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Pharmacological agents for preventing morbidity associated with the haemodynamic response to tracheal intubation

  1. Fauzia A Khan*,
  2. Hameed Ullah

Editorial Group: Cochrane Anaesthesia Group

Published Online: 3 JUL 2013

Assessed as up-to-date: 1 JUN 2011

DOI: 10.1002/14651858.CD004087.pub2


How to Cite

Khan FA, Ullah H. Pharmacological agents for preventing morbidity associated with the haemodynamic response to tracheal intubation. Cochrane Database of Systematic Reviews 2013, Issue 7. Art. No.: CD004087. DOI: 10.1002/14651858.CD004087.pub2.

Author Information

  1. Aga Khan University Hospital, Department of Anaesthesiology, Karachi, Sindh, Pakistan

*Fauzia A Khan, Department of Anaesthesiology, Aga Khan University Hospital, Stadium Road, PO Box 3500, Karachi, Sindh, 74800, Pakistan. fauzia.khan@aku.edu.

Publication History

  1. Publication Status: New
  2. Published Online: 3 JUL 2013

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Summary of findings    [Explanations]

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

 
Summary of findings for the main comparison.

Pharmacological agents compared with placebo or no treatment for attenuating the haemodynamic response to tracheal intubation

Patient or population: Adult patients 18 years and above undergoing elective surgery

Settings: Operating room

Intervention: Pharmacological agents given for the specific purpose of attenuating the haemodynamic response to tracheal intubation

Comparison: Control group receiving placebo or no treatment

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

Control groupPharmacological agents

Arrhythmias - by drug type in all patientsStudy population0.19

(0.14 to 0.27)
2902
(57)
⊕⊕⊕⊝
Moderate1
·  .

133 per 100028 per 1000
(21 to 40)

Arrhythmias - high risk patientsStudy population0.18

(0.05 to 0.59)
337
(9)
⊕⊕⊕⊝
Moderate2
· 

80 per 100015 per 1000
(4 to 49)

Myocardial Ischaemia - by drug type in all patientsStudy population0.36

(0.16 to 0.8)
1636
(30)
⊕⊕⊝⊝
Low3
· 

34 per 100013 per 1000

(6 to 28)

Myocardial Ischaemia - high risk patientsStudy population0.67

(0.27 to 1.67)
395
(12)
⊕⊕⊕⊝
Moderate4
·  

78 per 100053 per 1000

(22 to 123)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk Ratio; [other abbreviations, e.g.. OR, etc]

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 143 of the studies were blinded.All studies mentioned randomization but details were only provided by eight; 13 studies described allocation concealment
2Six studies out of nine with high risk patients were blinded
3Eight studies were blinded.In nine studies details of randomization were mentioned; 12 had allocation concealment and five studies had withdrawals
4Six studies out of 12 with high risk patients were blinded

 

Background

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

Both laryngoscopy and tracheal intubation are associated with a sympathetically mediated increases in blood pressure and heart rate, which may be deleterious in patients with underlying cardiovascular and cerebrovascular diseases (Shribman 1987). These changes are of little consequence in healthy patients (Kovac 1996) but have lead to myocardial ischaemia (reduced blood supply to the muscles of the heart) (Edwards 1994), malignant ventricular arrhythmias (abnormal rhythm), cardiac failure (Fox 1977), intracranial haemorrhage and raised intracranial pressure (Robinson 2001) in vulnerable patients.

Several drugs belonging to different pharmacological classes have been used in either attenuating or obliterating this response. These include narcotics (Crawford 1987; Kay 1985; McAtamney 1998), local anaesthetics (Sun 2009), calcium channel blockers (Atlee 2000) and other peripheral vasodilators, sympathetic blockers (Sharma 1995), and centrally acting adrenergic agonists (Scheinin 1992). Each class has undesirable side effects. The majority of studies do not provide any information regarding outcome in terms of morbidity. Few studies have evaluated the risk of ischaemia and arrhythmias induced by laryngoscopy and intubation (Ali 2009; Mahajan 1993; Puri 1998; Zargar 2002), but no clear cause effect relationship has been established. It still needs to be shown that suppression of this response is of benefit to the patients in terms of outcome.

 

Objectives

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

The primary objective of this review was to determine the effectiveness of pharmacological agents in preventing the morbidity and mortality resulting from the haemodynamic changes in response to laryngoscopy and tracheal intubation in adult patients aged 18 years and above who were undergoing elective surgery in the operating room setting.

 

Methods

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms
 

Criteria for considering studies for this review

 

Types of studies

We included prospective randomized controlled trials (RCTs) which studied the effect of different pharmacological agents on the haemodynamic response to laryngoscopy and tracheal intubation in the presence of a control group. We included both blinded and unblinded trials.

 

Types of participants

We included trials involving adult patients aged 18 years and above, of any race and of either sex, undergoing elective surgery in the operating room setting. We excluded trials of patients undergoing tracheal intubation at other sites such as the intensive care unit (ICU) and accident and emergency departments.

 

Types of interventions

We included any pharmacological agent given for the specific purpose of attenuating the tracheal intubation associated haemodynamic response. We excluded studies relating to anaesthetic agents which form part of routine anaesthesia for example sedatives, induction agents, inhalational anaesthetics, and muscle relaxants. We grouped the drugs as follows: local anaesthetics; calcium channel blockers; sympathetic blockers (beta blockers, alpha blockers, alpha and beta blockers, and ganglion blockers); peripheral vasodilators; centrally acting adrenergic agonists; angiotensin converting enzyme (ACE) inhibitors; narcotics; and a miscellaneous group.

We included drugs given by different routes that is oral, sublingual, intravenous, tracheal, topical, inhalational. The intravenous route included drugs given by either bolus injection or infusion.

We attempted to answer the following questions.

  1. Does the administration of either narcotics, local anaesthetics, calcium channel blockers and other peripheral vasodilators, sympathetic blockers, centrally acting adrenergic agonists, and other miscellaneous drugs result in a significant reduction in cardiac, neurological, any other morbidity, or mortality associated with laryngoscopy and tracheal intubation when compared with placebo?
  2. Is the administration of any of the above pharmacological agent more effective than the placebo in respect to question 1?
  3. Is the route of administration of the above agents associated with significant differences in respect of the outcomes in question 1?
  4. Is the administration of above agents associated with adverse haemodynamic respiratory or other unwanted effects?

 

Types of outcome measures

We included RCTs which mentioned the following outcomes (either primary or secondary) in the methodology, results, or discussion sections.

 

Primary outcomes

We considered as the primary outcome major morbidity or mortality related to haemodynamic changes which may follow tracheal intubation. As the majority of these changes settled within five to 15 minutes, only morbidity and mortality occurring during this period or as a direct consequence of these changes were included.

Examples of major morbidity were as follows.

  1. Electrocardiographic (ECG) evidence of intraoperative ischaemia following intubation subsequently leading to myocardial infarction (evidence of raised creatinine phosphokinase MB fraction or troponin).
  2. Rupture of an aneurysm.
  3. Acute cerebral haemorrhage.
  4. Sudden deterioration in cardiovascular status or neurological status related to the haemodynamic response leading to prolongation of operating room or recovery room stay or admission to a critical care area.

We collected the data as number of patients who had mortality or morbidity.

 

Secondary outcomes

We considered the following as secondary outcomes.

