.K.
      • Howe B.
      • Reade M.C.
      • et al.
      Sedation intensity in the first 48 hours of mechanical ventilation and 180-day mortality: a multinational prospective longitudinal cohort study.
      ] and indicate that early deep sedation in critically ill patients on mechanical ventilation is associated with mortality. It should be noted that early sedation depth is a modifiable variable among those known to be related to mortality [
      • Balzer F.
      • Weiss B.
      • Kumpf O.
      • Treskatsch S.
      • Spies C.
      • Wernecke K.D.
      • et al.
      Early deep sedation is associated with decreased in-hospital and two-year follow-up survival.
      ,
      • Shehabi Y.
      • Bellomo R.
      • Kadiman S.
      • Ti L.K.
      • Howe B.
      • Reade M.C.
      • et al.
      Sedation intensity in the first 48 hours of mechanical ventilation and 180-day mortality: a multinational prospective longitudinal cohort study.
      ,
      • Tanaka L.M.
      • Azevedo L.C.
      • Park M.
      • Schettino G.
      • Nassar A.P.
      • Rea-Neto A.
      • et al.
      Early sedation and clinical outcomes of mechanically ventilated patients: a prospective multicenter cohort study.
      ]. Compared with the general treatment as directed by the doctor, nurses play a crucial role in reducing mortality in the ICU and mitigating sedation-related adverse effects by maintaining an appropriate sedation depth for the patient [
      • Qi Z.
      • Yang S.
      • Qu J.
      • Li M.
      • Zheng J.
      • Huang R.
      • et al.
      Effects of nurse-led sedation protocols on mechanically ventilated intensive care adults: a systematic review and meta-analysis.
      ,
      • Ramoo V.
      • Abdullah K.L.
      • Tan P.S.
      • Wong L.P.
      • Chua Y.P.
      • Tang L.Y.
      Sedation scoring and managing abilities of intensive care nurses post educational intervention.
      ]. Since the early stage of mechanical ventilation is a phase when a doctor diagnoses a patient and determines the treatment direction, the patients' sedation depth may be considered relatively less important. The patient's target sedation level should be set. The nurse at the bedside can adjust the sedative medication dose without delay [
      • Qi Z.
      • Yang S.
      • Qu J.
      • Li M.
      • Zheng J.
      • Huang R.
      • et al.
      Effects of nurse-led sedation protocols on mechanically ventilated intensive care adults: a systematic review and meta-analysis.
      ] and make a faster clinical decision to guarantee a light sedation in keeping with the patient's condition during the early phase of ventilation. Also, the nurse’ protocol management skills can be improved with adequate educational intervention [
      • Ramoo V.
      • Abdullah K.L.
      • Tan P.S.
      • Wong L.P.
      • Chua Y.P.
      • Tang L.Y.
      Sedation scoring and managing abilities of intensive care nurses post educational intervention.
      ]. Thus, nurses must endeavor to accomplish early light sedation by performing a standardized sedation protocol.

      Conclusion

      This study confirmed that early sedation depth during the first 48 hours of mechanical ventilation is a modifiable factor that can potentially affect the mortality of patients. Considering bedside nurses play a leading role in controlling the sedation depth of critical patients, the protocol for inducing the transition into light sedation must be geared toward improving clinical outcomes of patients with mechanical ventilation. Additional studies on enhancing sedation depth in the first 48 hours are warranted.

      Funding

      This study was based on the first author's thesis and was supported by the Seoul Nurse Association. (No. 519).

      Conflict of interest

      The authors have declared no competing interests.

