Original Contribution

Prevention of awakening signs after rapid-sequence intubation: a randomized study

Morgan Jaffrelot MD^a, Joel Jendrin MD^b, Yolande Floch MD^c, David Lockey MD^d, Patricia Jabre MD^e, Muriel Vergne MD^a,

Fre’de’ric Lapostolle MD^e, Michel Galinski MD^e, Fre’de’ric Adnet MD, PhD^e,*

^aSamu 29 and Emergency Department, University Hospital, 29200 Brest, France ^bSamu 44 and Emergency Department, University Hospital, 44000 Nantes, France ^cEmergency Department, Quimpert Hospital, 29000 Quimpert, France

^dLondon Helicopter Emergency Medical Service, Royal London Hospital, E1 1BB London, UK

^eSamu 93, EA 3409, University Avicenne Hospital, 93000 Bobigny, France

Received 30 August 2006; revised 28 September 2006; accepted 29 September 2006

Abstract

Background: This study aimed to establish the incidence of signs of inadequate sedation after rapid-sequence intubation (RSI) and to determine whether a supplementary bolus of Induction agent decreases these signs.

Methods: A randomized, double-blind trial design was used. Patients were randomly assigned to 1 of 2 treatments: RSI plus etomidate bolus followed by continuous Sedative infusion (ETO group) or RSI plus placebo followed by continuous sedative infusion (placebo group). The primary outcome measure was a composite sedation score measured 6 minutes after induction. The components of the score were the Ramsay sedation score, the presence of cough or pulling at endotracheal (ET) tube, jaw relaxation, motor activity, and eye opening. The total score (0-10) was the sum of the 5 components.

Results: There were 21 patients in the ETO group and 20 patients in the placebo group. The percentage of patients presenting with at least 1 sign of awareness was 43% in the ETO group and 65% in the placebo group ( P = .16) 6 minutes after induction. The sedation score was significantly higher at 6 minutes in the placebo group compared with the ETO group (2.4 F 2.9 vs 0.9 F 1.4; P b.05). The use of additional sedative drugs during the observation period was 43% (9/21) in the ETO group compared with 55% (11/20) in the placebo group ( P = .44).

Conclusions: This study demonstrated that some patients have signs of inadequate sedation after RSI. These signs may be partially prevented by a supplementary dose of an induction agent but other supplementary sedation seems necessary.

D 2007

* Corresponding author. Samu 93-EA 3409, Hopital Avicenne, 93000 Bobigny, France. Tel.: +33 1 48 96 44 08.

E-mail address: [email protected] (F. Adnet).

Introduction

Critically ill patients who have emergency rapid-se- quence intubation (RSI) and mechanical ventilation usually

0735-6757/$ – see front matter D 2007 doi:10.1016/j.ajem.2006.09.016

then require continuous sedation. Sedative infusions are administered to (1) prevent awareness, (2) facilitate care, (3) reduce oxygen requirements, (4) provide analgesia, and (5) manage intracranial pressure in patients with head injury [1]. Inadequate sedation can lead to adverse events including unplanned extubation, loss of venous catheters, agitation, difficulty with ventilation, barotrauma, hyperten- sion, Intracranial hypertension, and hypoxemia. These complications may be associated with poor outcome especially in cases of head injury or Severe asthma [2]. The technique of RSI is widely used to intubate and ventilate emergency patients [3-5]. The drugs used in the technique are required to have rapid onset and Short duration of action. Etomidate is used in this system as an induction agent because of its excellent hemodynamic profile even in hypovolemic patients and safety profile in patients at risk of coronary ischemia and in those with head injuries [6]. Usually, continuous infusion of sedatives starts immediately after RSI. However, some patients show agitation or discomfort after recovering from the effects of the drugs used in RSI (eg, etomidate and succinylcholine) and before sedative infusions become effective. This period may be associated with the serious adverse events mentioned above. There are currently no recommendations for emergency induction that consider this vulnerable period.

This study was designed to establish the incidence of signs of inadequate sedation postemergency RSI and to

determine whether a supplementary bolus of induction agent decreased these signs.

Materials and methods

Patients

The inclusion criteria include adult patients (18 or older) requiring emergency intubation in the emergency depart- ment (ED) or by a prehospital medical team in the study period. All included patients had postintubation sedation by continuous infusion. Exclusion criteria were pregnancy, poisoning suicide attempt, history of difficult intubation, and known allergy to succinylcholine or etomidate.