  1. Arrhythmias: studies recording any cardiac arrhythmia during or following intubation were included. We collected the data as the number of patients who had arrhythmias during the above period.
  2. Studies observing ECG evidence of ischaemia. We collected the data as the number of patients who had ECG evidence of ischaemia, ST segment depression on the ECG during or as a consequence of tracheal intubation.

 

Search methods for identification of studies

 

Electronic searches

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2011, Issue 6), MEDLINE (1950 to June 2011), and EMBASE (1980 to June 2011) using the search strategies listed in the appendices (Appendix 1 (CENTRAL); Appendix 2 (MEDLINE); Appendix 3 (EMBASE)).

We reran the searches in December 2012 to identify papers published in 2011 to 2012 and the additional studies identified in this second search are listed in the Characteristics of studies awaiting classification. We will deal with these studies when we update our review.

Both authors independently searched the literature. We did not impose any language restriction. We did not seek unpublished studies.

 

Searching other resources

We handsearched the reference lists of the RCTs for additional studies.

 

Data collection and analysis

 

Selection of studies

We (FK, HU) independently reviewed the titles and the abstracts of the studies and reached a consensus on the abstracts that met the inclusion criteria. In the case of a disagreement regarding the inclusion of an abstract, we obtained the full article. We independently reviewed the full texts of all identified abstracts. We resolved any disagreements through discussion. As no major conflict arose we did not require a third review author. We were not blinded to the names of the authors, the institution, or the journal of publication.

We included RCTs on adult patients undergoing elective surgery, of either sex and any race, aged 18 years and above, who received a pharmacological intervention before or at induction of anaesthesia to prevent the haemodynamic response related to laryngoscopy and tracheal intubation.

We excluded RCTs involving patients in whom tracheal intubation was performed in other settings, for example the intensive care unit (ICU) or accident and emergency unit, or were undergoing emergency surgery. We also excluded trials without control groups. We excluded studies of tracheal intubation without the use of muscle relaxants or which involved the administration of induction agent with a target controlled infusion pump. We also excluded studies that simply mentioned looking for an 'abnormality in ECG' or 'changes in ECG'. This is because these authors did not differentiate between arrhythmias and the ECG changes of ischaemia.

We also tried contacting some of the study authors for clarification (Abdel-Razek 1991; Mikawa 1996) but to date we have not received a reply. We did not contact authors for unpublished data.

 

Data extraction and management

We (FK, HU) completed a data extraction form for each study reviewed (Appendix 4). We recorded the following information: the type and number of patients; pharmacological intervention (route, dose, and timing); outcome (primary and secondary, duration of observation, and any adverse effects of the given drug).

One author (HU) entered the data for the meta-analysis into Revman 5.1, which were then checked by the second author (FK).

 

Assessment of risk of bias in included studies

We (FK, HU) independently evaluated the validity and design characteristics of each selected study. This included: random sequence generation; allocation concealment; blinding of participants and personnel; blinding of outcome assessment; incomplete outcome data; and selective reporting, as recommended in the Cochrane Collaboration's recommended tool for assessing risk of bias (Higgins 2011).

We classified each trial quality component as: 'low risk of bias', 'high risk of bias', or 'unclear risk of bias'. We assessed attrition bias as low if the number of participants recruited in the trial was the same as the number of participants in whom the results were reported, or if an intention-to-treat (ITT) analysis had been performed after attrition. We assessed selective reporting as at low risk of bias if the expected outcome was pre-specified in the methodology section of the study. We resolved disagreements by discussion.

We completed a risk of bias summary table for each study.

 

Measures of treatment effect

Our outcome data were dichotomous. We used Peto odds ratios (OR) to establish the statistical difference between the intervention and control groups. We interpreted an OR of less than one as showing that the experimental intervention decreased the occurrence of an adverse outcome.

 

Unit of analysis issues

For any trials using cluster randomization or enrolling more than two arms we used the methods prescribed by the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) and identified and included data from only the intervention groups relevant to our systematic review. Detailed descriptions of only the groups relevant to our review are mentioned in the table Characteristics of included studies. We have mentioned any groups that were not included in our systematic review in the notes section of each study.

 

Dealing with missing data

Intention-to-treat analysis (ITT) analysis is recommended in order to minimize bias. No consensus exists on how to handle missing data in an ITT analysis in systematic reviews (Higgins 2011). We excluded all participants from the analysis where the outcomes were missing.

 

Assessment of heterogeneity

Our review was designed to include studies with several different pharmacological interventions for reducing morbidity associated with the haemodynamic response to tracheal intubation. We had specified in the protocol (Khan 2003) that we would combine the results from trials of similar pharmacological class of drugs. For assessing heterogeneity amongst the trials of each pharmacological class, by using the I2 statistic, we referred to the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We found an overlap between the classes. We therefore modified the given scale as follows:

  • 0% to 30% not important;

  • 31% to 60% moderate heterogeneity;

  • 61% to 80% substantial heterogeneity;

  • 81 % to 100% considerable heterogeneity.

 

Assessment of reporting biases

We looked at the outcomes listed in the methods section of the trials and compared them with the outcomes reported in the results section. When the outcome was not mentioned in the methods but only reported in the results we listed it as at high risk of reporting bias.

 

Data synthesis

We pooled the data from various trials, where appropriate, using Review Manager 5.1. We chose a fixed-effect model. The outcomes were rare events, therefore we used Peto's OR to estimate the effect size. We expressed the treatment effect as a pooled OR with 95% confidence interval (CI). We plotted the results of each study as point estimates with corresponding 95% CIs. We did not generate plots where only a single study was available for an intervention; these are mentioned in the text description and tallied in Appendix 5.

 

Subgroup analysis and investigation of heterogeneity

We planned the following subgroup analyses.

  1. Based on the pharmacological class of drugs that were used for suppressing the haemodynamic response related to tracheal intubation. These groups were: local anaesthetics, calcium channel blockers, sympathetic blockers, peripheral vasodilators, centrally acting alpha agonists, ACE inhibitors, narcotics, and a miscellaneous drugs group.
  2. Based on trials using the same drug within a single pharmacological group.
  3. Based on enrolment into the trials of high risk patients who were likely to have a higher risk of outcome events versus low risk patients.

For trials dealing with more than one pharmacological group, we broke them into the review intervention groups (one study group receiving one drug = one intervention). We then combined data from these individual intervention groups with the other studies of the same experimental pharmacological group to make a single group for subgroup analysis.

We assessed heterogeneity among trials by looking at the I2 statistic for heterogeneity. Where this figure was greater than 60%, it indicated substantial or considerable heterogeneity.

 

Sensitivity analysis

Due to the variability in the patient population, drug doses, and time points of measurements, sensitivity analysis was not applicable to this review.

 

Results

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms
 

Description of studies

 

Results of the search

(See Figure 1)

 FigureFigure 1. Flow diagram.

Our initial search (up to June 2011) identified 3854 citations across all sources, of which 290 were duplicate citations and 3188 were not relevant randomized trials. We were unable to obtain abstracts for 14 titles and full papers for an additional six titles identified in our initial search. These papers have been included in our Characteristics of studies awaiting classification.

We reran our search in 2012. A further seven studies were identified. These papers have also been placed in the Characteristics of studies awaiting classification and will be dealt with in our next update.

One publication (Fujii 1995) was initially selected but has now been removed to the Studies awaiting classification as the author is being investigated by his institution. We retrieved the full text of 376 trials. We excluded 275 trials because our primary or secondary outcomes were not mentioned in either the methodology, results, or discussion sections (Characteristics of excluded studies). One publication was a duplicate publication of Abdel-Razek 1991 (see Included studies) . We included 72 studies in the review.

