Article, Emergency Medicine

Analgosedative interventions after rapid sequence intubation with rocuronium in the emergency department

a b s t r a c t

Objectives: The use of etomidate and rocuronium for Rapid Sequence Intubation results in a duration of pa- ralysis that exceeds the duration of sedation. The primary objective of this study was to compare the number of analgosedative (AGS) interventions early versus late post-RSI, with this drug combination. The secondary objec- tive was to descriptively assess time to first AGS intervention.

Methods: This was a retrospective cohort study conducted in an academic ED in the United States between Jan- uary 2015 and June 2016. The study was conducted after a pharmacy-led education program. Consecutive adult patients who received the combination of etomidate and rocuronium for RSI were included. The primary out- come measure was the number of AGS interventions post-RSI. An AGS intervention was defined as initiation of an opioid or sedative, or a dose increase of an infusion rate. Interventions were categorized as early (0-30 min post-RSI) or late (60-90 min post-RSI).

Results: The sample (n = 108) had a mean age of 58 +- 19 years, and the majority was male (n = 62, 57%). The mean rocuronium dose was 1.1 +- 0.3 mg/kg. There was a median of 2 interventions (IQR 1-3) that occurred early versus 0 interventions (IQR 0 to 1) that occurred late post-RSI (p b 0.001). The median time to first AGS interven- tion was 7 min (IQR 3 to 13 min).

Conclusions: When rocuronium was used for RSI in the ED there was no delay in provision of post-intubation se- dation or analgesia, after a pharmacy-led educational program.

(C) 2017

Introduction

rapid sequence intubation is the most common method of air- way control in the emergency department (ED) [1]. RSI involves the near simultaneous administration of an Induction agent and neuromus- cular blocking agent to facilitate tracheal intubation. One of the most common induction agents used for RSI in the ED is etomidate, which has a rapid onset and Short duration of effect [1,2]. The most common Neuromuscular blocking agents used are rocuronium and succinylcho- line, which have been shown to be equivalent in terms of first pass

Abbreviations: AGS, analgosedative; ED, emergency department; RSI, rapid sequence intubation.

? Conflicts of interest: None

?? Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

??? Abstract presentation: American College of Emergency Physicians Scientific

Assembly. Washington DC. October 2017.

* Corresponding author at: 1295 N. Martin, PO Box 210202, Tucson, AZ 85721, USA.

E-mail address: [email protected] (A.E. Patanwala).

success [1,3]. Succinylcholine has a very Short duration of action, as does etomidate, which results in their effects wearing off at similar times. However, there are situations in which succinylcholine is contra- indicated, necessitating the use of rocuronium. Rocuronium has a long duration of effect which presents a problem when it is used with etomidate [4]. The mismatched durations of action can potentially lead to circumstances in which patients are pharmacologically para- lyzed but conscious in the post-RSI period.

Previous studies comparing rocuronium to succinylcholine for RSI have shown that when rocuronium is used, there are delays in provision of post-RSI sedative and analgesics [4,5]. Also, the doses of sedatives and analgesics used post-RSI may be lower when rocuronium is used [6]. This likely occurs because the prolonged neuromuscular blockade may mask the need for sedation after intubation with rocuronium. These studies imply that rocuronium use may be associated with inadequate provision of sedation and analgesia. Since these studies were published, institutions such as ours have implemented changes to address this con- cern. Also, these previous studies did not quantify the number and time- course of sedative and analgesic interventions post-RSI. The number of

https://doi.org/10.1016/j.ajem.2017.11.022

0735-6757/(C) 2017

interventions serves as a useful surrogate for provider involvement, while patients remain pharmacologically paralyzed post-RSI.

The primary objective of this study is to compare the number of analgosedative (AGS) interventions early versus late post-RSI. The sec- ondary objectives were to descriptively assess time to first AGS inter- vention, compare time to first AGS intervention when the pharmacist was present versus not present, and descriptively evaluate post-RSI AGS titration and dosing.

Methods

Study design

This was a retrospective cohort study. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guide- lines were followed for all aspects of the study [7]. The University’s Insti- tutional Review Board approved the study prior to data collection.

Study setting

The study was conducted at an academic, tertiary care ED in the United States. The institution is designated as a Level 1 trauma center and has 61 ED beds including a 7-bed resuscitation bay. Medications used for RSI are in an airway medication box that is stored in a con- trolled access cabinet (Pyxis(R) machine) in the resuscitation bay. This box is retrieved by a nurse or pharmacist prior to intubation and is avail- able at the bedside. All sedatives and analgesics that may be used post- intubation such as propofol and fentanyl are also in the same controlled access cabinet. Thus all medications used are readily available in the ED. The ED has a pharmacist present from 1200 to 2200 seven days a week. The ED pharmacist is responsible for facilitating the provision of medi- cations for RSI and post-intubation. Previous data from our institution has shown that there have been delays in the provision of post-intuba- tion sedation [4,8]. Since then pharmacist-led education has been con- ducted with nursing and physician staff. This has included lectures during emergency physician weekly conferences, discussions during nursing shift changes, and bedside teaching during each RSI. The ED also incorporated an RSI order-set within the electronic medical record system that prompts the provision of post-intubation sedation and analgesia.

