Dexmedetomidina para el tratamiento de la intubación fibróptica con el paciente despierto
Resumen
Antecedentes
La intubación fibróptica con el paciente despierto (IFOD) con frecuencia requiere sedación, ansiolisis y alivio del malestar sin afectar la asistencia respiratoria ni deprimir la función cardiovascular. El objetivo es permitir que el paciente sea receptivo y pueda cooperar. Se ha informado que los fármacos como el fentanilo, el remifentanilo, el midazolam y el propofol ayudan en la IFOD; sin embargo, estos agentes están asociados con efectos adversos cardiovasculares o respiratorios. La dexmedetomidina se ha propuesto como una opción para facilitar la IFOD.
Objetivos
El objetivo principal de esta revisión es evaluar y comparar la eficacia y la seguridad de la dexmedetomidina en el tratamiento de los pacientes con una vía respiratoria difícil o inestable y que son sometidos a la intubación fibróptica con el paciente despierto (IFOD).
Métodos de búsqueda
Se hicieron búsquedas en el Registro Cochrane Central de Ensayos Controlados (Cochrane Central Register of Controlled Trials, CENTRAL; 2012, número 5), MEDLINE (1966 hasta mayo de 2012) a través de Ovid, EMBASE (1980 hasta mayo de 2012) y Web of Science (1945 hasta mayo de 2012); se seleccionaron las listas de referencias de todos los ensayos y revisiones elegibles para buscar ensayos adicionales y se estableció contacto con los autores de los ensayos para obtener información adicional. Se hicieron búsquedas de ensayos en curso enhttp://www.controlledtrials.com/and http://clinicaltrials.gov/. Se volvió a ejecutar la búsqueda en todas las bases de datos mencionadas anteriormente el 21 de noviembre de 2013.
Criterios de selección
Se incluyeron ensayos controlados aleatorizados publicados y no publicados, de forma independiente del cegamiento o el idioma de la publicación, en participantes a partir de los 18 años de edad en los que se había programado una IFOD debido a una previsión de dificultad en la vía respiratoria. Los participantes recibieron dexmedetomidina o fármacos de control.
Obtención y análisis de los datos
Tres autores de la revisión, de forma independiente, extrajeron los datos sobre el diseño del estudio, los participantes, las intervenciones y los desenlaces. Se evaluó el riesgo de sesgo mediante la herramienta de la Colaboración Cochrane. Se calcularon las razones de riesgos (RR) o las diferencias de medias (DM) con intervalos de confianza (IC) del 95% para los resultados con datos suficientes; para otros desenlaces, se realizó un análisis cualitativo.
Resultados principales
Se identificaron cuatro ensayos controlados aleatorizados (ECA), que incluyeron a 211 participantes. Los cuatro ensayos compararon dexmedetomidina con midazolam, fentanilo, propofol o un placebo de cloruro de sodio, respectivamente. Los ensayos mostraron un riesgo de sesgo bajo o poco claro, principalmente debido a que la información proporcionada sobre la ocultación de la asignación y otras posibles fuentes de sesgo fue insuficiente. Debido a la heterogeneidad clínica y la potencial heterogeneidad metodológica, no fue posible llevar a cabo un metanálisis completo. Los hallazgos de los estudios individuales se presentaron de forma descriptiva o tabular. Hubo evidencia limitada disponible sobre la evaluación de los desenlaces de interés para esta revisión. Los resultados de los pocos ensayos incluidos indicaron que la dexmedetomidina redujo significativamente el malestar de los participantes sin observar diferencias significativas en la obstrucción de las vías respiratorias, niveles bajos de oxígeno ni episodios adversos cardiovasculares surgidos durante la IFOD en comparación con los grupos de control. Cuando se volvió a ejecutar la búsqueda (desde mayo de 2012 hasta noviembre de 2013), se observó que cuatro estudios estaban en espera de evaluación. Se considerarán estos estudios cuando se actualice la revisión.
Conclusiones de los autores
Los pocos ensayos pequeños aportan evidencia débil para apoyar la dexmedetomidina como una opción para los pacientes con una previsión de dificultad en la vía respiratoria y que son sometidos a la IFOD. Los hallazgos de esta revisión deben corroborarse con más investigaciones controladas.
PICO
Resumen en términos sencillos
¿Es la dexmedetomidina una buena opción para realizar la intubación fibróptica con el paciente despierto?
Esta es una revisión de la evidencia clínica de los ensayos controlados aleatorizados sobre el efecto de la dexmedetomidina en el tratamiento de la intubación fibróptica con el paciente despierto. La revisión fue realizada por investigadores de la Colaboración Cochrane. La intubación fibróptica con el paciente despierto (IFOD) está indicada para el tratamiento de los pacientes con una vía respiratoria difícil o inestable (crítica), como los que presentan deformidades o tumores en las vías respiratorias, lesiones en las vías respiratorias o inestabilidad de la médula espinal. En dicha situación, es necesario mantener la cooperación del paciente y reducir la ansiedad del paciente sin causar efectos adversos graves durante la IFOD. Se ha informado que muchos agentes, incluido el fentanilo, el remifentanilo, el midazolam y el propofol, ayudan con la IFOD. Sin embargo, estos agentes pueden causar paro respiratorio, pérdida del control de las vías respiratorias o reducción de la función cardiovascular (cardíaca), especialmente cuando se utilizan en dosis altas y, por lo tanto, aumentar el riesgo de niveles bajos de oxígeno (hipoxemia), aspiración, presión arterial baja (hipotensión) o frecuencia cardíaca lenta (bradicardia).