 
Control

The total numbers of patients in the control group for arrhythmias was 993, and the total number for ECG evidence of myocardial ischaemia was 604. The control group in all but four studies received a placebo (normal saline). In the four studies (Kale 1988; Lindgren 1987; Stone 1988; Wang 2003) no drug was administered in the control group.

 
Interventions

There were 1939 patients in the intervention group of studies looking at arrhythmias.

There were 1012 patients in the intervention group studying ECG changes of myocardial ischaemia.

Of the included studies, 54 assessed a single drug, 15 assessed two different drugs, and three studies assessed three different drugs.

 
Route of administration

The intravenous route (IV) was used in 49 studies, the oral route in 13. Of the remaining 10 studies, two used the sublingual route (calcium channel blockers), one used the transdermal route (nitroglycerine), five administered local anaesthetics either by inhalation or transtracheally, and two used both the oral and IV route in different arms of the same study.

 
Type of patients

In 50 studies, the patients investigated were American Society of Anesthesiologists classification of anaesthesia risk (ASA) 1 and 2 only. Apart from the high risk studies, four studies additionally included ASA 3 and ASA 4 patients in addition to ASA 1 and 2 patients (Inada 1989; Mallon 1990; Miller 1991; Splinter 1989). Further details on status were only available from one study (Miller 1991), where these patients had several additional risk factors for example ischaemic heart disease, diabetes, obesity, etc. In one study the ASA status of the patients was not mentioned (Mikawa 1992a).

We identified 17 studies that investigated only high risk patients. Data from two studies were not included (Davies 1981; Stone 1988). The number of patients enrolled in the studies looking at arrhythmias was 337 in the high risk studies in comparison with 28,36l enrolled in the lower risk studies. There were 395 patients enrolled in the high risk studies that looked at myocardial ischaemia compared to 1306 in the lower risk studies.

 

Follow-up

The period of follow-up varied from three minutes post-intubation (Mikawa 1991b) to 20 minutes following the study drug (Singh 1995).

 

Included studies

We included 72 publications with an adult population aged above 18 years. The sample size varied from 12 (Denlinger 1974) to 548 participants (Miller 1991). Nine studies investigated local anaesthetics, 10 studies calcium channel blockers, 19 studies sympathetic blockers, 10 studies narcotics, five studies peripheral vasodilators, two studies centrally acting alpha agonists, and six studies miscellaneous drugs. The remaining 11 studies investigated drugs belonging to more than one pharmacological class in the same trial. For more details see Characteristics of included studies.

 

Excluded studies

No study was excluded.

 

Studies awaiting classification

One study (Fujii 1995) with hypertensive patients was available but the lead author is being investigated by his institution for intellectual dishonesty (see Characteristics of studies awaiting classification).

There were 20 additional titles identified in our initial search which may be relevant. Abstracts were available for only six studies and titles only for the remaining 14. Full texts of these publications were not available through our library, inter-library loans, or through the Cochrane Anaesthesia Review Group (CARG). Of these 20 studies, 17 are from non-English journals (see Characteristics of studies awaiting classification).

We reran our search from 2011 to 2012. Seven studies identified in our search rerun have also been added to this section. We will deal with them when we update the review.

 

Risk of bias in included studies

We evaluated the overall quality of the trials based on the domains described in the following subsections. The various bias domains are presented in the Risk of bias in included studies (see Figure 2; Figure 3).

 FigureFigure 2. Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
 FigureFigure 3. Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

 

Random sequence generation

All included studies were randomized and mentioned randomization in the methodology, but the actual method used for randomization was stated by only 10 trials (Ali 2009; Kale 1988; Koç 2007; Lee 2011; Memis 2006; Montazeri 2011; Singh 1995; Song 1997; Sun 2009; Victory 1995).

 

Allocation

In 63 studies, the authors did not state the method of concealment of allocation (whether the investigators were unable to predict the prospective group to which a participant would be allocated). We categorized these studies as 'unclear'. Concealment was adequate in nine studies (Ali 2009; Kaya 2008; Koç 2007; Lee 2011; Memis 2006; Montazeri 2011; Oxorn 1990; Puri 1998; Sun 2009).

 

Blinding

Both participants and outcome assessors were blinded in 53 studies; 16 studies were not blinded. Three studies (Mallon 1990; Oxorn 1990; Stone 1988) used subject experts (cardiologists) for analysis of the ECG changes.

 

Incomplete outcome data

Withdrawals were specifically mentioned in seven trials (Cucchiara 1986; Ko 1998; Lee 2011; Montazeri 2011; Puri 1998; Song 1997; Wang 2003). In the rest of the studies, the number of participants entering the trials and the number subjected to analysis, as mentioned in the results, were the same. Two studies (Puri 1998; Song 1997) reported six withdrawals each and one study (Wang 2003) reported 10 withdrawals. Two studies (Cucchiara 1986; Montazeri 2011) reported 12 dropouts but no ITT analysis was performed. Lee 2011 reported four patients who did not complete the study and ITT analysis was performed. The reasons for withdrawal were protocol violation in one study (Cucchiara 1986); difficulty in tracheal intubation in four studies (Ko 1998; Lee 2011; Song 1997; Wang 2003); the use of active pharmacological intervention to keep blood pressure stable in two studies (Montazeri 2011; Puri 1998); and refusal to participate in one study (Montazeri 2011).

 

Selective reporting

In order to detect apparent reporting bias, we observed if the authors mentioned an outcome in their objective or methodology section but then failed to report it, or they reported a primary or secondary outcome without indicating that this was intended. We also noted when the authors failed to report on hypertension and tachycardia. Of the included studies, 13 mentioned a relevant outcome in the aims or methodology (Ali 2009; Davies 1981; Jakobsen 1992; Ko 1998; Lindgren 1987; Mallon 1990; Montazeri 2011; Oxorn 1990; Ryhanen 1977; Scheinin 1989; Stone 1988; Wang 2003; Zargar 2002); 59 trials mentioned outcomes only in the results. All of these articles also mentioned the associated changes in blood pressure and heart rate.

 

Effects of interventions

See:  Summary of findings for the main comparison

In total, 60 trials looked for arrhythmias (data from two trials were not included (Jakobsen 1992; Ryhanen 1977)) and enrolled 2932 participants, with 1939 participants allocated to receive an intervention. Of the included studies, 31 trials looked at myocardial ischaemia (data from two trials were not included (Davies 1981; Stone 1988)) and enrolled 1616 participants, with 1012 allocated to receive an intervention.

 

Outcomes

 

Primary outcome

 

1. Mortality

Only one study reported mortality as an outcome (Miller 1991). The author stated that there were no deaths reported in a multicentre trial of 548 patients who received either placebo or esmolol in a dose of 100 or 200 mg for controlling the haemodynamic response. This trial did not mention either arrhythmias or myocardial ischaemia as an outcome.

 

2. Major morbidity

Only one study reported morbidity as an outcome (Mikawa 1996). The authors stated in the discussion section that 60 patients, who either received placebo, diltiazem, nicardipine, or verapamil, were followed up for morbidity. No specific morbidity or period of follow-up was identified by the author. This trial additionally mentioned arrhythmias as an outcome.

 

Secondary outcomes

Arrhthymias only were observed as an outcome in 40 trials, 11 trials observed only myocardial ischaemia as an outcome, and 20 trials observed both arrhythmias and myocardial ischaemia.