      References

        • Balzer F.
        • Weiss B.
        • Kumpf O.
        • Treskatsch S.
        • Spies C.
        • Wernecke K.D.
        • et al.
        Early deep sedation is associated with decreased in-hospital and two-year follow-up survival.
        Crit Care. 2015; 19: 197https://doi.org/10.1186/s13054-015-0929-2
        • Lee J.M.
        • Lee S.H.
        • Kwak S.H.
        • Kang H.H.
        • Lee S.H.
        • Lim J.M.
        • et al.
        Comparison of morphine and remifentanil on the duration of weaning from mechanical ventilation.
        Korean J Crit Care Med. 2016; 31: 381https://doi.org/10.4266/kjccm.2014.29.4.281.e01
        • Park C.S.
        The current state of sedation outside the operating room.
        J Korean Med Assoc. 2013; 56: 264-270
        • Shehabi Y.
        • Bellomo R.
        • Reade M.C.
        • Bailey M.
        • Bass F.
        • Howe B.
        • et al.
        Early intensive care sedation predicts long-term mortality in ventilated critically ill patients.
        Am J Respir Crit Care Med. 2012; 186: 724-731https://doi.org/10.1164/rccm.201203-0522OC
        • Strom T.
        • Martinussen T.
        • Toft P.
        A protocol of no sedation for critically ill patients receiving mechanical ventilation: a randomised trial.
        Lancet. 2010; 375: 475-480https://doi.org/10.1016/s0140-6736(09)62072-9
        • Treggiari M.M.
        • Romand J.A.
        • Yanez N.D.
        • Deem S.A.
        • Goldberg J.
        • Hudson L.
        • et al.
        Randomized trial of light versus deep sedation on mental health after critical illness.
        Crit Care Med. 2009; 37: 2527-2534https://doi.org/10.1097/CCM.0b013e3181a5689f
        • Barr J.
        • Fraser G.L.
        • Puntillo K.
        • Ely E.W.
        • Gelinas C.
        • Dasta J.F.
        • 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: 263-306https://doi.org/10.1097/CCM.0b013e3182783b72
        • Devlin J.W.
        • Skrobik Y.
        • Gelinas C.
        • Needham D.M.
        • Slooter A.J.C.
        • Pandharipande P.P.
        • et al.
        Clinical practice guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the ICU.
        Crit Care Med. 2018; 46: e825-e873https://doi.org/10.1097/m.0000000000003299
        • Shehabi Y.
        • Bellomo R.
        • Kadiman S.
        • Ti L.K.
        • Howe B.
        • Reade M.C.
        • et al.
        Sedation intensity in the first 48 hours of mechanical ventilation and 180-day mortality: a multinational prospective longitudinal cohort study.
        Crit Care Med. 2018; 46: 850-859https://doi.org/10.1097/ccm.0000000000003071
        • Stephens R.J.
        • Evans E.M.
        • Pajor M.J.
        • Pappal R.D.
        • Egan H.M.
        • Wei M.
        • et al.
        A dual-center cohort study on the association between early deep sedation and clinical outcomes in mechanically ventilated patients during the COVID-19 pandemic: the COVID-SED Study. Res Sq [Preprint].
        2022 ([cited 2022 May 1]. Available from: https://doi.org/10.21203/rs.3.rs-1389892/v1)
        • Tanaka L.M.
        • Azevedo L.C.
        • Park M.
        • Schettino G.
        • Nassar A.P.
        • Rea-Neto A.
        • et al.
        Early sedation and clinical outcomes of mechanically ventilated patients: a prospective multicenter cohort study.
        Crit Care. 2014; 18: R156https://doi.org/10.1186/cc13995
        • Fuller B.M.
        • Roberts B.W.
        • Mohr N.M.
        • Knight Iv W.A.
        • Adeoye O.
        • Pappal R.D.
        • et al.
        The ED-SED study: a multicenter, prospective cohort study of practice patterns and clinical outcomes associated with emergency department sedation for mechanically ventilated patients.
        Crit Care Med. 2019; 47: 1539-1548https://doi.org/10.1097/CCM.0000000000003928
        • Stephens R.J.
        • Dettmer M.R.
        • Roberts B.W.
        • Ablordeppey E.
        • Fowler S.A.