Patient selection

Consecutive adult patients who received the combination of etomidate and rocuronium for RSI between January 2015 and June 2016 were included. Patients were excluded if they had a GCS of 3 prior to intubation, initiated on infusions other than propofol or fentanyl after intubation, given a neuromuscular blocking agent post-intubation, died within 90 min post-intubation, had missing medical records, or transferred out of the ED within 90 min. The intent was to select pa- tients who were responsive prior to RSI and were in the ED for at least 90 min, which was the measurement period.

Data collection

Data were collected through medical record review and entered into Research Electronic Data Capture (REDCap), which is a secure online system to collect patient data for research. Data collection variables in- cluded: demographics, clinical variables (e.g. Glasgow Coma Scale [GCS] prior to intubation, trauma status, intracranial hemorrhage), medication data (RSI medications, post-intubation sedatives and anal- gesics), blood pressure, and vasopressor use. After data collection, accu- racy and reliability was ensured with a double check of random data entries (10% of sample) by two other investigators not involved in initial data collection. The data were also evaluated for outlying values and

inconsistencies that appeared to be erroneous. If a potential error was identified than the medical record was reviewed again for confirmation.

Study outcomes

The primary outcome measure was the number of AGS interventions after RSI. An AGS intervention was defined as any one of the following: sedative or opioid bolus, sedative or opioid infusion rate increase. Previ- ous studies have reported time to first intervention. However, this mea- sure alone does not provide a full picture of provider involvement in the post-intubation phase. Thus we chose to evaluate the number of AGS in- terventions in addition to the time to first intervention. The interven- tions were categorized as: early (0 to 30 min) or late (60 to 90 min) after RSI. The primary comparison was the number of interventions that occurred between the early and late phases. A sensitivity analysis was conducted by re-defining early versus late interventions as b 30 min versus >= 30 min, respectively. This was done because we were uncertain of when the clinical effects of neuromuscular blockade from rocuronium would no longer be in effect and our primary thresh- old of 60 min could be too late after RSI for this measurement. The time- course of AGS interventions was also evaluated descriptively during the 90-minute period.

The secondary objectives were to descriptively assess time to first AGS intervention (time 0 was defined as when etomidate was adminis- tered), compare time to first AGS intervention when the pharmacist was present versus not present, and descriptively evaluate post-RSI sed- ative and analgesic titration and dosing.

Data analyses

The data were evaluated descriptively. Continuous variables were reported as means with standard deviations if normally distributed or medians with interquartile ranges if not normally distributed. Normali- ty was assessed visually via the use of histograms. Categorical variables were reported as percentages. The median number of AGS interventions was compared between the early and late phases using the Wilcoxon signed-rank test. The time to first sedative intervention was compared when the pharmacist was present or not present in the ED using the Wilcoxon rank-sum test.

Assuming a mean of 1 intervention in the early phase and 2 inter- ventions in the late phase, using a standard deviation of the difference of 2, alpha 0.05, and power 80%, we estimated that we would need 34 patients. Note that in this study patients served as their own control (i.e. early versus late interventions were compared in the same pa- tients). Given that there was uncertainty regarding our baseline as- sumptions, we targeted a sample of 100 patients for this study. All statistical evaluations were performed using Stata 13 (Stata Corpora- tion, College Station, TX). The a priori alpha level used was 0.05.

Results

Study sample

There were 179 intubations in adults using rocuronium and etomidate during the study period. Of these 33 had a GCS of 3 on arrival, 13 used infusions other than propofol or fentanyl after intubation, 10 were given a neuromuscular blocking agent post-RSI, 7 developed car- diac arrest post-RSI, 5 medical records could not be obtained, and 3 were transferred out of the ED within 90 min. Thus 108 patients were included in the study cohort. The mean age was 58 +- 19 years, and ma- jority of patients were male (n = 62, 57%). There were a few trauma pa- tients (n = 14, 13%) and patients with intracranial hemorrhage (n = 16, 15%). The median Glasgow Coma Scale was 11 (IQR 8-14) prior to RSI. In terms of medications used for RSI, the induction dose of etomidate used was 20 mg, (n = 93, 86%), 10 to 20 mg (n = 14, 13%), or 40 mg (n = 1, 1%). The mean dose of rocuronium used was 1.1 +- 0.3 mg/kg.