 

Outcome 1. Arrhythmias

 

1.1 All studies reporting arrhythmias, with subgroup analysis by drug type

This outcome was reported by 60 studies. The analysis from two studies was not included (Jakobsen 1992; Ryhanen 1977). The reason for not including the analysis is given under the respective subheadings.

Of the 993 participants, 134 (13.4%) in the control group experienced an arrhythmia compared to 80 out of 1939 in the combined active group (4.1%). This difference of 9.2% was statistically significant (the odds of an arrhythmia with an active drug compared to control was: OR 0.19, 95% CI 0.14 to 0.26, P < 0.00001, I2 = 47%) ( Analysis 1.1).

The test for a subgroup difference showed a P value of 0.15 (I2 = 41.4%).

A list of all drugs used in these studies reporting arrhythmias, and their dosages, is given in Appendix 6 .

 
Local anaesthetics

Arrhythmia was reported as an outcome with the use of local anaesthetics in 15 studies (Artru 1985; Asfar 1990; Denlinger 1974; Durrani 2000; Inada 1989; Jakobsen 1992; Kindler 1996; Pouttu 1988; Ryhanen 1977; Singh 1995; Sklar 1992; Splinter 1989; Sun 2009; Victory 1995; Wang 2003). An analysis of 13 of the 15 studies is included in this review. Different doses and different routes of administration of drugs were used. The largest group was lignocaine. Of these studies, 10 investigated lignocaine in different doses with different routes (spray 4%, spray 10%, 100 mg IV, 1 mg kg-1 IV, 1.5 mg kg-1 IV, 2 mg kg-1 IV, 40 mg inhalational) and different times of administration in relation to tracheal intubation (Asfar 1990; Denlinger 1974; Inada 1989; Kindler 1996; Pouttu 1988; Singh 1995; Sklar 1992; Splinter 1989; Sun 2009; Wang 2003). One study used 0.75% bupivacaine via aerosol (Victory 1995) and one used etidocaine 50 mg and 70 mg via aerosol (Artru 1985). One study compared 4.5 mg kg-1 IV chloroprocaine with placebo (Durrani 2000).

Of 362 participants, 29 (8%) in the local anaesthetic group experienced an arrhythmia compared to 32 out of 188 (17.0%) in the control group. This difference of 9.0% was statistically significant (the odds of an arrhythmia with local anaesthetic pretreatment compared to control therapy: OR 0.34, 95% CI 0.18 to 0.62, P = 0.0006, I2 = 79%) ( Analysis 1.1).

We considered subgroup analysis by the individual agents within this group but there were insufficient data to make such a comparison meaningful since different routes and different dosages of drugs were used. 

 
Calcium channel blockers

Arrhythmia was reported as an outcome by 11 studies using calcium channel blockers (Abdel-Razek 1991; Atlee 2000; Kale 1988; Maekawa 1992; Maekawa 1993; Mikawa 1990a; Mikawa 1990b; Mikawa 1992a; Mikawa 1994; Mikawa 1996; Puri 1986). Two of the studies administered verapamil 0.1 mg kg-1 IV (Mikawa 1996; Puri 1986); two studies diltiazem 0.2 mg kg-1, 0.3 mg kg-1 IV (Mikawa 1990a; Mikawa 1996); three studies nicardipine 15 µg kg-1, 30 µg kg-1 IV (Atlee 2000; Mikawa 1990b; Mikawa 1996); two studies nifedipine 10 mg sublingual (Abdel-Razek 1991; Kale 1988); and one each with oral nisoldipine 5 mg and 10 mg (Maekawa 1992), oral nivaldipine 2 mg and 4 mg (Mikawa 1992a), oral manidepine 5 mg and 10 mg (Mikawa 1994), nitrandepine 5 mg and 10 mg (Maekawa 1993).

Of 128 participants, 11 (8.5%) in the control group experienced an arrhythmia compared to three out of 253 (1.18%) in the intervention group. This difference of 7.3% was statistically significant (the odds of an arrhythmia with calcium channel blocker pretreatment compared to control: OR 0.13, 95% CI 0.04 to 0.41, P = 0.0004, I2 = 0%) ( Analysis 1.1). We considered subgroup analysis by the individual agents within this group but there were insufficient data to make such a comparison meaningful.

 
Sympathetic blockers

Arrhythmia as an outcome was reported in 18 studies with sympathetic blockers. The largest group was beta blockers (14 studies). Three studies (Amar 1991; Bernstein 1989; Inada 1989) reported on arrhythmias with combined alpha and beta blockers and one reported on arrhythmias with alpha blockers (Quere 1990).

One study had two interventional arms, one with beta blockers and another with combined alpha and beta blockers (Maharaj 1983).

Of 470 participants, 19 (4%) in the sympathetic blocker group experienced an arrhythmia compared to 34 out of 272 (12.5%) in the control group. This difference of 8.5% was statistically significant (the odds of an arrhythmia with sympathetic blocker pretreatment compared to control therapy: OR 0.22 , 95% CI 0.12 to 0.41, P = 0.00001, I 2 = 0%. The test for a subgroup difference was not significant (P = 0.62, I2 = 0%) ( Analysis 1.2).

In addition to the above mentioned studies , Jakobson (Jakobsen 1992) looked at the effect of 100 mg oral metoprolol administered preoperatively, and Ryhanen (Ryhanen 1977) studied the effect of 0.02 mg kg-1 IV practolol. The results of both of these studies have not been included in the analysis. Jacobson observed arrhythmias throughout the perioperative period and did not differentiate between arrhythmias following tracheal intubation and the rest of the perioperative period. Ryhanen used atropine 0.02 mg kg-1 in all patients prior to giving practolol. Some patients had arrhythmias due to the atropine.

 
1.2 Subgroup analysis for sympathetic blockers
 
Beta blockers

Arrhythmias were reported as an outcome by 14 studies (Atlee 2000; Cucchiara 1986; Kindler 1996; Korpinen 1995a; Korpinen 1995b; Magnusson 1986; Maharaj 1983; Mallon 1990; Mikawa 1991a; Oxorn 1990; Sharma 1995; Singh 1995; White 2003; Zargar 2002). Ten studies investigated esmolol in different doses and with different regimens (25 mg IV, 50 mg IV, 100 mg IV, 200 mg IV, 2 µg kg-1 IV, 3 µg kg-1 IV, 1.4 mg kg-1 IV, 1 mg kg-1 IV, 500 µg bolus IV injection followed by infusion), one study investigated pindolol (2 µg kg-1, 4 µg kg-1 IV), two studies metoprolol (4 mg IV, 15 mg IV), and one practolol (0.4 mg kg-1 IV).

Of 218 participants in the control group, 31 (14.2%) experienced an arrhythmia compared to 18 out of 371 (4.8%) in the experimental group. This difference of 9.4% was statistically significant (the odds of an arrhythmia with beta blocker pretreatment compared to the control therapy: OR 0.23, 95% CI 0.12 to 0.44, P = 0.0001, I2 = 0%) ( Analysis 1.2). We considered further subgroup analysis by specific doses within this group but there were insufficient data to make such a comparison meaningful.