La dexmedetomidina es un agonista selectivo de receptores adrenérgicos alfa‐2 que puede causar sedación, ansiolisis, reducción de analgésicos, reducción en la secreción salival y depresión respiratoria mínima, lo cual podría ser beneficioso para los pacientes con una vía respiratoria difícil o inestable sometidos a la IFOD.
Se realizaron búsquedas en la literatura médica hasta mayo de 2012 y se identificaron cuatro ensayos controlados aleatorizados con 211 pacientes que fueron apropiados para su inclusión en la revisión. Estos estudios compararon dexmedetomidina versus midazolam, fentanilo, propofol o un placebo de cloruro de sodio en pacientes sometidos a la IFOD. Se volvió a ejecutar la búsqueda en noviembre de 2013, y cuatro estudios están a la espera de evaluación. Se considerarán cuando se actualice la revisión.
La dexmedetomidina redujo significativamente el malestar del paciente durante la IFOD en comparación con los grupos de control en dos ensayos incluidos. No se informó ninguna diferencia significativa en el tiempo de intubación, la obstrucción de las vías respiratorias, los niveles bajos de oxígeno ni los episodios adversos cardiovasculares surgidos durante la IFOD entre el grupo de dexmedetomidina y el grupo de control.
La dexmedetomidina no pareció ser inferior a otros fármacos. Los datos de esta base de datos de evidencia de tamaño moderado aporta evidencia limitada para apoyar el uso de dexmedetomidina como una opción alternativa o primaria para la IFOD. Los estudios de investigación adicionales deberían centrarse en este importante tema. Se necesitan ensayos controlados aleatorizados adicionales bien diseñados para analizar los beneficios exactos de la dexmedetomidina en el tratamiento de la IFOD.
Authors' conclusions
Background
Description of the condition
Awake fibreoptic intubation (AFOI) is indicated in a variety of clinical situations. An integral part of AFOI is the management of patients with a critical (difficult or unstable) airway, such as airway deformity or tumour, airway injury or spinal cord instability. An ideal situation for AFOI requires sedation, anxiolysis and relief of discomfort without impairing ventilation and depressing cardiovascular function, while allowing the patient to be responsive and co‐operative. Many medications, such as fentanyl, remifentanil, midazolam and propofol, have been reported to assist AFOI (Knolle 2003; Lallo 2009; Machata 2003; Rai 2008). However, these agents can cause respiratory arrest, loss of airway control or cardiovascular depression, especially when used at high doses (Bergese 2007; Rai 2008). This increases the risk of hypoxaemia, aspiration, hypotension or bradycardia (Bailey 1990).
Description of the intervention
Dexmedetomidine is a selective alpha‐2‐adrenoceptor agonist with properties of sedation, anxiolysis, analgesic sparing and inhibition of salivary secretion (Gerlach 2007). The alpha‐2/alpha‐1‐adrenoceptor selectivity ratio is eight‐fold greater than for clonidine, the classic alpha‐2‐adrenoceptor agonist (Virtanen 1988). Dexmedetomidine has a half‐life (t1/2) of approximately two hours, a duration of action of approximately four hours and a side effect profile that is shorter in duration than that of clonidine (i.e. much shorter influence on normal physiology).
When used at higher doses, dexmedetomidine exhibits minimal respiratory depression (Ebert 2000; Venn 2000). Thus dexmedetomidine has been proposed as a promising drug to use during AFOI for managing patients with a difficult or unstable airway (Hall 2000; Kamibayashi 2000). Dexmedetomidine has been approved for use in intubated and mechanically ventilated patients in the intensive care unit (ICU), as well as in non‐intubated patients undergoing surgical or other procedures (Ebert 2000).
Although dexmedetomidine has beneficial attributes, increasing concentrations of dexmedetomidine in humans results in bradycardia and a biphasic (low, then high) dose‐response relation for mean arterial pressure, especially in patients with intrinsic or drug‐induced bradycardia, hypovolaemia, advanced heart block or severe ventricular dysfunction (Ebert 2000). It is recommended that dexmedetomidine be administered at a loading dose of 1 mcg/kg for at least 10 minutes, followed by a maintenance infusion of 0.2 to 0.5 mcg/kg/h.
How the intervention might work
Dexmedetomidine is pharmacologically unique in that the induced conscious sedation involves activation of the endogenous sleep‐promoting pathway (Coursin 2001). Dexmedetomidine could provide sedation and anxiolysis via receptors within the locus coeruleus, which is an important modulator of wakefulness. Meanwhile, dexmedetomidine could provide analgesic sparing via receptors in the spinal cord and attenuation of the stress response with no significant respiratory depression (Gerlach 2007).
As an alpha‐2‐adrenoceptor agonist, dexmedetomidine when infused may lead to short‐loop feedback inhibition of adrenaline (epinephrine) release from the adrenal gland. The clinical significance of this has yet to be determined.
Why it is important to do this review
The properties of dexmedetomidine may be beneficial for patients with a difficult or unstable airway undergoing AFOI when used as a sole infusion or as an adjuvant (Abdelmalak 2007; Maroof 2005). Case reports and studies have demonstrated the successful use of dexmedetomidine in AFOI (Bergese 2007; Grant 2004; Jooste 2005). On the other hand, dexmedetomidine has sympathetic modulating properties, which may be responsible for potential haemodynamic side effects, such as bradycardia, hypotension or conduction block, particularly in those who are hypovolaemic or bleeding or who have cardiac conduction or cardiac contractility limitations. It is important to perform a systematic review to assess the effectiveness of dexmedetomidine during AFOI and to document possible adverse effects or complications.
Objectives
The primary objective of this review is to evaluate and compare the efficacy and safety of dexmedetomidine in the management of patients with a difficult or unstable airway undergoing awake fibreoptic intubation (AFOI).
Methods
Criteria for considering studies for this review
Types of studies
We included published and unpublished randomized controlled trials, regardless of blinding or language of publication.
