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Time to Sedation after Rapid Sequence Intubation in the Emergency

Department:

A Retrospective Chart Review

Andrew Osinga, BSc, PharmD

Department of Pharmacy, The Ottawa Hospital

Sabrina Natarajan, BSc, BScPhm, ACPR

Department of Pharmacy, The Ottawa Hospital

Edmund SH Kwok, MD, MHA, MSc, FRCPC

Department of Emergency Medicine, The Ottawa Hospital

Assistant Professor, University of Ottawa

Clinician Investigator, The Ottawa Hospital Research Institute

Salmaan Kanji, BSc, PharmD, ACPR

Departments of Pharmacy and Critical Care Medicine, The Ottawa Hospital

Associate Scientist, The Ottawa Hospital Research Institute

Corresponding author:

Sabrina Natarajan, BSc, BScPhm, ACPR Pharmacy Department The Ottawa Hospital - General Campus 501 Smyth Rd, Ottawa, ON, K1H 8L6 E-mail: snatarajan@toh.ca The authors report no potential conflict of interest.

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Abstract

Introduction: Patients requiring rapid sequence intubation in the Emergency Department will

typically receive a short-acting sedative followed by a paralytic agent to facilitate endotracheal

intubation. These patients are at risk of paralysis without sedation, unless further sedation is

administered post-intubation in a timely manner.

Objectives: To determine if there exists a delay in post-intubation sedation in the Emergency

Departments at The Ottawa Hospital; to determine the predictors of delayed time to post-

intubation sedation; and to determine if there exists a delay in analgesia administration in the

post-intubation period.

Methods: A retrospective observational study with 150 eligible patients intubated in the

Emergency Departments at The Ottawa Hospital identified from April 1st, 2016 to February 1st,

2017. Data pertaining to patient demographics, administration times of peri-intubation agents,

and proposed predictors of delayed sedation were collected.

Results: The median time to post-intubation sedation was 10 minutes. 19.3% of patients

received sedation in an inadequate timeframe. The median time to post-intubation analgesia

was 75.5 minutes. Of the proposed predictors (choice of paralytic agent, pre-printed order

completion, presence of trauma code or cardiac arrest, transfer shortly after intubation,

designation of individual performing intubation, campus of intubation) only cardiac arrest

showed a statistically significant prediction of time to sedation (p=0.002).

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Conclusion: A considerable proportion of Emergency Department patients received post-

intubation sedation within an inadequate timeframe and was therefore at risk of paralysis

without sedation. Further study is required to determine the possible barriers to initiation of

timely post-intubation sedation.

Key Words: Rapid sequence intubation, Emergency Department, sedation, paralysis, analgesia.

Abstract word count: 243

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Introduction

Rapid sequence intubation (RSI) is a process used to facilitate endotracheal intubation that is

usually done in an Emergency Department (ED) setting. The critical step of RSI is the sequential

administration of a rapid-acting sedative induction agent and a neuromuscular blocker, which

allows ideal conditions for placement of the endotracheal tube (1).

Succinylcholine and rocuronium are two rapid-acting paralytic agents that are commonly used

for RSI. A single dose of succinylcholine has a duration of action of approximately 4 to 6

minutes, much shorter than that of rocuronium, where paralysis lasts between 30 and 60

minutes (2-3). Commonly used sedative induction agents include propofol, midazolam,

etomidate, and ketamine. Most induction agents have durations of action of less than ten

minutes; however midazolam may last as long as two hours (4-8).

If the duration of action of a paralytic is longer than that of the induction agent, there is the

potential for a patient to be paralyzed but not sedated. Thus, after induction, paralysis, and

intubation are complete, the patient should receive further sedation and analgesia. The

Canadian Patient Safety Institute has created a list of “Never Events” in hospital care, which

constitutes preventable patient safety incidents that cause serious patient harm (10). Included

in this list is “neuromuscular blockade without sedation, airway control and ventilation

capability.” Pharmacologic paralysis with concurrent awareness and lack of ability to

communicate is undoubtedly traumatic and painful, and has been well documented (11-13).