 
Combined alpha and beta blockers

Four studies reported arrhythmias as an outcome with labetalol in the following doses: 0.15, 0.25, 0.5, 0.75 mgkg-1 IV; 5 mg, 10 mg bolus IV (Amar 1991; Bernstein 1989; Inada 1989; Maharaj 1983). Three out of 29 (10.3%) participants in the control group experienced an arrhythmia compared to one out of 74 (1.3%) in the labetalol group. This difference of 9.0% was not statistically significant (the odds of an arrhythmia with labetalol pretreatment compared to control therapy: OR 0.13, 95% CI 0.01 to 1.17, P = 0.07, I2 = 0%) ( Analysis 1.2).

 
Ganglion blockers

No study was identified in this subgroup.

 
Alpha blockers

Only one study reported arrhythmias as an outcome in this group, using urapidil (Quere 1990). There were no positive outcomes ( Analysis 1.2).

 
Centrally acting alpha agonists

Three studies reported arrhythmia as an outcome using clonidine (0.3 mg oral, 1.25 and 0.625 µg kg-1 IV) and gunabenz (4 and 6 mg oral) (Carabine 1991; Mikawa 1993; Montazeri 2011). One out of 36 (2.7%) participants in the control group experienced an arrhythmia compared to none out of 72 in the treatment group. This difference of 2.7% was not statistically significant (the odds of an arrhythmia with a centrally acting alpha agonist pretreatment compared to control therapy: OR 0.05, 95% CI 0.00 to 3.18, P = 0.16, heterogeneity not applicable) ( Analysis 1.1).

All these studies were blinded and in low risk patients.

 
Peripheral vasodilators

Three studies reported arrhythmias (Mahajan 1993; Mikawa 1992b; Singh 1995). Nitroglycerine was used in the following doses: 1.5 µg kg-1, 2 µg kg-1 or 2.5 µg kg-1, 5 µg kg-1 IV; or 2% transdermally. None of the participants in the control group or in the treatment group experienced arrhythmias.

 
Narcotics

Arrhythmia was reported as an outcome by 12 studies (Abdel-Razek 1991; Black 1984; Crawford 1987; Dahlgren 1981; Iyer 1988; Kay1987; Ko 1998; Korpinen 1995a; Korpinen 1995b; Lindgren 1987; Scheinin 1989; Splinter 1989). Four studies investigated alfentanil in different doses: 75 µg IV bolus, 0.03 mg kg-1 IV, 10 µg kg-1 IV, 15 µg kg-1 IV, 30 µg kg-1 IV, 40 µg kg-1 IV (Crawford 1987; Korpinen 1995a; Korpinen 1995b; Scheinin 1989); six reported on fentanyl (1 µg kg-1 IV, 1.5 µg kg-1 IV, 2 µg kg-1 IV, 3 µg kg-1 IV, 5 µg kg-1 IV; 0.8 µg kg-1 infusion) (Abdel-Razek 1991; Dahlgren 1981; Iyer 1988; Ko 1998; Lindgren 1987; Splinter 1989); and one studied sufentanil (0.5 µg kg-1, 1 µg kg-1) (Kay1987). One study was a multi-arm study (Black 1984) comparing fentanyl and alfentanil.

Of the 166 participants in the control group, 56 (33.7%) experienced an arrhythmia compared to 29 out of 454 (6.3%) in the intervention group. This difference of 27.4% was statistically significant (the odds of an arrhythmia with pretreatment with a narcotic compared to control therapy: OR 0.12, 95% CI 0.07 to 0.21, P < 0.00001, I2 = 58%) ( Analysis 1.1). We considered subgroup analysis by individual agents and dosages within this group but there were insufficient data to make such comparisons meaningful.

 
ACE inhibitors

No study was identified for inclusion in this group.

 
Miscellaneous drugs

Eight studies reported arrhythmias as an outcome (Ali 2009; Bafna 2011; Kaya 2008; Koç 2007; Memis 2006; Mikawa 1991b; Montazeri 2011; Puri 1998). None of the patients in the control or the treatment groups experienced an arrhythmia. 

Six of these studies used oral gabapentin (400, 600, 800, 1000 and 1200 mg) (Ali 2009; Bafna 2011; Kaya 2008; Koç 2007; Memis 2006; Montazeri 2011). Dexamethasone 8 mg IV was used in the second arm of one study (Koç 2007).

One study reported arrhythmia with ATP (0.05 mg kg-1 or 0.1 mg kg-1) as an outcome (Mikawa 1991b) and another used magnesium sulphate (50 mg kg-1) (Puri 1998).

 

1.3 All studies reporting arrhythmias, studies including high risk patients versus low risk patients

To investigate the possible influence of baseline risk in these patients we conducted a subgroup analysis to compare those trials enrolling high risk patients only to trials enrolling low risk patients. In the nine studies where high risk patients were enrolled (Cucchiara 1986; Dahlgren 1981; Denlinger 1974; Inada 1989; Iyer 1988; Kale 1988; Magnusson 1986; Mahajan 1993; Puri 1986), there was a statistically significant difference observed between placebo and the treatment groups for the risk of developing arrhythmias (OR 0.18, 95% CI 0.05 to 0.59, P < 0.005, I2 = 80%) ( Analysis 1.3). In the 49 trials enrolling lower risk patients there was again a significant difference observed between the placebo and treatment groups (OR 0.20, 95% CI 0.14 to 0.28, P < 0.00001, I2 = 44%) ( Analysis 1.3).

The test for a subgroup difference showed a P value of 0.86 (I2 = 0%).

 

Outcome 2. ECG evidence of myocardial ischaemia

 

2.1 All studies reporting ECG evidence of myocardial ischaemia, by drug type

This outcome was reported by 31 studies, but we analysed 29 studies only. The reason for not including data from two studies (Davies 1981; Stone 1988) is given under the subgroup 'Sympathetic blockers'. Of 604 participants in the control group, 21 (3.4%) showed evidence of the ECG changes of myocardial ischaemia compared to 10 out of 1012 (0.98%) in the treatment group. This difference of 2.4% was significant (the odds of ECG changes of myocardial ischaemia with an active drug compared to control: OR 0.45, 95% CI 0.22 to 0.92, P = 0.03, I2 = 19%) (  Analysis 2.1).

The test for a subgroup difference showed a P value of 0.17 (I2 = 37.4%). 

A list of all the drugs used in these studies and their dosages is given in Appendix 6.

 
Local anaesthetics

Four studies used lignocaine (1 mg kg-1 IV, 1.5 mg kg-1 IV; or inhalation of 5 ml of 2%, 1 mg kg-1, 4% transtracheal, 1 mg kg-1, 10% via atomizer) and reported ischaemic changes in the ECG as an outcome (Asfar 1990; Singh 1995; Splinter 1989; Sun 2009). Four patients in the control group compared to none in the treatment group showed ECG evidence of myocardial ischaemia in one study (Asfar 1990). In the other three studies none of the participants in the control group or in the lignocaine group had a positive outcome. Four patients out of 67 (5.9%) in the control group showed evidence of the ECG changes of myocardial ischaemia compared to none out of 125 in the treatment group. This difference of 5.9% was significant (the odds of ECG changes of myocardial ischaemia with an active drug compared to control: OR 0.02, 95% CI 0.00 to 0.16 , P = 0.0004) ( Analysis 2.1).

 
Calcium channel blockers

Two studies reported ischaemic changes on the ECG as an outcome (Kale 1988; Song 1997). None of the 35 participants in the control group or the 95 in the treatment with calcium channel blocker (nifedipine, nicardipine, diltiazem) reported ischaemic changes.