Types of participants
We included any patient older than 18 years of age who was scheduled for an elective AFOI because of an anticipated difficult airway.
Types of interventions
Dexmedetomidine versus any other control.
Types of outcome measures
Primary outcomes
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Discomfort during AFOI (heavy grimacing, verbal objection, defensive movement of head or hand or prolonged cough).
Secondary outcomes
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Intubation time.
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Airway obstruction (requiring neck extension or jaw retraction).
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Hypoxia (saturated peripheral oxygen (SpO2) < 90%).
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Treatment‐emergent cardiovascular adverse events, mainly hypotension and bradycardia.
Search methods for identification of studies
Electronic searches
We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2012, issue 5) using the search terms detailed in Appendix 1 MEDLINE (1966 to May 2012) through Ovid; EMBASE (1980 to May 2012); and Web of Science (1945 to May 2012), using a similar strategy. (The search strategies will be found in Appendix 2Appendix 3 and Appendix 4.) We combined the sensitive strategies described in Section 6.4 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) to search for randomized controlled trials (RCTs) in MEDLINE and EMBASE. We used the free text and associated exploded MeSH terms in combination with the RCT sensitive search strategy detailed in Appendix 5. We incorporated any identified new terms into the search strategy. We reported the modified search strategy in full in the final review.
We reran our search of all databases described above on 21 November 2013.
We applied no language restrictions.
Searching other resources
We screened the reference lists of all eligible trials and reviews.
We contacted experts to identify unpublished research and trials still under way. We searched for ongoing trials at http://www.controlledtrials.com/ and http://clinicaltrials.gov/ .
Data collection and analysis
Selection of studies
Using results of the above searches, we screened all titles and abstracts for eligibility. Two review authors (X‐YH and J‐PC) independently performed this screening. Each review author documented the reason for exclusion of each trial. We resolved disagreements by consulting with a third review author (X‐YS), who decided on inclusion. In the case of insufficient published information available for decision making about inclusion, we contacted the first author of the relevant trial.
Data extraction and management
1. Extraction.
Two review authors (X‐YH and J‐PC) independently screened the titles and abstracts of search results for trial eligibility. We extracted and collected on a paper form the data from any trial that met our inclusion criteria. We noted the reasons for exclusions. We resolved disagreements by consulting with a third review author (X‐YS), who decided on inclusion. If further information was required from the trial authors, X‐YH would contact the first author of the relevant trial.
2. Management.
2.1 Conversion of ordinal to dichotomous outcome measures.
We converted ordinal outcome measures to dichotomous outcome measures by identifying cut‐off points on rating scales and dividing participants accordingly into 'clinically significant response' or 'no clinically significant response'. It was generally assumed that if participants displayed heavy grimacing, verbal objection, defensive movement of head or hand or prolonged cough, this could be considered as clinically significant discomfort. Similarly, if participants required neck extension or jaw retraction, this could be considered a case of clinically significant airway obstruction.
Assessment of risk of bias in included studies
Two review authors (X‐YH and J‐PC) independently assessed the methodological quality of eligible trials. We resolved disagreements by discussion with a third review author (X‐YS).
We performed the assessment as suggested in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) and by Juni (Juni 2001).
We considered a trial as having a low risk of bias if all of the following criteria were assessed as adequate. We considered a trial as having a high risk of bias if one or more of the following criteria were not assessed as adequate.
We assessed each trial according to the following quality domains.
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Random sequence generation: We considered allocation adequate if it was generated by a computer or by a random number table algorithm. We judged other processes as adequate, such as tossing of a coin, if the whole sequence was generated before the start of the trial, and if it was performed by a person not otherwise involved in participant recruitment. We considered allocation inadequate if a non‐random system such as dates, names or identification numbers was used.
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Allocation concealment: We considered concealment adequate if the process used prevented participant recruiters, investigators and participants from knowing the intervention allocation of the next participant to be enrolled in the study. Acceptable systems included a central allocation system, sealed opaque envelopes and an on‐site locked computer. We considered concealment inadequate if the allocation method that was used allowed participant recruiters, investigators or participants to know the treatment allocation of the next participant to be enrolled in the study (e.g. alternate medical record numbers, reference to case record numbers or date of birth, an open allocation sequence, unsealed envelopes).
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Blinding: We considered blinding adequate if participants and outcome assessors were each blinded to the intervention. We considered blinding inadequate if participants and outcome assessors were not blinded to the intervention.
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Intention‐to‐treat: We considered intention‐to‐treat (ITT) adequate if all dropouts or withdrawals were accounted for. We considered ITT inadequate if the number of dropouts or withdrawals was not stated, or if the reasons for dropouts or withdrawals were not stated.
We reported the 'Risk of bias' table as part of the table Characteristics of included studies and presented 'Risk of bias summary' figures (Figure 1Figure 2, which detailed all judgements made for all studies included in the review.
Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.
Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
Measures of treatment effect
We presented dichotomous data as risk ratios. We presented numerical comparisons as differences between means.
Unit of analysis issues
The following were addressed: studies with multiple treatment groups. We combined all relevant experimental intervention groups of the study into a single group, and we combined all relevant control intervention groups into a single control group.
Dealing with missing data
We contacted the first author of included trials to try to obtain missing data. In the case of missing data, we used best case and worst case imputation of missing data. We ignored data that were missing at random, and we dealt with missing data not at random by using imputed data or statistical models.
Assessment of heterogeneity
1. Clinical heterogeneity.
We considered all included studies before determining clinical heterogeneity. We inspected all studies for outlying clinical situations or participants. When such situations or participant groups arose, we discussed them.