Previous studies have shown that paralysis without adequate sedation or analgesia post-RSI is

not uncommon (14-18). A retrospective cohort analysis estimated that over half of patients

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undergoing endotracheal intubation in EDs in the United States did not receive a sedative drug

in the ED (14). In the setting of a pediatric emergency centre, another retrospective study found

a mean time of 46 minutes to post-intubation sedation in patients who underwent RSI with

rocuronium and etomidate (15). In this population, 63% received sedation more than 15

minutes post-RSI. In a trauma centre ED, Bonomo et al. concluded that 74% of patients received

inadequate or no sedation after RSI (18).

Although it is clear from the literature that delays to sedation after intubation are not

uncommon in the ED, evidence on the effectiveness of potential solutions (such as standardized

checklists or order sets) to address this gap have been lacking.

At The Ottawa Hospital (TOH), most intubations are performed by either Emergency Medicine

staff physicians (with FRCPC or CCFP-EM designations) or medical residents (Emergency

Medicine or off-service) under direct supervision of an aforementioned staff physician. There is

an ED at each of the two main TOH Campuses: the Civic specializes as a trauma, neurosurgical,

and cardiac centre; the General specializes as a cancer and medical centre. There is not

currently an intubation checklist or guide that is utilized for RSI at TOH. However there is a post-

intubation analgesia and sedation management pre-printed order (PPO) that is available in both

EDs at TOH (figure 1). This PPO has been available since December 2006, but has recently been

updated for the purpose of improving how analgesia is ordered after intubation and to include

a more comprehensive pain scale. The updated PPO was rolled out between January-March

2016 and education was provided through nursing in-services, at TOH Grand Rounds, and at

TOH Morbidity & Mortality Rounds.

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The purpose of this study was to characterize current practices regarding post-RSI sedation in

the ED of a tertiary care academic hospital where a standardized PPO had already been

implemented. Objectives include: to determine if there exists a delay in post-intubation

sedation in the EDs at The Ottawa Hospital; to determine the predictors of delayed time to

post-intubation sedation; and to determine if there exists a delay in analgesia administration in

the post-intubation period.

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Methods

This retrospective observational study was reviewed and approved by The Ottawa Hospital

Research Ethics Board.

Patient selection

Consecutive patients over the age of sixteen were eligible for inclusion in this study if they were

intubated at either of the two EDs at TOH from April 1st, 2016 to February 1st, 2017. Charts were

excluded if: the patient did not receive a dose of a paralytic agent; the patient was receiving a

continuous infusion of a sedative or opioid prior to RSI; charts contained incomplete

documentation of medication names and/or administration times; or the patient was

extubated or expired in the ED within the duration of action of the induction agent given for

RSI. A random number generator was used to screen charts until a total of 150 satisfied our

inclusion and exclusion criteria.

Study Objectives and Data Collection

Data was extracted from electronic medical records and collated in Excel Spreadsheets© by a

single investigator (AO). The main outcomes of this study were the times to post-intubation

sedation and analgesia, and the proportion of patients receiving sedation within an adequate

timeframe from the time that the induction agent was given.

The time to sedation was defined as the number of minutes from the administration of the

induction agent to the time at which the post-RSI sedation was started, as measured by the

times documented in the nursing notes. If a patient received a repeat bolus of the induction

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agent within the duration of action of that agent, the time was measured from which the last

bolus dose was administered.

Patients were deemed to have received post-intubation sedation within an “adequate

timeframe” if a sedative was given within the following timeframes: 15 minutes after propofol,

ketamine, and etomidate induction; 120 minutes after midazolam induction. These timeframes

are conservative estimates based upon the duration of action listed in the agents’ respective

product monographs (4-8). If there was no other sedative documented as given, it was assumed

that no additional sedative was given. Patients were also deemed to have received sedation in

an “inadequate timeframe” if any gap in sedation existed within the duration of action of the

paralytic agent given. The duration of action of rocuronium and succinylcholine were defined as

60 minutes and 10 minutes respectively. These timeframes are conservative estimates based

upon the duration of action listed in the agents’ respective product monographs (2-3).

For the purpose of this study, “sedative” was defined as a bolus dose or infusion of one of the

following: propofol, etomidate, ketamine, any benzodiazepine, dexmedetomidine. Patients

receiving bolus doses or infusions of opioids (fentanyl, hydromorphone, or morphine) were also

considered to have received “sedation”.