Table 1

Time to sedatives and analgesics

Variable Median (IQR)

[minutes]

Time to propofol infusion (n = 81) 9 (4-15) Time from propofol start to first titration increase (n = 25) 40 (15-55) Time from propofol start to first titration decrease (n = 15) 26 (10-53) Time to fentanyl infusion (n = 90) 9 (5-22) Time from fentanyl start to first titration increase (n = 18) 38 (23-55) Time from fentanyl start to first titration decrease (n = 10) 31 (15-37) Time to first sedative or analgesic bolus (n = 69) 9 (5-18)

The mean SBP prior to intubation was 135 +- 34 mm Hg (MAP 100 +- 26 mm Hg) and this decreased to a minimum value of 113 +- 30 mm Hg (MAP 82 +- 22 mm Hg) during the 90 min period post-intubation. A total of 23 (21%) patients achieved a lowest SBP of b 90 mm Hg (range 38 to 89 mm Hg) post-intubation. However, 7 of these 23 patients had a SBP b 90 mm Hg (range 60 to 81 mm Hg) prior to intubation. There were 14 (13%) patients who received a vasopressor. Of these, 12 re- ceived a norepinephrine infusion, 2 received a vasopressin infusion, and 1 received a dopamine infusion. In addition, 3 received a push dose of epinephrine, and 2 received a push dose of phenylephrine.

Main results

There was a median of 2 AGS interventions (IQR 1-3) in the early (0- 30 min) phase compared to 0 AGS interventions (IQR 0 to 1) in the late (60-90 min) phase post-RSI (p b 0.001). There were 0 AGS interven- tions (IQR 0 to 1) between 30 and 60 min. In the sensitivity analysis, early versus late interventions were re-defined as b 30 min versus

>= 30 min, respectively. There remained a significant difference in the median number interventions between the early phase (2 interven- tions, IQR 1-3) and late phase (1 intervention, IQR 0-2) using this definition (p b 0.001). The median time to first sedative AGS interven- tion was 7 min (IQR 3 to 13 min). Details with regard to timing of administration of propofol or fentanyl infusions, rate increases, and bo- luses are in Table 1. The time to first AGS intervention was similar (p = 0.260) when a pharmacist was present (7 min, IQR 3-12 min) or not present (8 min, IQR 3-15 min). The cumulative number of AGS inter- ventions in the 90 min post-RSI period is depicted in Fig. 1. It is apparent

from the figure that there was no spike in AGS interventions when the effect of rocuronium is expected to wear off.

Most patients were started on both propofol and fentanyl infusions (n = 70, 64%). Some patients received a fentanyl infusion only (n = 20, 19%), propofol infusion only (n = 11, 10%), or no infusion (n = 7, 7%). Of the 7 patients who received no infusions, 1 was given fentanyl and midazolam boluses, and 2 patients were hypotensive on vasopres- sors. There did not appear to be a reason for avoidance of AGS in the re- maining 4 patients. The initial propofol infusion rate was 20 mcg/kg/ min (IQR 10 to 20 mcg/kg/min). The initial propofol infusion rate was decreased or held in 15/81 (19%) patients (rate decrease by 5 to 40 mcg/kg/min). The infusion was increased in 25/81 (31%) patients (rate increase by 5 to 30 mcg/kg/min). Fig. 2 shows initial and subse- quent titrations of propofol. The initial fentanyl infusion rate was 100 mcg/h (IQR 50 to 100 mcg/h). The fentanyl infusion was decreased or held in 11/90 (12%) patients (rate decrease by 25 to 100 mcg/h) and increased in 18/90 (20%) patients (rate increase by 20 to 100 mcg/h). Fig. 3 shows initial and subsequent titrations of fentanyl. Table 2 has the bolus doses of sedatives and analgesics given post-RSI. The most common sedative bolus given was midazolam and the most common analgesic bolus given was fentanyl.

Discussion

The key finding of this study was that most patients who underwent RSI in the ED with etomidate and rocuronium received early rather than late AGS interventions. Our hypothesis was that as the effect of rocuronium wears off, the unmasking of under-sedation would prompt AGS interventions. This would have provided us with evidence that pa- tients who receive rocuronium were under-sedated in the immediate post-RSI period. However, it appears that the management of patients in our study resulted in relatively few patients requiring late interven- tions. This is seen from the figure of the time course of AGS interven- tions in the post-RSI period. The results highlight that the pharmacy- led process changes at our institution improved the management of post-intubation sedation.

This study characterizes in detail the manner in which sedatives and analgesics were used in the post-RSI period, which provides addi- tional insight for clinicians. For instance an initial regimen of propofol 20 mcg/kg/min in combination with fentanyl 100 mcg/h, which was

Fig. 1. Cumulative frequency of sedative and analgesic interventions in the 90 min post-intubation period.