Study protocol

A randomized, double-blind trial design was used. Patients were randomly assigned to 1 of 2 treatments: RSI plus etomidate bolus at 0.4 mg d kg^–1 followed by continuous infusion of sedatives (ETO group) or RSI plus placebo (saline serum) followed by continuous infusion of sedatives (placebo group). Study syringes were calibrated according to patient estimated weight; 20-mL syringes were used with etomidate dilution of 2 mg mL^–1 or placebo. Then, 2 mL per 10 kg of estimated weight was injected. Study syringes (etomidate or placebo) were packaged in a

Fig. 1 Study protocol.

sealed study kit. Continuous pulse oximetry and cardiac monitoring were established. Noninvasive Blood pressure measurement was carried every 3 minutes out on the contralateral arm to the intravenous infusion. Rapid- sequence intubation consisted of preoxygenation with 100% oxygen for 4 minutes by facemask, Cricoid pressure, and induction with 0.4 mg kg^–1 of etomidate (Hypnomi- date; Jansen, Beerse, Belgium) followed by Neuromuscular blockage using 1 mg kg^–1 succinylcholine (Celocurin; Pharmatia, Espoo, Finland). After muscle fasciculation was observed, orotracheal intubation was performed. The size of the Laryngoscope blade (3 or 4) and the endotracheal tube (7.0 to 8.0 mm internal diameter [ID]) were selected according to the emergency physician’s preference. Endo- tracheal tube placement was confirmed by clinical exami- nation and a capnometry device. Only 2 attempts at intubation (defined as insertion of the laryngoscope in the mouth) and a total procedure time of 3 minutes were permitted. Failure to comply with these restrictions was defined as a study failure, and other techniques of intubation could be used at the physician’s discretion. Immediately after intubation has been achieved, sedatives in continuous infusion were started, consisting of midazolam (0.1 mgd kg^–1 h^–1) in combination with sufentanil (0.3 lg d kg^–1 d h^–1). The study protocol is summarized in Fig. 1.

Heart rate (HR), BP, and oxygen saturation were recorded at 3, 6, and 9 minutes after induction.

The primary outcome measure was a composite score of sedation evaluated 6 minutes after syringe injection of succinylcholine. The composite score includes the Ramsay score [7], the presence of cough or pulling at endotracheal (ET) tube, jaw relaxation, motor activity, and eye opening. Each item may take 0, 1, or 2 points. The awakening scale is the sum of the points of the 5 items. This scale ranged from 0 (very sedated) to 10 (awake). This scale is detailed in Table 1. This score was collected at 3, 6, and 9 minutes after study syringe injection.

Table 1 Sedation scoring scale

pulling at

tracheal tube

coughs when

stimulated

Motor activity Absence

cough or

pulling at the tube

Present when Spontaneous stimulated

^a Ramsay scale: 1–anxious and agitated or restless or both; 2– cooperative, oriented, and calm; 3–responding to commands only; 4– brisk response to light glabellar tap; 5–sluggish response to light glabellar tap; 6–no response to light glabellar tap.

Item	0	1	2
Eye opening	Absence	At stimulation	Present
Ramsay scalea	5-6	3-4	1-2
Jaw relaxation	Completely	Resistance	Biting the
		at mouth	tube
		opening
Cough or	Absence	Slightly	Vigorous

Characteristics	Placebo group	Etomidate group	P
	(n = 20)	(n = 21)
Age, mean F SD, y	55 F 19	52 F 24	.39
Sex, male/female	13/7	13/8	.84
Initial clinical
condition
GCS, median	6 [5;8]	7 [5;8]	.47
[25th;75th] SBP, mean F SD,	146 F 54	148 F 36	.44
mm Hg DBP, mean F SD,	85 F 30	81 F 18	.21
mm Hg
Spo2, median	99 [94;100]	97 [89;100]	.15
[25th;75th] RR, mean F SD,	24 F 8	21 F 9	.13
cycle/min HR, mean F SD,	90 F 19	91 F 24	.39
beats/min
Aetiologies, n (%)			.53
Trauma	4 (20)	6 (28)
Coma	13 (65)	9 (43)
Dyspnea	2 (10)	4 (19)
Collapse	1 (5)	2 (10)

The secondary outcomes were mortality, HR, BP, pulse oximetry readings, and the need to infuse additional sedative during the observation time. Early significant complications and adverse outcomes were identified and reviewed by the investigators.

Table 2 Baseline patient characteristics

GCS indicates Glasgow Coma Scale; SBP, systolic blood pressure;

DBP, diastolic blood pressure; Spo₂, pulse oxygen saturation; RR, respiratory rate.