        • Kollef M.H.
        • et al.
        Practice patterns and outcomes associated with early sedation depth in mechanically ventilated patients: a systematic review and meta-analysis.
        Crit Care Med. 2018; 46: 471-479https://doi.org/10.1097/ccm.0000000000002885
        • Ko J.Y.
        • Park H.J.
        • In Y.W.
        • Lee Y.M.
        • Kim J.M.
        • Lee S.Y.
        Effect of pharmacist's intervention and management of pain and sedation protocol on clinical outcomes in medical ICU.
        J Korean Soc Health-Syst Pharm. 2018; 35: 268-280
        • Kim H.H.
        • Choi S.C.
        • Ahn J.H.
        • Chae M.K.
        • Heo J.
        • Min Y.G.
        Analysis of trends in usage of analgesics and sedatives in intensive care units of South Korea: a retrospective nationwide population-based study.
        Medicine (Baltim). 2018; 97e12126https://doi.org/10.1097/md.0000000000012126
        • Sim J.K.
        • Lee S.M.
        • Kang H.K.
        • Kim K.C.
        • Kim Y.S.
        • Kim Y.S.
        • et al.
        Change in management and outcome of mechanical ventilation in Korea: a prospective observational study.
        Korean J Intern Med. 2022; 37: 618-630https://doi.org/10.3904/kjim.2020.285
        • Sessler C.N.
        • Gosnell M.S.
        • Grap M.J.
        • Brophy G.M.
        • O'Neal P.V.
        • Keane K.A.
        • et al.
        The richmond agitation-sedation scale: validity and reliability in adult intensive care unit patients.
        Am J Respir Crit Care Med. 2002; 166: 1338-1344https://doi.org/10.1164/rccm.2107138
        • Moreno R.P.
        • Metnitz P.G.
        • Almeida E.
        • Jordan B.
        • Bauer P.
        • Campos R.A.
        • et al.
        SAPS 3--From evaluation of the patient to evaluation of the intensive care unit. part 2: development of a prognostic model for hospital mortality at ICU admission.
        Intensive Care Med. 2015; 31: 1345-1355https://doi.org/10.1007/s00134-005-2763-5
        • Johnson R.A.
        • Bhattacharyya G.K.
        Statistics: principles and methods.
        in: Chapter 7, Variation in repeated samples-sampling distributions. 6th ed. John Wiley & Sons, United States of America2019: 276-277
        • Riker R.R.
        • Shehabi Y.
        • Bokesch P.M.
        • Ceraso D.
        • Wisemandle W.
        • Koura F.
        • et al.
        Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial.
        JAMA. 2009; 301: 489-499https://doi.org/10.1001/jama.2009.56
        • Puntillo K.
        • Pasero C.
        • Li D.
        • Mularski R.A.
        • Grap M.J.
        • Erstad B.L.
        • et al.
        Evaluation of pain in ICU patients.
        Chest. 2009; 135: 1069-1074https://doi.org/10.1378/chest.08-2369
        • Gélinas C.
        • Fillion L.
        • Puntillo K.A.
        • Viens C.
        • Fortier M.
        Validation of the critical-care pain observation tool in adult patients.
        Am J Crit Care. 2006; 15: 420-427https://doi.org/10.4037/ajcc2006.15.4.420
        • Schoenfeld D.A.
        • Bernard G.R.
        Statistical evaluation of ventilator-free days as an efficacy measure in clinical trials of treatments for acute respiratory distress syndrome.
        Crit Care Med. 2002; 30: 1772-1777https://doi.org/10.1097/00003246-200208000-00016
        • Desbiens N.A.
        • Wu A.W.
        Pain and suffering in seriously ill hospitalized patients.
        J Am Geriatr Soc. 2000; 48: S183-S186https://doi.org/10.1111/j.1532-5415.2000.tb03130.x
        • Li D.T.
        • Puntillo K.
        A pilot study on coexisting symptoms in intensive care patients.
        Appl Nurs Res. 2006; 19: 216-219https://doi.org/10.1016/j.apnr.2006.01.003
        • Chanques G.
        • Sebbane M.
        • Barbotte E.
        • Viel E.
        • Eledjam J.J.
        • Jaber S.
        A prospective study of pain at rest: incidence and characteristics of an unrecognized symptom in surgical and trauma versus medical intensive care unit patients.