Fig. 2. Flow diagram of propofol titration post-intubation.

common in our cohort, can serve as a starting point for Post-intubation sedation and analgesia post-RSI in the ED. In the intensive care unit, starting doses of propofol 5 mcg/kg/min is common [9]. In the ED set- ting, a deeper level of sedation may be desired to facilitate imaging or in- vasive procedures that need to be conducted in a short time frame. Patient agitation during this critical period can be harmful leading to de- lays in Life-saving interventions. Also, it is preferred to overestimate the need for sedation while patients are under the influence of neuromus- cular blockade. Previous studies have shown that patients intubated using rocuronium are at risk for under-dosing of sedation [6]. It is possi- ble that the higher starting dose of propofol in this study in immediate post-RSI phase, helped reduce the need for additional sedative interven- tions after the effects of neuromuscular blockade were no longer pres- ent. However, it is important to note that 19% of these patients

required a subsequent dose decrease of propofol. Our post-intubation protocol also recommends a bolus fentanyl dose prior to the infusion. This did occur in a large proportion of patients, but ideally should be done in all patients.

In a previous study in the ED at our institution, we showed that rocuronium-assisted RSI was associated in delays in post-intubation se- dation provision when the pharmacist was not present [8]. In this previ- ous study, the time to sedation provision post-RSI was much longer (9 versus 28 min) when the pharmacist was not present. The study includ- ed data prior to June 2011 and steps have been taken to make improve- ments, such as education of the ED staff during conferences, shift changes, and at the bedside as described in our methods. The data for the current investigation is several years since that period. The time to AGS intervention in the current study was only 8 min (IQR 3-15 min)

Fig. 3. Flow diagram of fentanyl titration post-intubation.

Table 2

Sedative and analgesic bolus doses.

Midazolam

Lorazepam

Propofol

Fentanyl

Hydromorphone

N Dose (mg)

N Dose (mg)

N Dose (mg)

N

Dose (mcg)

N Dose (mg)

Bolus 1

12 2-20

1 2

2 80-100

53

50-100

– –

Bolus 2

10 3-10

2 2

– –

22

50-100

– –

Bolus 3

2 5

1 4

1 40

8

50-150

1 1

Bolus 4

1 5

– –

1 20

2

100

– –

even when the pharmacist was not present. This shows that an educa- tion campaign and involvement of the pharmacist during RSI has a car- ryover effect that was sustained even during the hours when the pharmacist is not present. It is also likely that results from the previous study that were shared with providers had an effect on changing practice.

The issue of inadequate provision of post-RSI sedation is especially problematic when rocuronium is used, instead of succinylcholine for RSI [4,5,10]. Watt et al. performed a retrospective cohort study compar- ing the time from intubation to post-intubation sedative use between patients who received rocuronium and succinylcholine for RSI [4]. This study found that patients in the rocuronium group received sedation later than the succinylcholine group (27 +- 29 min versus 15 +- 13 min, p b 0.001). Johnson et al. performed a similar retrospective study comparing time from RSI to continuous sedation between pa- tients who received succinylcholine and rocuronium [5]. The results of this study found that the time to continuous sedation was also longer in the rocuronium group when compared to succinylcholine group (34 +- 36 min versus 16 +- 21 min, p = 0.002). However, the results of our study suggest that this potential disadvantage of rocuronium can be overcome with process changes in institutions.

This study has a few limitations that are related to the retrospective study design. We had to rely on the accuracy of the documentation in the electronic medical record with regard to doses and timing of all medications administered. Thus the results are based on the assumption that documentation was accurate. early interventions were defined as interventions that occurred within 30 min post-RSI. However, the dura- tion of effect of etomidate is b 5 min [11]. Thus the goal is to initiate se- dation immediately after RSI and even early interventions as defined in the study may not be optimal. Our intent was to capture the number of interventions during 30-minute intervals so that we could make com- parisons between each interval, which led to this definition. For in- stance, a large number of late interventions, after rocuronium is no longer in effect, would have indicated inadequate sedation in the imme- diate post-RSI period. However, this did not occur based on our results. Also, we were interested in the number of interventions rather than the first intervention, because it provides a better understanding of the de- gree of provider involvement for provision of patient comfort. Although we did this to build upon existing literature, we also reported time to the provision of sedatives and analgesics, to enable comparisons with previous investigations.

Conclusions

After a targeted series of educational and systems interventions in an academic emergency department, rocuronium use during RSI was not associated with delays in the provision of post-intubation sedation or analgesia. Patients did not appear to be under-sedated in the immediate post-RSI period as evidenced by few late interventions. Pharmacist-led education can change the culture of post-RSI sedation such that appro- priate interventions occur even when the pharmacist is not present in the ED.

Acknowledgements

None.

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