2. Methodological heterogeneity.
We considered all included studies initially before determining methodological heterogeneity. We inspected all studies for outlying methods. When methodological outliers arose, we discussed them clearly.
3. Statistical heterogeneity.
We assessed statistical heterogeneity with the I2 statistic, thereby estimating the percentage of total variance across studies that was due to heterogeneity rather than to chance alone (Higgins 2011). The importance of the observed value of I2 depended on:
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magnitude and direction of effects; and
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strength of evidence for heterogeneity (e.g. P value from the Chi2 test, or confidence interval (CI) for I2).
We considered a value of I2 greater than or equal to 50% accompanied by a statistically significant I2 statistic as evidence of substantial levels of heterogeneity, although we acknowledged that values of I2 ranging from 30% to 60% might also indicate substantial heterogeneity. When we found substantial levels of heterogeneity, we explored reasons for the heterogeneity. If strong heterogeneity was present (I2 ≥ 75%) and could not be explained by differences across trials in terms of clinical or methodological features, or by subgroup analyses, we did not combine the trials in a meta‐analysis, but we presented the results in a forest plot.
Assessment of reporting biases
If more than 10 studies were included, we planned to assess publication bias and small‐study effects in a qualitative manner, using a funnel plot. We planned to use arcsine asymmetry tests that stabilized the variance of binary outcomes (Rucker 2008).
Data synthesis
We intended to analyse data by using Review Manager software (RevMan 5.1) with a Mantel‐Haenzsel fixed‐effect model. This approach was intended to minimize the impact of small studies on the primary analysis of data, while addressing the issue of small‐study effects. However, we were unable to implement these methods, as the appropriate data were not available in the included studies.
Subgroup analysis and investigation of heterogeneity
We performed no subgroup analyses.
Sensitivity analysis
We performed sensitivity analyses of trials with a low risk of bias versus a high risk of bias. We compared random‐effects model and fixed‐effect model estimates for each outcome variable. We excluded and included any study that appeared to have a large effect size (often the largest or earliest study) to assess its impact on the results of the meta‐analysis. If large variations in the control group event rate were noted, we also subjected trials with different rates to sensitivity analysis.
Results
Description of studies
See Characteristics of included studies; Characteristics of excluded studies; and Characteristics of studies awaiting classification.
Results of the search
We identified six potentially eligible studies following screening of abstracts of potential studies. We found no ongoing trials and no trials awaiting assessment. The two review authors (X‐YH and J‐PC) completely agreed on the selection of included studies. We obtained no additional information from the primary authors. We reran our search on 21 November 2013, and four studies are awaiting assessment (Cattano 2012; Hu 2013; Li 2012; Qiu 2013). We will deal with these studies when we update the review.
Included studies
We included in this review four studies (Bergese 2010a; Bergese 2010b; Chu 2010; Tsai 2010) published between 2010 and May 2012. See Figure 3.
Study flow diagram.
1. Methods.
All studies were started to be randomized and double‐blinded. For further details, please see sections below on Allocation (selection bias) and Blinding (performance bias and detection bias).
2. Design.
All studies were randomized control trials and presented a parallel longitudinal design.
Bergese 2010a This was a double‐blinded (participant and assessor), randomized comparison study. Participants were randomly assigned (by computer‐generated randomization schedule) to the midazolam (MDZ) group (n = 24) or the dexmedetomidine‐midazolam (DEX‐MDZ) group (n = 31) 15 minutes before fibreoptic intubation. MDZ participants received IV midazolam 0.05 mg/kg with additional doses at 0.05 mg/kg until their Ramsay Sedation Score (RSS) was ≥ 2. DEX‐MDZ participants received midazolam 0.02 mg/kg followed by dexmedetomidine 1 μg/kg bolus infusion over 15 minutes. DEX‐MDZ participants then received dexmedetomidine 0.1 to 0.7 μg/kg/h infusion until their RSS was ≥ 2. Topical local anaesthesia was performed with 2% lidocaine solution followed by a 4‐mL injection of lidocaine 4% transtracheally. One of two trained, independent, study‐blinded observers assessed participant reaction to the fibreoptic intubation on a scale of one to five (one = no reaction; two = slight grimacing; three = severe grimacing; four = verbal objection; and five = defensive movement of head, hands or feet).
Ramsay Sedation Scale (RSS: one to six): one: Participant is anxious and agitated or restless, or both; two: Participant is co‐operative, oriented and tranquil; three: Participant responds to command only; four: Participant exhibits brisk response to light glabellar (between the eyebrows) tap or loud auditory stimulus; five: Participant exhibits a sluggish response to light glabellar tap or loud auditory stimulus; six: Participant exhibits no response to stimulus.
Bergese 2010b This was a prospective, randomized, double‐blind, placebo‐controlled study. The study drug was started 15 minutes before airway topicalization for AFOI and was continued through intubation. Dexmedetomidine participants (n = 47) received a loading dose of 1.0 mcg/kg over 10 minutes followed by a continuous infusion of 0.7 mcg/kg‐1/h‐1. Placebo participants (n = 39) received a loading dose and a maintenance infusion of 0.9% sodium chloride for injection at a volume and rate equal to that of dexmedetomidine. Fifteen minutes after the start of the study drug infusion and before airway topicalization, the participant's level of sedation was assessed using the RSS. Any participant rated as < two on this scale was given rescue midazolam in 0.5‐mg bolus doses until RSS ≥ two was attained. Airway anaesthesia was achieved using lidocaine via aerosol, spray, topical jelly, gargle and/or nerve blocks. Study drug infusion was stopped upon completion of the AFOI. All adverse effects and concomitant medications were recorded.