        Anesthesiology. 2007; 107: 858-860https://doi.org/10.1097/01.anes.0000287211.98642.51
        • Faust A.C.
        • Rajan P.
        • Sheperd L.A.
        • Alvarez C.A.
        • McCorstin P.
        • Doebele R.L.
        Impact of an analgesia-based sedation protocol on mechanically ventilated patients in a medical intensive care unit.
        Anesth Analg. 2016; 123: 903-909https://doi.org/10.1213/ane.0000000000001393
        • Aoki Y.
        • Niwa T.
        • Shiko Y.
        • Kawasaki Y.
        • Mimuro S.
        • Doi M.
        • et al.
        Remifentanil provides an increased proportion of time under light sedation than fentanyl when combined with dexmedetomidine for mechanical ventilation.
        J Int Med Res. 2021; 493000605211002683https://doi.org/10.1177/03000605211002683
        • Chan K.
        • Burry L.D.
        • Tse C.
        • Wunsch H.
        • De Castro C.
        • Williamson D.R.
        Impact of ketamine on analgosedative consumption in critically ill patients: a systematic review and meta-analysis.
        Ann Pharmacother. 2022; https://doi.org/10.1177/10600280211069617
        • Patanwala A.E.
        • Martin J.R.
        • Erstad B.L.
        Ketamine for analgosedation in the intensive care unit: a systematic review.
        J Intensive Care Med. 2017; 32: 387-395https://doi.org/10.1177/0885066615620592
        • Wang H.
        • Wang C.
        • Wang Y.
        • Tong H.
        • Feng Y.
        • Li M.
        • et al.
        Sedative drugs used for mechanically ventilated patients in intensive care units: a systematic review and network meta-analysis.
        Curr Med Res Opin. 2019; 35: 435-446https://doi.org/10.1080/03007995.2018.1509573
        • Choi S.J.
        • Cho Y.A.
        Prevalence and related risk factors of delirium in intensive care units as detected by the CAM-ICU.
        J Korean Clin Nurs Res. 2014; 20: 406-416https://doi.org/10.22650/JKCNR.2014.20.3.406
        • Pun B.T.
        • Ely E.W.
        The importance of diagnosing and managing ICU delirium.
        Chest. 2007; 132: 624-636https://doi.org/10.1378/chest.06-1795
        • Krewulak K.D.
        • Stelfox H.T.
        • Leigh J.P.
        • Ely E.W.
        • Fiest K.M.
        Incidence and prevalence of delirium subtypes in an adult ICU: a systematic review and meta-analysis.
        Crit Care Med. 2018; 46: 2029-2035https://doi.org/10.1097/ccm.0000000000003402
        • Motzkus C.A.
        • Chrysanthopoulou S.A.
        • Luckmann R.
        • Rincon T.A.
        • Lapane K.L.
        • Lilly C.M.
        ICU admission source as a predictor of mortality for patients with sepsis.
        J Intensive Care Med. 2018; 33: 510-516https://doi.org/10.1177/0885066617701904
        • Caspi O.
        • Naami R.
        • Halfin E.
        • Aronson D.
        Adverse dose-dependent effects of morphine therapy in acute heart failure.
        Int J Cardiol. 2019; 293: 131-136https://doi.org/10.1016/j.ijcard.2019.06.015
        • Hu A.M.
        • Shan Z.M.
        • Zhang Z.J.
        • Li H.P.
        Comparative efficacy of fentanyl and morphine in patients with or at risk for acute respiratory distress syndrome: a propensity score-matched cohort study.
        Drugs R&D. 2021; 21: 149-155https://doi.org/10.1007/s40268-021-00338-3
        • Qi Z.
        • Yang S.
        • Qu J.
        • Li M.
        • Zheng J.
        • Huang R.
        • et al.
        Effects of nurse-led sedation protocols on mechanically ventilated intensive care adults: a systematic review and meta-analysis.
        Austral Crit Care. 2020; https://doi.org/10.1016/j.aucc.2020.07.013
        • Ramoo V.
        • Abdullah K.L.
        • Tan P.S.
        • Wong L.P.
        • Chua Y.P.
        • Tang L.Y.
        Sedation scoring and managing abilities of intensive care nurses post educational intervention.
        Nurs Crit Care. 2017; 22: 141-149https://doi.org/10.1111/nicc.12180