 
Sympathetic blockers
 
Beta blocker

Ischaemic changes in the ECG were reported by 11 studies as an outcome (Cucchiara 1986; De Brujin 1987; Ebert 1989; Girard 1986; Magnusson 1986; Mallon 1990; Newsome 1986; Oxorn 1990; Sharma 1995; Singh 1995; Zargar 2002). Of these studies, 10 had investigated esmolol in different doses. Eight out of 190 (4.2%) of the participants in the control group had ECG evidence of myocardial ischaemia compared to five out of 269 (1.8%) in the treatment group. This difference of 2.4% was not statistically significant (the odds of ECG evidence of myocardial ischaemia with a beta blocker pretreatment compared to control therapy: OR 0.61, 95% CI 0.19 to 1.94, P = 0.41, I2 = 39 %) ( Analysis 2.1). Further subgroup analysis was not considered since 10 of the studies were with esmolol and the data indicated homogeneity.

Additionally, one study (Stone 1988) observed the risk of myocardial ischaemia in untreated hypertensive patients who received a single oral dose of labetalol 100 mg, atenolol 50 mg, or oxprenolol 20 mg two hours before induction. We did not include the results of this study in our analysis as the authors reported the overall risk of myocardial ischaemia (seven patients had ischaemia during induction) but did not specify the percentage of patients who had myocardial ischaemia related to tracheal intubation. The anaesthesia technique was also not standardized.

Six of the included studies were with high risk patients (Cucchiara 1986; De Brujin 1987; Ebert 1989; Girard 1986; Magnusson 1986; Newsome 1986) and four of the included studies were not blinded (De Brujin 1987; Girard 1986; Magnusson 1986; Sharma 1995).

 
Combined alpha and beta blockers

No study was identified in this group.

 
Peripheral vasodilators

Four studies reported ECG evidence of ischaemia (Hart 1989; Mahajan 1993; Singh 1995; Thomson 1984). Five participants in the control group out of 39 (12.8%) compared to five out of 44 (11.3%) patients in the treatment group experienced ischaemic changes on the ECG. This difference of 1.5% was not significant (the odds of ischaemic changes on ECG with nitroglycerine pretreatment: OR 1.47, 95% CI 0.26 to 8.18, P = 0.66). Heterogeneity was not applicable.

In addition, one study (Davies 1981) looked at haemodynamic responses related to intubation in 21 patients undergoing neurosurgical procedures. Of these patients 10 were pretreated with hydralazine and the others with saline. The authors mentioned the CM5 lead configuration to detect myocardial ischaemia but did not report these results in their study.

 
Centrally acting alpha agonists

Only one study reported ischaemic changes on the ECG as an outcome in this group (Montazeri 2011). There were no positive outcomes, therefore we did not perform an analysis.

 
Narcotics

Six studies (Chraemmer-Jorgensen 1992; Crawford 1987; Dahlgren 1981; Ebert 1989; Lee 2011; Splinter 1989) were identified in this group. Two of the studies were in high risk patients (Dahlgren 1981; Ebert 1989). None of the patients in the treatment group experienced ECG evidence of ischaemia. One patient in the control group experienced ECG evidence of ischaemia. This difference of 0.7% was not significant (the odds of ECG changes of myocardial ischaemia with an active drug compared to control: OR 0.14, 95% CI 0.00 to 6.82, P = 0.32, I2 not applicable) ( Analysis 2.1).     

 
ACE inhibitors

No study was identified in this group.

 
Miscellaneous drugs

Six studies were identified in this group (Ali 2009; Kaya 2008; Koç 2007; Memis 2006; Montazeri 2011; Puri 1998). Only one study reported a positive outcome on ischaemic ECG changes (Puri 1998). In this study three participants out of 14 (21.4%) compared to none out of 16 in the magnesium sulphate group showed ECG evidence of ischaemia. Combining all six studies, three of the participants in the control group out of 135 (2.2%) showed evidence of ECG changes of myocardial ischaemia compared to none out of 203 in the treatment group. This difference of 2.2% was significant (the odds of ECG changes of myocardial ischaemia with an active drug compared to control: OR 0.10, 95% CI 0.01 to 1.05, P = 0.05) ( Analysis 2.1). 

 

2.2 All studies reporting ECG evidence of myocardial ischaemia, analysis of studies with high risk patients versus low risk patients

Of the studies, 14 (Cucchiara 1986; Dahlgren 1981; Davies 1981; De Brujin 1987; Ebert 1989; Girard 1986; Hart 1989; Kale 1988; Magnusson 1986; Mahajan 1993; Newsome 1986; Puri 1998; Stone 1988; Thomson 1984) were in high risk patients. To investigate the possible influence of baseline risk we conducted a subgroup analysis of studies in high risk patients compared to low risk patients, with the exclusion of two studies (Davies 1981; Stone 1988). In the 12 studies where the high risk patients were enrolled 15 out of 193 participants in the control group (7.7%) and 10 out of 202 in the treatment group (4.9%) had ECG changes of myocardial ischaemia. This difference was not significant (OR 0.67, 95% CI 0.27 to 1.67, P = 0.39, I2 = 40%) ( Analysis 2.2).

In the 17 studies enrolling lower risk patients none of the 810 patients in the treatment group had myocardial ischaemia compared to six out of 411 (1.4%) in the control group. This difference was significant (OR 0.03, 95% CI 0.01 to 0.18, P = 0.0001, I2 = 0%) ( Analysis 2.2).

The test for a subgroup difference showed a P value of 0.003 (I2 = 89%).

 

Outcome 3. Adverse effects associated with pharmacological interventions, analysis by drug type

 
Local anaesthetics

Side effects were reported following lignocaine administration in three trials (Pouttu 1988; Splinter 1989; Wang 2003). One patient in the lignocaine group had bradycardia (heart rate (HR) < 37 beats min- 1 two hours after drug administration) (Pouttu 1988) and two patients had restlessness when given 2 mg kg-1 10 minutes before tracheal intubation (Wang 2003). One study (Splinter 1989) reported tinnitus with lignocaine 1.5 µg kg-1 IV in 48% of participants. 

A statistically significant difference was observed between the placebo and treatment groups with 16 patients out of 153 showing adverse effects compared to none in the control group (the odds of side effects with the active drug compared to control therapy: OR 12.27, 95 % CI 4.03 to 37.36, P < 0.0001, I2 = 0%) ( Analysis 3.1).

 
Calcium channel blockers

Hypotension requiring treatment was not observed in any of the studies using calcium channel blockers. In one study (Maekawa 1992) one patient had flushing following a 5 mg nitrendipine oral dose.

 
Sympathetic blockers

Five trials of sympathetic blockers reported side effects. Mallon 1990 reported bradycardia (HR < 50 beats min-1) and bronchospasm in one patient who received a dose of 200 mg esmolol as an IV bolus. In another study, one patient developed hypotension requiring treatment following esmolol 1.4 mg kg-1 (Singh 1995). One study reported increased bronchomotor tone and a HR of < 70 beat min-1 in two patients with esmolol (Sharma 1995). Miller 1991 reported bronchospasm in four patients who received esmolol 100 and 200 mg IV compared to two patients who received placebo. In Cucchiara 1986 one patient in the treatment group developed bronchospasm following esmolol infusion 500 µg kg-1, and also in the control group.

A statistically significant difference was observed between the placebo and treatment groups with 37 patients out of 156 showing adverse effects in the treatment group compared to one out of 103 in the control group (the odds of side effects with the active drug compared to control therapy: OR 24.17, 95 % CI 8.88 to 65.79, P < 0.00001, I2 = 63%) ( Analysis 3.2).