Chu 2010: This was a randomized controlled study. Participants in the Dex group (n = 16) received dexmedetomidine infusion, while the control group (n = 14) received fentanyl infusion. Each participant was given a loading dose of dexmedetomidine (1.0 μg/kg‐1) or fentanyl (1.0 μg/kg‐1) for 10 minutes. After the middle of infusion, topical anaesthesia was performed: Bilateral inferior nasal canals were packed with 6% cocaine (60 mg), and the tongue and the hypopharynx were then sprayed with 10% lidocaine (60 mg). Two experienced consultant anaesthetists performed airway management. While one consultant performed AFOI, another consultant controlled the drug infusion and recorded anaesthetic data. Immediately at the end of study drug infusion, the consultant started to perform fibreoptic scope. The consultant who performed AFOI, the participants and the postoperative recorder were blinded to each participant's group. Main outcomes measures were nasal intubation score (one: no movement; two: grimacing; three: mild cough; four: major limb movement; five: prolonged cough). Secondary outcomes included consumption time from insertion of fibreoptic scope to confirmation of nasal tracheal intubation, hypoxic episode (SpO2 < 95%) and the use of atropine or ephedrine for haemodynamic support.
Tsai 2010: This was a randomized controlled study. Participants in the Dex group (n = 20) received a loading dose of dexmedetomidine (1.0 μg/kg‐1) infused over 10 minutes. Participants in the propofol group (n = 20) received propofol administered by a Primea TCI pump (Fresenius Kabi, Brezins, France). The initial target effect site concentration (Ce) was set at 3 μg/mL‐1 and was adjusted by 1.0 μg/mL‐1 according to participant comfort during the procedure. While waiting for the desired level of sedation to be achieved, topical anaesthesia was applied to the airway. Cocaine 6% (60 mg) packs were applied bilaterally to the inferior nasal canals; then, the tongue and the hypopharynx were sprayed with lidocaine 10% (60 mg). Fibreoptic intubation was performed once the dexmedetomidine infusion had ended, or when the propofol infusion target concentration at the effect site (Ce) had equilibrated with the plasma concentration (Cp). Two experienced consultant anaesthetists performed airway management. While one anaesthetist performed fibreoptic intubation, the other anaesthetist controlled the drug infusion. Anaesthetic data and postoperative visits were documented by a study nurse. The intubating anaesthetist, participants and the study nurse who recorded details of the procedures were all blinded to the study. The primary outcome measurements were participant tolerance, as assessed by a five‐point fibreoptic intubation comfort score (one: no reaction; two: slight grimacing; three: heavy grimacing; four: verbal objection; five: defensive movement of head or hands). Other parameters assessed in relation to awake fibreoptic intubation included an airway obstruction score (one: patent airway; two: airway obstruction relieved by neck extension; three: airway obstruction requiring jaw retraction); intubation time (time from insertion of the fibreoptic scope to confirmation of nasotracheal intubation); any hypoxic episode (SpO2 < 90%); and the need for atropine or adrenaline administration.
3. Duration.
Three studies (Bergese 2010a; Chu 2010; Tsai 2010) were of short duration (less than two days), but one (Bergese 2010b) had a follow‐up period of 30 days.
4. Participants.
The total number of included participants was 211. All participants were 18 years of age and older and were scheduled for an elective AFOI because of an anticipated difficult airway.
5. Setting.
All studies were conducted in a hospital setting. Two studies (Bergese 2010a; Bergese 2010b) were conducted in the USA, and the remaining two studies (Chu 2010; Tsai 2010) were conducted in Taiwan.
6. Interventions.
Dexmedetomidine was compared with no treatment in one study (Bergese 2010b), with propofol in one study (Tsai 2010) and with fentanyl in one study (Chu 2010). In addition, dexmedetomidine with midazolam was compared with midazolam only in one study (Bergese 2010a).
7.Outcomes.
The primary outcome "Discomfort during awake fibreoptic intubation" was not presented in raw data in two studies (Chu 2010; Tsai 2010); this made it impossible to extract data for synthesis, so we contacted the first author of the relevant study and obtained details of the raw data (Table 1; Table 2). Other outcomes were expressed by numerical data or ordinal data.
| FOI comfort (1, 2, 3, 4, 5) | Dexmedetomidine | Fentanyl |
| 1 | 6 | 0 |
| 2 | 5 | 2 |
| 3 | 5 | 7 |
| 4 | 0 | 4 |
| 5 | 0 | 1 |
| FOI comfort (1, 2, 3, 4, 5) | Dexmedetomidine | Propofol |
| 1 | 7 | 0 |
| 2 | 9 | 9 |
| 3 | 3 | 6 |
| 4 | 1 | 3 |
| 5 | 0 | 2 |
Excluded studies
The review excluded two studies published between 2010 and 2012 (Boyd 2011; Swaniker 2011).
Risk of bias in included studies
We used The Cochrane Collaboration's risk of bias tables to assess the validity and quality of the included trials. The trials showed low or unclear risk of bias primarily because of inadequate information on allocation concealment and other potential sources of bias. For a more detailed description of individual trial qualities, see the table Characteristics of included studies. The various bias domains are presented in the 'Risk of bias graph' and in a 'Risk of bias summary' (Figure 1; Figure 2).
Allocation
All studies were unclear about allocation concealment. One study (Tsai 2010) was not explicit about how allocation was achieved other than using the phrase "randomly allocated".
Blinding
All studies were conducted on a double‐blind basis. One study (Bergese 2010b) did not explicitly describe how this was undertaken. We have, however, rated the other three studies as being of higher quality because they stated that the studies were double‐blinded and specifically that either the raters or the participants were blinded.
Incomplete outcome data
In all studies, every person who completed the trial was analysed.