“Analgesia” was considered to be a dose of any opioid or ketamine. As with sedation, the time

to analgesia was defined as the number of minutes from the administration of the induction

agent to the time at which the post-RSI analgesia was started as measured by the times

documented in the nursing notes.

Statistical Analysis

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Multivariate linear regression was performed to assess time to sedation and time to analgesia

prediction, using variables selected a priori (p<0.05 for significance): choice of paralytic agent,

PPO completion, presence of trauma code or cardiac arrest, transfer shortly after intubation,

designation of individual performing intubation, campus of intubation. Analysis was performed

using SPSS v20.0 software©.

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Results

Five hundred and ninety-nine charts identified from health records were screened for inclusion

and exclusion criteria (figure 2). A total of 150 charts satisfied these criteria. Baseline

characteristics are presented in Table 1. The usage of paralytic agents was evenly split between

succinylcholine and rocuronium (49% and 51% respectively). The most commonly used

induction agents were propofol and ketamine (50% and 39%), with propofol the most

frequently used post-intubation sedative (75%). Full results are presented in Figure 3.

Table 2 includes the main post-intubation sedation and analgesia outcomes. The median time

to post-intubation sedation was 10 minutes (Q1-Q3: 5-18 minutes). The percentage of patients

who received post-intubation sedation greater than 15, 30, and 45 minutes after induction

were 26.8%, 13.4%, 9.9% respectively. Twenty-nine (19.3%) patients were judged to have

received post-intubation sedation in an inadequate timeframe. Twenty-six of these cases were

due to a delay in initiation of post-intubation sedation, whereas there were three were cases in

which there was a gap in sedation while the paralytic agent was still active. All of these patients

received rocuronium as the paralytic.

The median time to post-intubation analgesia was 75.5 minutes (Q1-Q3: 18-179 minutes). The

percentage of patients who did not receive post-intubation analgesia while in the ED was

30.7%, whereas 21.3% of patients did not receive any analgesia within 24 hours post-

intubation, time to extubation, or prior to expiry.

Multiple linear regression was performed to predict time to sedation based on the use of a

paralytic, use of the pre-printed order form, presence or absence of a trauma code or cardiac

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arrest, transfer to a ward within an hour, level of education of the person intubating and site. A

significant regression equation was found (F(7, 139) = 2.977, p=0.006) with an R2 of 0.130. Only

cardiac arrest was identified as a significant predictor (p=0.002). Time to sedation increased by

57.7 minutes if the patient experienced a cardiac arrest (95% CI: 22.1 – 93.3 minutes). When

the largest outlier of time to sedation was removed, none of the included variables predicted

time to sedation.

When multiple linear regression was used to determine predictors of time to analgesia the

regression model was not a good fit of the data (F(7,110) = 2.047, p=0.055) with an R2 of 0.115.

Therefore, none of the predictor variables could explain the variance around time to analgesia.

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Discussion

Although the range varied considerably, the median time to post-intubation sedation (10

minutes) was not considerably delayed. More importantly however, almost 20% of patients

were deemed to have received sedation in an inadequate timeframe. This percentage of

patients who were at high risk for paralysis without sedation is unacceptably high. By definition,

the goal is for this to never occur.

This result is most likely a conservative estimate of the true occurrence of this “Never Event” at

TOH. A conservative 15 minute cut-off (120 minutes for midazolam) was chosen to establish an

adequate timeframe in which post-intubation sedation could be given to avoid paralysis

without sedation. This cut-off is considerably greater than the single-dose durations of action of

the two most commonly used induction agents as listed in their product monographs (7-8

minutes and 5-10 minutes for propofol and ketamine respectively). Therefore cases of

“inadequate timeframe” may have been underestimated. Furthermore, there were 9 cases

where the time to sedation was equal to 15 minutes and deemed as “adequate timeframe”. If

these cases have been deemed “inadequate”, then the percentage of patients that received

sedation in an inadequate timeframe would have increased to 25.5%.

Due to its short duration of action, all patients who received succinylcholine after induction

were deemed to have received post-intubation sedation within an adequate timeframe.

Therefore it was only possible for patients who received rocuronium to have received post-

intubation sedation in an “inadequate timeframe”. The proportion of patients who received

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rocuronium as a paralytic and did not receive post-intubation sedation within an adequate

timeframe totalled 34.7%.