 
Combined alpha and beta blockers

Amar 1991 reported a transient decrease of the mean arterial pressure (MAP) during surgery in two patients who received labetalol 0.75 µg kg-1.

Inada 1989 reported one patient who developed bronchospasm following labetalol 5 mg.

 
Centrally acting alpha agonists

Intravenous clonidine 1.25 µg kg-1 in one patient resulted in bradycardia of 45 beats min-1 and hypotension five minutes after completion of the study (Carabine 1991). No side effects were seen associated with oral gunabenz.

 
Narcotics

Iyer 1988 reported a significant fall in blood pressure (BP) after induction in all patients in the treatment group who received fentanyl (2, 5, 10, and 15 µg kg-1) compared to seven in the control group. Splinter 1989 reported respiratory depression in one patient who had received fentanyl.

Crawford 1987 reported a 40% fall in MAP and bradycardia following a 40 µg kg-1 dose of alfentanil in one ASA 3 patient; this hypotension was resistant to IV fluid and IV atropine. In this study, out of 15 patients 11 received more than 750 ml of fluid to keep the MAP at 60 mm Hg. 

In Scheinin 1989 a dose of 75 µg kg-1 alfentanil resulted in chest rigidity and difficulty in ventilation in 40% of the patients compared to none in the control group.

A statistically significant difference was observed between the placebo and treatment groups with 79 patients out of 155 showing adverse effects in the treatment group compared to none out of 63 in the control group (the odds of side effects with the active drug compared to control therapy: OR 149.5, 95 % CI 35.07 to 637.6, P < 0.00001, I2 = 92%) ( Analysis 3.4).

 
Miscellaneous

Puri 1998 reported three patients out of 16 who required pharmacological management of hypotension in the group who received magnesium sulphate 50 mg kg-1. The same participants also expressed a feeling of warmth after the injection. Some patients in the same trial experienced hypotension, the number of these patients was not identified but they were the patients who were also on beta blockers or calcium channel blockers preoperatively.

In Ali 2009, one patient who received gabapentin 800 mg orally had a transient decrease in systolic arterial pressure ( Analysis 3.5).

A summary of these results on side effects is presented in Appendix 8.

 

Route of administration and morbidity

The intravenous route was used in 48 trials. Lignocaine and nitroglycerine were the two drugs where a variety of routes were used. As the dosage of these drugs was not the same in the different trials, we did not perform any further analysis based on route as no meaningful conclusion could be drawn.

 

High risk patient studies

Seventeen trials were conducted in high risk patients. Different drugs and different dosages were used.

Twelve studies investigated patients with coronary artery disease. The following drugs were tested: lignocaine spray via the tracheal route (Denlinger 1974), IV lignocaine (Inada 1989), sublingual nifedipine (Kale 1988), topical nitroglycerine (Mahajan 1993), IV nitroglycerine (Hart 1989; Thomson 1984), IV esmolol (De Brujin 1987; Girard 1986; Newsome 1986), IV labetalol (Denlinger 1974; Inada 1989), magnesium sulphate (Puri 1998), and IV fentanyl (Iyer 1988). Ebert 1989 investigated the effects of esmolol and fentanyl in ASA 3 and 4 patients. This was a mixed group with hypertension and Ischaemic heart disease.

Two studies investigated hypertensive patients (Magnusson 1986; Stone 1988) and looked at the effects of metoprolol, labetalol, atenolol, and oxprenolol. Dahlgren 1981 included neurosurgical patients in the trial and looked at the effects of IV fentanyl. Davies 1981 recruited patients undergoing intracranial surgery. Cucchiara 1986 studied the effects of IV esmolol in patients undergoing carotid endarterectomy.

Four studies observed participants only for arrhythmias (Dahlgren 1981; Denlinger 1974; Inada 1989; Iyer 1988), eight observed participants only for ischaemia (Davies 1981; De Brujin 1987; Ebert 1989; Girard 1986; Hart 1989; Newsome 1986; Stone 1988; Thomson 1984), and five observed participants for both (Cucchiara 1986; Kale 1988; Magnusson 1986; Mahajan 1993; Puri 1998).

The details of the results of these studies have been summarized in Appendix 9 and Appendix 10. The analysis of studies with high risk patients has been presented in the text. Data from two studies has not been included in the appendices (Davies 1981; Stone 1988) but have been discussed in the text.

 

Pharmacological agents where only a single study was available

Appendix 5 lists the summary of results where only a single study was available for a particular drug. In addition, single studies were available for hydralazine (Davies 1981), atenolol, and oxprenolol (Stone 1988) but they have not been included in the Appendix.

 

Discussion

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

This review concerns the randomized evidence for the use of pharmacological agents to modify the haemodynamic response to laryngoscopy and tracheal intubation. Specifically, we have collated the data on the clinically relevant outcomes of morbidity and mortality (primary outcomes) and the surrogate measures (secondary outcomes) arrhythmia and ECG evidence of myocardial ischaemia.

 

Summary of main results

Only two studies reported each of our primary outcomes of mortality and morbidity (Mikawa 1996; Miller 1991). Neither of these outcomes was reported in any arm of any other study, suggesting that these clinical outcomes are probably rare (as we anticipated).

To find out the risk of arrhythmias and myocardial ischaemia, we reviewed 72 studies involving eight different pharmacological groups (local anaesthetics, calcium channel blockers, sympathetic blockers, peripheral vasodilators, centrally acting alpha agonists, narcotics, ACE inhibitors, and a group of miscellaneous drugs). We found data on a total of 32 different drugs.Data from four trials was not included in the analysis. In total, 60 studies reported arrhythmias and 31 reported the ECG changes of myocardial ischaemia as an outcome measure. Our systematic review suggests that the pre-anaesthetic administration of local anaesthetics, calcium channel blockers, beta blockers, or narcotics is associated with a significant decrease in the risk of arrhythmias associated with laryngoscopy and intubation when compared to placebo. Arrhythmias were observed in 134 out of 993 patients in the control group compared to 80 out of 1939 in the intervention group (P < 0.00001).

In total, 31 studies included myocardial ischaemia as an outcome. None of the studies examined the association of intraoperative ECG changes to any clinical outcome such as postoperative myocardial infarction or postoperative persistent changes in ECG. Overall, the use of pharmacological agents resulted in a significant reduction in the risk of ischaemic episodes. Myocardial ischaemia was observed in 21 out of 604 patients in the control group compared to 10 out of 1012 in the treatment group with a statistically significant result (P = 0.01). This result should be treated with caution, however, because in 20 of the included studies no patient in either the control or interventional group suffered this outcome and thus only nine studies contributed to the analysis. Further, the local anaesthetic group was the only subgroup analysis that indicated a significant difference with pretreatment, and that analysis was dominated by a single study (Asfar 1990). The largest subgroup contributing to this data was studies with beta blockers (five studies with positive outcomes) and pretreatment did not show a statistically significant difference compared to placebo. These results could be explained on the basis that myocardial ischaemia was a relatively rare event and the studies were underpowered to look at this complication. Larger datasets may be required to reach meaningful conclusions.

In the subgroup analysis comparing the effects of pharmacological agents on the risk of myocardial ischaemia in high risk patients versus low risk patients, treatment was effective in low risk patients but no effect was observed in high risk patients. This could again be due to the rarity of the events or due to the fact that patients may have been on other medications that may influence the outcome. More studies are needed in the high risk population.