Selective reporting
The data in this review originated from published papers. We did not have an opportunity to compare outcomes described in the protocol and those reported in the full publications. So we considered selective reporting possible. One study (Bergese 2010a) did not provide data on our secondary outcome "Intubation time", and another study (Bergese 2010b) did not provide data on our primary outcome "Discomfort during awake fibreoptic intubation" and the secondary outcome "Intubation time".
Other potential sources of bias
All studies had small or very small sample sizes. Two studies (Bergese 2010a; Bergese 2010b) were funded by Hospira, the maker of dexmedetomidine.
Effects of interventions
Owing to clinical heterogeneity and potential methodological heterogeneity, it was impossible to conduct a full meta‐analysis. We described findings from individual studies or presented them in tabular form.
Primary outcomes
1, Discomfort during awake fibreoptic intubation (heavy grimacing, verbal objection, defensive movement of head or hand or prolonged cough).
This outcome was reported in three studies involving 125 participants (Bergese 2010aChu 2010Tsai 2010; Table 3). In two studies, participants experienced less discomfort during awake fibreoptic intubation in the dexmedetomidine group than in the control group (Bergese 2010a; Tsai 2010). However, in Chu 2010, no significant difference was reported between the dexmedetomidine group and the control group. This outcome was not reported in Bergese 2010b.
| Primary outcome | Discomfort during awake fibreoptic intubation |
| Dexmedetomidine group reacted less (P < 0.001) | |
| Not reported | |
| No significant difference between groups | |
| Dexmedetomidine group reacted less (P < 0.05) |
Secondary outcomes
1. Intubation time.
Only two studies (Chu 2010; Tsai 2010; Table 4) involving 70 participants reported on this outcome, both showing no significant difference between the dexmedetomidine group and the control group.
| Secondary outcome | Intubation time | Airway obstruction | Hypoxia | Treatment‐emergent cardiovascular adverse events |
| Not reported | Not clearly reported | No significant difference between groups | No significant difference between groups | |
| Not reported | Not clearly reported | No significant difference between groups | No significant difference between groups | |
| No significant difference between groups | No significant difference between groups | No significant difference between groups | No significant difference between groups | |
| No significant difference between groups | No significant difference between groups | No significant difference between groups | No significant difference between groups |
2. Airway obstruction (requiring neck extension or jaw retraction).
This outcome was reported clearly in two studies involving 70 participants (Chu 2010; Tsai 2010; Table 4). Tsai 2010 showed that dexmedetomidine alleviated airway obstruction significantly (P value 0.007), and Chu 2010 showed no significant difference between the dexmedetomidine group and the control group.
3. Hypoxia (saturated peripheral oxygen (SpO2) < 90%).
This outcome was reported in four studies involving 211 participants (Bergese 2010a; Bergese 2010b; Chu 2010; Tsai 2010; Table 4). Bergese 2010a reported no complications in either group, and none of the DEX‐MDZ participants experienced respiratory depression. Bergese 2010b showed that dexmedetomidine had no significant effect on respiratory function and gas exchange at the doses used in this trial. Tsai 2010 showed no significant difference between the dexmedetomidine group and the control group. Chu 2010 reported no episode of apnoea or decreased oxygen saturation less than 95% in both groups.
4. Treatment‐emergent cardiovascular adverse events, mainly hypotension and bradycardia.
This outcome was reported in four studies involving 211 participants (Bergese 2010a; Bergese 2010b; Chu 2010; Tsai 2010; Table 4). Bergese 2010a showed no significant haemodynamic difference between the two subject groups. Bergese 2010b reported that seven dexmedetomidine‐treated participants and four placebo‐treated participants received an intravenous fluid bolus or medication to treat blood pressure or heart rate (HR) during study drug infusion. The difference was insignificant. Both Tsai 2010 and Chu 2010 showed that haemodynamic support did not differ significantly between the dexmedetomidine group and the control group.
Discussion
Summary of main results
The research on dexmedetomidine for the management of awake fibreoptic intubation has started only within the past few years, so in this review, only four studies involving 211 participants were included (Bergese 2010a; Bergese 2010b; Chu 2010; Tsai 2010). It is true that some outcomes of interest for this review were not reported in these studies. The analytic results were derived from sparse data.
Dexmedetomidine‐treated participants reacted less than control‐treated participants to awake fibreoptic intubation in two trials (Bergese 2010a; Tsai 2010). The decreased discomfort achieved with dexmedetomidine favours maintaining patient co‐operation and reducing anxiety during AFOI and could play an important role in securing the airway of patients with an unstable cervical spine or a compromised spinal cord.
No suggestion indicates that dexmedetomidine had a greater effect on intubation time than was seen with the control. Dexmedetomidine does not predispose to airway obstruction and respiratory depression. Airway obstruction occurred more frequently in the propofol group than in the dexmedetomidine group. The incidence of hypoxia was similar between the dexmedetomidine group and the control group and was clinically insignificant. Treatment‐emergent cardiovascular adverse events, mainly hypotension and bradycardia, were reported in some studies for the dexmedetomidine group and for the control group as well. Most adverse effects were mild or moderate in severity and could be easily managed with atropine, ephedrine and intravenous fluid administration. The results of this review do not suggest that dexmedetomidine causes significantly more cardiovascular adverse events.
Overall completeness and applicability of evidence
No outcomes in this review involved large numbers of participants. The primary outcome "Discomfort during awake fibreoptic intubation" was not reported in one study (Bergese 2010b). All studies were performed in hospital settings, and all included participants were anticipated to have a difficult or unstable airway. The intervention dexmedetomidine is readily accessible, and the outcomes are objective in terms of clinical practice. Dexmedetomidine had important effects, so the findings might well be applicable.