The median time to post-intubation analgesia was quite delayed (75.5 minutes), with more

than 20% of patients not receiving post-intubation analgesia within the first 24 hours or for the

duration of their intubation. Although not directly impacting the “Never Event” of paralysis

without sedation, the administration of analgesia is a standard of post-intubation care.

Only one pre-selected variable, cardiac arrest, was significantly associated with a delayed time

to sedation. This was a surprising result. We hypothesized that, compared to succinylcholine,

the use of rocuronium would predict a delayed time to sedation since there would be a longer

time without a physical cue that the patient was not sedated. This phenomenon has been

observed in a previous study (19).

Since the variables chosen a priori were not well predictive of delayed time to sedation, further

study and discussion is required to establish specific barriers that exist at our site which delay

efficient post-intubation sedation initiation in so many cases. Notably, the presence of a pre-

printed order did not prevent these outcomes from occurring. Cases where completion of the

PPO is significantly delayed after intubation may explain this non-significant finding. A solution

may be to make this form more accessible during the “critical” post-intubation period so that it

functions as a prompt to initiate post-intubation sedation. However, it is likely that a set of

diverse solutions are required to address this problem.

The limitations of this study are largely related to its retrospective design. For data collection,

we relied on the accuracy of chart documentation. For example, if there was no documentation

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of additional sedation, it was assumed not to be given. At TOH, it is standard for a nurse to have

the sole task of documenting medication administration times when rapid sequence intubation

occurs. Therefore, we feel that the documentation was generally complete for this study. Of the

599 charts screened, only 21 were excluded due to incomplete documentation.

The main outcome of this study was related to the timing of post-intubation sedative use rather

than the confirmation of recall or awareness during paralyzation. As well, it is unclear how

paralysis without sedation would impact patients who presented with altered mental status or

consciousness. It was outside the scope of this study to follow up with patients who were at

high risk for paralysis without sedation; therefore we used a different measure to evaluate this.

As well, no objective measure of neuromuscular blockade (i.e. Train of Four) is routinely

completed for this patient population and therefore was not collected.

Despite these limitations, this study identifies an important patient safety issue at The Ottawa

Hospital. Moving forward, formal quality improvement methodologies such as process mapping

may be required to identify modifiable areas of process improvement.

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Conclusion

One fifth of Emergency Department patients at The Ottawa Hospital received post-intubation

sedation within an inadequate timeframe and were at risk of paralysis without sedation, an

event that should never occur. Only the presence of a cardiac arrest seemed to predict a

delayed time to post-intubation sedation. Further exploration of the possible barriers to

initiation of timely post-intubation sedation is required.

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References

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3. Rocuronium bromide injection product monograph. Kirkland, PQ: Merck Canada; 2015.

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1995;33:131-154.

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6. Midazolam injection product monograph. Kirkland, PQ: Pfizer Canada; 2014.

7. Ketamine hydrochloride injection product monograph. Boucherville, PQ: Sandoz Canada;

2015.

8. Etomidate injection product insert. Lake Forest, IL: Hospira; 2011.

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management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit

Care Med. 2013;41(1):263-306.

10. The Canadian Patient Safety Institute. Never Events for Hospital Care in Canada: Safer Care

for Patients. Edmonton; 2015. Available from:

http://www.patientsafetyinstitute.ca/en/toolsResources/NeverEvents/Pages/default.aspx.

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11. Topulos G, Lansing R, Banzett R. The experience of complete neuromuscular blockade in

awake humans. J Clin Anesth. 1993;5(5):369-374.

12. Ballard N, Robley L, Barrett D, Fraser D, Mendoza I. Patients’ recollections of therapeutic

paralysis in the intensive care unit. Am J Crit Care. 2006;15:86–95.

13. Kimball D, Kincaide R, Ives C, Henderson S. Rapid Sequence Intubation from the patient’s

perspective. West J Emerg Med. 2011;12(4):365-367.

14. Weingart G, Carlson J, Callaway C, Frank R, Wang H. Estimates of sedation in patients

undergoing endotracheal intubation in US EDs. Am J Emerg Med. 2013;31(1):222-226.