P value was calculated using the Wilcoxon test for quantitative data and the v² test or Fisher exact test for qualitative data.

The study was approved by an ethics committee (Comite’ de Protection des Personnes se Pre’tant a` la Recherche Biome’dicale, Aulnay’s Hospital, Sevran, France). Informed consent was waived based on the nature of the interventions and the fact that only regimens in current practice were used. Retrospective informed consent was established before data analysis.

Statistics

Categorical data are reported as numbers (%) and quantitative data as means F SD or medians with 25th to 75th percentiles. Univariate associations were evaluated with Wilcoxon test for quantitative data and the v² test for qualitative data or Fisher exact test for groups with low frequencies. All statistical tests were 2-tailed, and P values less than .05 were considered significant. Data were analyzed using SAS software version 9.1.3 (SAS Institute Inc, Cary, NC, USA).

Sample size analysis predicted that 40 patients (20 in each group) would be required to demonstrate with a power of 80% and a 2-tailed test, a difference in

Fig. 2 Detailed awakening score scale at 6 minutes in the 2 groups, P indicates placebo group; E, ETO group.

sedation scale at 6 minutes of 2 points (a = 5%). An estimated SD of 3 was determined during a preliminary analysis of this scale.

Results

Patient characteristics

From September 2004 to August 2005, 41 patients were recruited for the study. A total of 21 patients were included in the etomidate group (ETO group) and 20 in the placebo group. The baseline characteristics of the 41 patients are shown in Table 2. There were no significant differences between the 2 groups. There were no difficult intubations, and the time taken to intubate was always less than 3 minutes.

No patients were excluded because of missing data, and the primary outcome was analyzed in all patients.

Primary outcomes

The percentage of patients presenting with at least 1 sign of inadequate sedation (defined by 1 component of sedation score more than zero value) was 43% in the ETO group and 65% in the placebo group ( P = .16) 6 minutes after

Table 3 sedation scores scale
Sedation score scale	Placebo group (n = 20)	Etomidate group (n = 21)	P
At 3 min	0.5 F 1.2	0.3 F 0.8	.44
At 6 min	2.4 F 2.8	0.9 F 1.4	b.05
At 9 min	0.9 F 1.3	1.0 F 1.2	.30
Values are means F SD.

intubation. Detailed sedation scores are shown in Fig. 2. At 6 minutes after intubation, 2 (10%) patients in the ETO group versus 7 (35%) in the placebo group had a Ramsay score less than 5 ( P b .05). There was a significant increase in the score at 6 minutes in the placebo group compared with the ETO group (2.4 F 2.8 vs 0.9 F 1.4; P b .05) (Table 3). Sedation score increased significantly at 6 minutes (compared to 3 minutes) in the placebo group ( P b .01) (Table 3).

Secondary outcomes

The hemodynamic profile of the 2 groups is shown in Fig. 3. The HR and the BP were not significantly different in the 2 groups. The overall mortality was 29% and did not differ significantly between the 2 groups. Recourse to sedative drugs during the observation period was 43%

Fig. 3 Hemodynamic profile after RSI. Heart rate and systolic BP. Vertical bars denote standard error of the mean.

Table 4 Requirement for additional sedative drugs
Recourse to sedative drugs	Placebo group (n = 20)	Etomidate group (n = 21)
Midazolam	7 (35)	9 (43)
Etomidate	4 (20)	1 (5)
Sufentanil	5 (25)	5 (24)
Other (not specified)	3 (15)	0 (0)
Values are number (percent).

(9/21) in the ETO group and 55% (11/20) in the placebo group ( P = .44) (Table 4). No important adverse event or side effect was detected.

Discussion

This study demonstrated signs of inadequate sedation between the end of RSI and the onset of continuous sedation reflected by the significant increase in sedation score from 3 to 6 minutes after RSI in the placebo group. These signs can be partially prevented by a supplementary bolus of induction agent immediately after RSI as reflected by the significant decrease in sedation score in the ETO group at 6 minutes.

Of the patients in the placebo and etomidate groups, 65% and 43%, respectively, demonstrated at least 1 sign of inadequate sedation. A previous study found that 77% of patients demonstrated signs of inadequate sedation after RSI despite continuous infusion started immediately after intubation. In this study, the rate was decreased by infusion of a bolus of sufentanil [8]. Approximately half (49%) of our patients required additional sedation. Gindre et al [8] found that 94% of patients needed supplementary sedation in the same situation. Thus, the induction agent used in RSI seems to be insufficient to produce a high level of sedation in the time between induction and the effect of continuous sedative infusion. This is the case even when the infusion is started immediately after induction.