Quality of the evidence
The largest study in this area (Bergese 2010b) was a multicentre (17 medical centres) study that included 86 participants between August 7, 2006, and January 26, 2007. It is impossible to detect subtle yet important differences due to dexmedetomidine with any confidence. Although the four studies are all RCTs without high risk of bias, the overall quality of reporting of these studies was very low because allocation concealment was not described and other bias could not be excluded. In addition, the small study size and the poor reporting of studies would be associated with an exaggeration of effect of the experimental treatment if an effect had been detected (Juni 2001). Comparisons were performed between dexmedetomidine and any control (including sodium chloride, fentanyl, midazolam and propofol) in the four different studies included in this review. In consideration of the clinical heterogeneity and the likely methodological heterogeneity (measurement of outcomes) that might cause a negative influence in the quality of evidence, we did not perform a full meta‐analysis instead of a narrative analysis (Table 5).
| Study | Interventions | Outcomes | Main results |
| MDZ group (n = 24): Participants received IV midazolam 0.05 mg/kg with additional doses to achieve a Ramsay Sedation Scale (RSS) score ≥ two DEX‐MDZ group (n = 31): Participants received midazolam 0.02 mg/kg followed by dexmedetomidine 1 μg/kg, then an infusion of dexmedetomidine 0.1 μg/kg/h and titrated to 0.7 μg/kg/h to achieve RSS ≥ two Topical local anaesthetics were given | Discomfort during awake fibreoptic intubation (Participants were assessed on a scale of one to five: one: no reaction; two: slight grimacing; three: severe grimacing; four: verbal objection; five: defensive movement of head, hands or feet) Airway obstruction (no details) Hypoxia (no details) Treatment‐emergent cardiovascular adverse events (no details) | DEX‐MDZ participants reacted less to AFOI than did MDZ participants (P < 0.01) No complications were reported in either participant group, and none of the 31 DEX‐MDZ participants experienced respiratory depression | |
| Dexmedetomidine (n = 47): Participants received a loading dose of 1.0 mcg/kg over 10 minutes, followed by a continuous infusion of 0.7 mcg/kg‐1/h‐1. The study drug was started 15 minutes before airway topicalization for AFOI Placebo group (n = 39): Participants received a loading dose and a maintenance infusion of 0.9% sodium chloride for injection at a volume and rate equal to that of dexmedetomidine. Fifteen minutes after the start of the study drug infusion and before airway topicalization, any participant with Ramsay Sedation Scale < two received rescue midazolam to achieve targeted sedation (RSS >= two) before topicalization and throughout AFOI | Airway obstruction Hypoxia (no details) Treatment‐emergent cardiovascular adverse events (no details) | Dexmedetomidine has no significant effect on respiratory function and gas exchange at the doses used in this trial. Dexmedetomidine is well tolerated and does not compromise the airway Seven dexmedetomidine‐treated participants (12.7%) and four placebo‐treated participants (8.0%) received intravenous fluid bolus or medication to treat blood pressure or HR during study drug infusion | |
| Dex group (n = 16): Participants received dexmedetomidine (1.0 μg/kg‐1) infusion Control group (n = 14): Participants received fentanyl (1.0 μg/kg‐1) infusion Topical anaesthesia was performed after the middle of infusion | Discomfort during awake fibreoptic intubation (Participants were assessed on a scale of one to five: one: no movement; two: grimacing; three: mild cough; four: major limb movement; five: prolonged cough) Intubation time (from insertion of fibreoptic scope to confirmation of nasal tracheal intubation) Airway obstruction (Participants were assessed on a scale of one to three: one: patent airway; two: airway obstruction relieved by neck extension; three: airway obstruction requiring jaw retraction) Hypoxia (SpO2 < 94%) Treatment‐emergent cardiovascular adverse events | No differences between the two groups were noted for discomfort during awake fibreoptic intubation, intubation time, airway obstruction, hypoxia or treatment‐emergent cardiovascular adverse events | |
| Dexmedetomidine group (n = 20): Participants received a loading dose of dexmedetomidine (1.0 μg/kg‐1) infused over 10 minutes Propofol group (n = 20): Participants received propofol. The initial target effect site concentration (Ce) was set at 3 μg/mL‐1. This was adjusted by 1.0 μg/mL‐1 according to participant comfort during the procedure. If a comfort score exceeded three or a persistent cough occurred during the procedure, the TCI was titrated upwards, after which the intubating anaesthetist waited for 60 seconds before proceeding. While waiting for the desired level of sedation to be achieved, topical anaesthesia was applied to the airway | Discomfort during awake fibreoptic intubation (Participants were assessed on a scale of one to five: one: no reaction; two: slight grimacing; three: heavy grimacing; four: verbal objection; five: defensive movement of head or hands) Intubation time (time taken from insertion of the fibreoptic scope to confirmation of nasotracheal intubation) Airway obstruction (Participants were assessed on a scale of one to three: one: patent airway; two: airway obstruction relieved by neck extension; three: airway obstruction requiring jaw retraction) Hypoxia (no details) Treatment‐emergent cardiovascular adverse events (no details) | DEX participants reacted less to AFOI than did the propofol participants (P < 0.01) No differences between the two groups were noted for intubation time or hypoxia The dexmedetomidine group experienced fewer airway events and less heart rate response than did the propofol group (P < 0.003 and P value 0.007,respectively) |
Potential biases in the review process
1. Missing studies.
Although we have tried our best to identify all relevant studies, it is possible that some small studies are missing from this review. However, because of the comprehensive searching strategy provided by Karen Hovhannisyan (Cochrane Anaesthesia Review Group Trials Search Co‐ordinator), we are confident that we have not failed to identify large relevant studies.
Agreements and disagreements with other studies or reviews
No previous Cochrane review or relevant systemic review was performed.
Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.
Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
Study flow diagram.
| FOI comfort (1, 2, 3, 4, 5) | Dexmedetomidine | Fentanyl |
| 1 | 6 | 0 |
| 2 | 5 | 2 |
| 3 | 5 | 7 |
| 4 | 0 | 4 |
| 5 | 0 | 1 |
| FOI comfort (1, 2, 3, 4, 5) | Dexmedetomidine | Propofol |
| 1 | 7 | 0 |
| 2 | 9 | 9 |
| 3 | 3 | 6 |
| 4 | 1 | 3 |
| 5 | 0 | 2 |
| Primary outcome | Discomfort during awake fibreoptic intubation |
| Dexmedetomidine group reacted less (P < 0.001) | |
| Not reported | |
| No significant difference between groups | |
| Dexmedetomidine group reacted less (P < 0.05) |
| Secondary outcome | Intubation time | Airway obstruction | Hypoxia | Treatment‐emergent cardiovascular adverse events |
| Not reported | Not clearly reported | No significant difference between groups | No significant difference between groups | |
| Not reported | Not clearly reported | No significant difference between groups | No significant difference between groups | |
| No significant difference between groups | No significant difference between groups | No significant difference between groups | No significant difference between groups | |
| No significant difference between groups | No significant difference between groups | No significant difference between groups | No significant difference between groups |
| Study | Interventions | Outcomes | Main results |
| MDZ group (n = 24): Participants received IV midazolam 0.05 mg/kg with additional doses to achieve a Ramsay Sedation Scale (RSS) score ≥ two DEX‐MDZ group (n = 31): Participants received midazolam 0.02 mg/kg followed by dexmedetomidine 1 μg/kg, then an infusion of dexmedetomidine 0.1 μg/kg/h and titrated to 0.7 μg/kg/h to achieve RSS ≥ two Topical local anaesthetics were given | Discomfort during awake fibreoptic intubation (Participants were assessed on a scale of one to five: one: no reaction; two: slight grimacing; three: severe grimacing; four: verbal objection; five: defensive movement of head, hands or feet) Airway obstruction (no details) Hypoxia (no details) Treatment‐emergent cardiovascular adverse events (no details) | DEX‐MDZ participants reacted less to AFOI than did MDZ participants (P < 0.01) No complications were reported in either participant group, and none of the 31 DEX‐MDZ participants experienced respiratory depression | |
| Dexmedetomidine (n = 47): Participants received a loading dose of 1.0 mcg/kg over 10 minutes, followed by a continuous infusion of 0.7 mcg/kg‐1/h‐1. The study drug was started 15 minutes before airway topicalization for AFOI Placebo group (n = 39): Participants received a loading dose and a maintenance infusion of 0.9% sodium chloride for injection at a volume and rate equal to that of dexmedetomidine. Fifteen minutes after the start of the study drug infusion and before airway topicalization, any participant with Ramsay Sedation Scale < two received rescue midazolam to achieve targeted sedation (RSS >= two) before topicalization and throughout AFOI | Airway obstruction Hypoxia (no details) Treatment‐emergent cardiovascular adverse events (no details) | Dexmedetomidine has no significant effect on respiratory function and gas exchange at the doses used in this trial. Dexmedetomidine is well tolerated and does not compromise the airway Seven dexmedetomidine‐treated participants (12.7%) and four placebo‐treated participants (8.0%) received intravenous fluid bolus or medication to treat blood pressure or HR during study drug infusion | |
| Dex group (n = 16): Participants received dexmedetomidine (1.0 μg/kg‐1) infusion Control group (n = 14): Participants received fentanyl (1.0 μg/kg‐1) infusion Topical anaesthesia was performed after the middle of infusion | Discomfort during awake fibreoptic intubation (Participants were assessed on a scale of one to five: one: no movement; two: grimacing; three: mild cough; four: major limb movement; five: prolonged cough) Intubation time (from insertion of fibreoptic scope to confirmation of nasal tracheal intubation) Airway obstruction (Participants were assessed on a scale of one to three: one: patent airway; two: airway obstruction relieved by neck extension; three: airway obstruction requiring jaw retraction) Hypoxia (SpO2 < 94%) Treatment‐emergent cardiovascular adverse events | No differences between the two groups were noted for discomfort during awake fibreoptic intubation, intubation time, airway obstruction, hypoxia or treatment‐emergent cardiovascular adverse events | |
| Dexmedetomidine group (n = 20): Participants received a loading dose of dexmedetomidine (1.0 μg/kg‐1) infused over 10 minutes Propofol group (n = 20): Participants received propofol. The initial target effect site concentration (Ce) was set at 3 μg/mL‐1. This was adjusted by 1.0 μg/mL‐1 according to participant comfort during the procedure. If a comfort score exceeded three or a persistent cough occurred during the procedure, the TCI was titrated upwards, after which the intubating anaesthetist waited for 60 seconds before proceeding. While waiting for the desired level of sedation to be achieved, topical anaesthesia was applied to the airway | Discomfort during awake fibreoptic intubation (Participants were assessed on a scale of one to five: one: no reaction; two: slight grimacing; three: heavy grimacing; four: verbal objection; five: defensive movement of head or hands) Intubation time (time taken from insertion of the fibreoptic scope to confirmation of nasotracheal intubation) Airway obstruction (Participants were assessed on a scale of one to three: one: patent airway; two: airway obstruction relieved by neck extension; three: airway obstruction requiring jaw retraction) Hypoxia (no details) Treatment‐emergent cardiovascular adverse events (no details) | DEX participants reacted less to AFOI than did the propofol participants (P < 0.01) No differences between the two groups were noted for intubation time or hypoxia The dexmedetomidine group experienced fewer airway events and less heart rate response than did the propofol group (P < 0.003 and P value 0.007,respectively) |