15. Kendrick DB, Monroe KW, Bernard DW, Tofil NM. Sedation after intubation using etomidate

and a long-acting neuromuscular blocker. Pediatr Emerg Care. 2009;25(6):393-6.

16. Chong I, Sandefur B, Rimmelin D, Arbelaez C, Brown C, Walls R et al. Long-acting

neuromuscular paralysis without concurrent sedation in emergency care. Am J Emerg Med.

2014;32(5):452-456.

17. Chao A, Huang C, Pryor J, Reilly P, Schwab C. Analgesic use in intubated patients during

acute resuscitation. J Trauma. 2006;60(3):579-582.

18. Bonomo JB, Butler AS, Lindsell CJ, Venkat A. Inadequate provision of postintubation

anxiolysis and analgesia in the ED. Am J Emerg Med. 2008;26(4):469-72.

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19. Watt JM, Amini A, Traylor BR, Amini R, Sakles JC, Patanwala AE. Effect of paralytic type on

time to post-intubation sedative use in the emergency department. Emerg Med J. 2013;30:893-

895.

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Tables and Figures

Table 1. Patient demographics

Age at intubation in years, mean (SD) 55 (21)

Female, n (%) 61 (40.7)

TOH campus of intubation, n (%)

General 39 (26)

Civic 111 (74)

Final diagnosis group, n (%)

Stroke/brain hemorrhage/meningitis 35 (23.3)

Trauma 33 (22)

Overdose ingestion 21 (14)

Cardiac arrest/ROSC/ACS 16 (10.7)

Pneumonia/AECOPD/respiratory failure 13 (8.7)

Seizure/status epilepticus 13 (8.7)

Decreased LOC/delirium unknown cause 6 (4)

Hemorrhage, other 5 (3.3)

Sepsis 3 (2)

DKA/HHS 3 (2)

Other 2 (1.3)

SD: standard deviation; ROSC: return of spontaneous circulation; ACS: acute coronary syndrome;

AECOPD: acute exacerbation of chronic obstructive pulmonary disorder; LOC: level of consciousness;

DKA: diabetic ketoacidosis; HHS: hyperglycemic hyperosmolar syndrome

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Table 2. Post-intubation sedation and analgesia outcomes

Time to sedation in minutes, median (Q1,Q3) 10 (5,18)

Inadequate timeframe, n (%) 29 (19.3)

Delayed sedation, n (%) 26 (17.3)

Gap in sedation¶, n (%) 3 (2)

Post-intubation sedation >15 minutes†, n (%) 38 (26.8)

Post-intubation sedation >30 minutes†, n (%) 19 (13.4)

Post-intubation sedation >45 minutes†, n (%) 14 (9.9)

Time to analgesia in minutes, median (Q1,Q3) 75.5 (18,179)

Post-intubation analgesia given in ED, n (%) 72 (48)

Post-intubation analgesia given after transfer from ED, n (%) 46 (30.7)

No post-intubation analgesia given‡, n (%) 32 (21.3)

Q1: 1st quartile; Q3: 3rd quartile; ED: Emergency Department; ¶Any point in time after initial post-

intubation sedation is given where the patient is paralyzed but not sedated; †Including only patients who

received one of the fast-acting induction agents (n=142); ‡No analgesia given within the shortest

timeframe of: 24 hours post-intubation, time of extubation, or time of expiry.

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Figure 1. Analgesia and sedation management for intubated patients pre-printed order

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Figure 2. Flow diagram of chart selection

599 charts identified by Health Records

461 charts randomly screened

150 charts included

311 charts excluded:•51 intubated without paralytic•21 incomplete documentation•5 started sedative infusion prior to RSI•234 no intubation in ED

• 155 put on BiPAP in ED• 48 intubated at other site• 14 presented on home oxygen• 13 intubated by EMS at scene• 4 unclear why included

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Figure 3. Usage of peri-intubation medications

Paralytic agent

Rocuroniumn=76

Succinylcholinen=74

Induction agentPropofoln=75Ketaminen=58Midazolamn=5Etomidaten=5Lorazepamn=2Fentanyln=2No inductionn=3

Post-intubation sedative

Propofoln=112Ketaminen=5Opioidn=9Etomidaten=1Sevofluranen=1Benzodiazepinen=22