Continuously infused intravenous sedation is a corner- stone of supportive care for emergency patients who are critically ill and require mechanical ventilation [9]. Common sedation practices include the combination of drugs, for example, benzodiazepine and opioid titrated to a desired sedation level. Interruption of sedation in the initial period after management of airway may exacerbate a patient’s condition (eg, causing Elevated intracranial pressure or significantly elevated airway pressures [10]). Thus, adequate sedation and analgesia must always be a priority in intubated critically ill patients, particularly those with head injuries. Some recent studies have demonstrated an association between paramedic intubation and adverse outcomes in traumatic brain-injured patients. Wang et al [11] found an increase in mortality when patients were intubated by paramedics in the prehospital phase (odds ratio, 3.99; 95% confidence interval, 3.21-4.93). The authors noted that paramedics do not always have access to the sedative drugs

used in EDs. Use of continuous sedative infusion adminis- tered by pumps is very rare in paramedic practice. Dunford et al [2] found a high incidence of transient hypoxia and pulse rate reactivity during paramedic RSI in patients with severe head injury. These adverse effects may be partially explained by the lack of adequate sedation. Even in the absence of high- quality evidence that links inadequate sedation and adverse outcomes, it seems reasonable to consider this relation and pursue appropriate levels of sedation.

Rapid initiation of sedation after RSI may prevent clinical evaluation of patients during mechanical ventilation. However, we believe that for patients with a risk of barotrauma, the risk/benefit ratio tends to favor rapid sedation to facilitate ventilation.

Continuous sedative infusion without a loading dose is associated with a long onset of action. For example, a continuous infusion of midazolam at 0.1 mg kg^–1 h^–1 reaches maximum plasma concentration only after 20 minutes [8]. Etomidate when used as an induction agent has a rapid onset (approximately 5-15 seconds) and a Duration of action of 5 to 14 minutes [6]. These figures highlight a short period after the induction agent has ceased to be effective and continuous sedation has not reached peak plasma levels. In our study, this theoretical period translated to clinical signs of inadequate sedation.

Interestingly, the need for additional sedatives did not differ significantly between the 2 groups. Although the use of 1 supplementary bolus of etomidate significantly decreased the sedation score at 6 minutes, signs of inadequate sedation were still frequent (43% of patients included in the ETO group). The use of additional sedation may explain the mean sedation score close to zero at 9 minutes.

A bolus of a Sedative agent with longer duration of action than etomidate (eg, midazolam) administered immediately after RSI may provide better sedation. However, boluses of midazolam have been found to be potentially deleterious for hemodynamically unstable patients [12].

Limitations of the study

There are limitations to this study. First, the choice of etomidate as an induction agent and for supplementary sedation may not be entirely appropriate. The use of etomidate, even as a single bolus, has been recently called into question [13,14]. It is well recognized as a cause of relative Adrenal insufficiency and for this reason is not used for prolonged sedation [15]. In unstressed patients, the administration of 0.3 mg kg^–1 of etomidate as a single intravenous injection inhibits the synthesis of major corticosteroid hormones for at least 5 hours [16]. Recent studies have suggested an association with the use of etomidate in RSI and poor outcomes in intensive care unit patients. Malerba et al [17] found that the administration of a single intravenous dose of etomidate for intubation increased the risk of adrenal insufficiency by 12 times. There are however no good quality studies that demonstrate

a direct bcause-effectQ relationship between morbidity or mortality and the use of single bolus of etomidate. This study did not attempt to investigate in-hospital morbidity related to the use of etomidate. The drug remains popular in European RSI practice because of its relative hemodynamic stability [18-20]. Our study highlighted the need for a supplementary sedation agent but not necessarily the agent we used. Because the potential deleterious effects of etomidate on adrenal function have been recently empha- sized, we now advocate the use of Alternative agents (eg, midazolam) to achieve the same objectives.

Another limitation of this study was the nonvalidated sedation scale used. We based this scale on the basis of items widely used for evaluating sedation during anes- thesia and intensive care [7,21,22]. More advanced measures of sedation, for example, bispectral index monitoring [23,24], may be appropriate but were not available and were not validated for the clinical signs of inadequate sedation.

Conclusion

Our results demonstrate that some patients have signs of inadequate sedation after RSI even when a sedative infusion is commenced immediately. This transient period has the potential to adversely affect outcome. These signs may be partially prevented by an etomidate bolus, but other supplementary sedation seems necessary. Rapid-sequence intubation protocols should take into account the vulner- able period between induction and the effective sedation provided by sedative infusions.

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