 

Overall completeness and applicability of evidence

The majority of studies (70%) in our review were conducted in relatively healthy ASA 1 and 2 patients, and therefore there are limitations in extrapolating these results to high risk, vulnerable patients. There were only two studies (Mikawa 1996; Miller 1991) that reported our primary outcome but provided no details. Most of the remaining studies were primarily designed to observe the blood pressure and heart rate changes, and only nine studies addressed the consequence of these changes as part of their objectives or methodology (Hart 1989; Ko 1998; Lee 2011; Lindgren 1987; Mallon 1990; Stone 1988; Sun 2009; Thomson 1984; Wang 2003). We were unable to usefully compare the effectiveness of individual drugs within each pharmacological class because of the variation in dose, timing, and route of administration. This review nevertheless suggests that even these low risk patients are susceptible to cardiac arrhythmia and ECG evidence of myocardial ischaemia as a consequence of haemodynamic changes related to tracheal intubation. Of these low risk patients, 13% had arrhythmias and 1.4 % had myocardial ischaemia when a placebo was given prior to laryngoscopy and intubation. Pre-induction use of pharmacological agents reduced this risk to 4.5% for arrhythmias and nil for myocardial ischaemia.

In clinical practice, the use of agents to reduce the response to laryngoscopy and intubation is likely to be of most importance in those patients at high risk of morbidity due to concurrent cardiovascular disease. In this review, 17 (23%) of the studies were conducted in high risk patients; two enrolled hypertensive patients, 12 enrolled patients with coronary artery disease, two enrolled neurosurgical patients, and one enrolled patients with carotid artery disease. Data from two of these studies were not subjected to analysis (Davies 1981; Stone 1988). It is in this vulnerable population of patients where it is most important to attenuate the haemodynamic response related to tracheal intubation in order to avoid important morbidity. When the high risk studies were pooled (15 studies), pharmacological treatment resulted in a reduction in the risk of arrhythmias but not in ECG evidence of ischaemia. It is difficult to comment on the negative results as, despite pooling these studies, our analysis may still be underpowered to reliably quantify any protective effect. There was also considerable heterogeneity with varying doses of individual agents used in these studies, therefore a particular dose of any agent cannot be recommended.

All the studies in our review only mentioned the nature and the risk of arrhythmia but did not comment on the percentage of participants requiring treatment or any further morbidity related to the rhythm disturbance. Patient anxiety was not taken into consideration and indeed, the premedication given to the participants was variable and may have influenced the outcome in some trials.

Different ECG leads were used for detection of myocardial ischaemia. Some studies used lead 2 for intraoperative ECG monitoring, whereas others did not mention the lead used. Lead 2 is not the best lead to be used for intraoperative ECG monitoring of ischaemia.

Substantial heterogeneity was seen in the results with two of the groups that is local anaesthetics (I² = 79%) and narcotics (I² = 58%) suggesting that drug effect may not be uniform across these groups. On the other hand, the calcium channel blocker group and beta blocker group were fairly homogenous across the studies indicating that different drugs within these classes may exhibit a similar magnitude of effect.

Pharmacological treatment was seen to be effective in both high risk and low risk patients, but substantial heterogeneity was seen in the studies of high risk patients for arrhythmia (I2 = 80%).

Despite this clinical heterogeneity, the studies did show a benefit over placebo with some pharmacological agents in decreasing the risk of arrhythmia and future research should concentrate on further evaluation of these drugs.

The above limitations should be kept in mind when applying this evidence in everyday practice

 

Quality of the evidence

While we only included randomized studies in this review, many of them (particularly those done before year 2000) did not report details of randomization and treatment allocation. We included both blinded and non-blinded studies. Many of the blinded studies did not report the details of the blinding process. Therefore, in general, the methodological quality of the majority of the included studies was poor (Figure 2).

There were many other sources of heterogeneity present in this review. In total, 27 studies used only a small sample size of 10 or fewer participants in one of the study arms. This is likely to result in a lot of random variation. A sample size calculation was again not mentioned in the majority of studies.

Different routes and dosages were used in the same pharmacological group or for the same drug in the different studies. There were also variations in the use of induction agents and the muscle relaxant used for tracheal intubation. The timing of the administration of the same drugs in relation to induction was different in different studies. Factors like duration of laryngoscopy were controlled in some studies but not in all. This type of heterogeneity made it difficult to compare different trials of even the same drug. Because of this heterogeneity we were unable to get an answer to our third review question that is whether the route of administration of the agents was associated with a significant difference in respect of the studied outcomes.

 

Potential biases in the review process

We attempted to minimize bias by following the guidelines recommended in the Cochrane Handbook for Systematic Reviews of Interventions.The eligibility for inclusion and exclusion and assessment of risk of bias of the different studies was carried out independently by two authors.

 

Agreements and disagreements with other studies or reviews

We are unaware of other systematic reviews specifically addressing the complications related to the haemodynamic response to laryngoscopy and tracheal intubation. Two systematic reviews addressed the efficacy of esmolol (Figueredo 2001) and landilol ( Ionue 2009) on the haemodynamic changes following laryngoscopy and tracheal intubation but they did not include myocardial ischaemia or arrhythmia as an outcome. Another narrative review (Kovac 1996) reviewed the common causes and treatment of hypertension and tachycardia during laryngoscopy and tracheal intubation but did not include myocardial ischaemia or arrhythmia as an outcome. A French narrative review (Bruder 1992) looked at the consequences and prevention methods of haemodynamic changes during laryngoscopy and intratracheal intubation. We are awaiting translation of this review.

 

Authors' conclusions

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

 

Implications for practice

This review suggests that pre-induction or co-induction administration of local anaesthetics, calcium channel blockers, beta blockers, or narcotics are effective in reducing the risk of arrhythmias associated with laryngoscopy and tracheal intubation. There is no evidence that these agents influence morbidity or mortality in this setting. The evidence does not allow us to determine a recommended dose or route of administration for these agents.

The results of a single study (Asfar 1990) suggest that the administration of lignocaine in this setting also reduces the risk of ECG changes suggestive of myocardial ischaemia. Overall, these studies have a low power to detect a reduction in the risk of such changes and we are unable to confirm any benefit from the use of other agents for this purpose.

 
Implications for research

There is a deficiency of literature that has looked at morbidity related to the haemodynamic response to laryngoscopy and tracheal intubation and there is need to focus on this aspect in future research. Researchers looking at the blood pressure and heart rate responses should report the consequences of these short lived changes and refer to them as part of their methodology rather than a chance comment in the results. They should also look at short term immediate effects as well as any postoperative effects of these changes. The identified trials were heterogeneous in terms of drug dosages, routes of administration, and timing of intervention of the same drug as well as different study drugs and the anaesthetic drugs used for induction. These need to be standardized to allow pooling of data.

Most literature on the haemodynamic response to tracheal intubation has focused on healthy ASA 1 and 2 patients. In view of the difficulty in undertaking placebo controlled trials in the high risk population, a combination of smaller doses of effective drugs can be compared with doses of single drugs that were found effective in isolated studies.

Randomized controlled trials may not be a good study design to assess the rate of complications for interventions like tracheal intubation. One approach may be to establish prospective registries or a multi-database for a large cohort. Recently a similar approach was taken for looking at complications related to paediatric regional blocks, where a consortium of 14 North American hospitals established the Paediatric Regional Anaesthesia Network (PRAN) to study paediatric epidural data. They recently published their report on the first three years of data (Polaner 2012). Another design approach could be a large scale survey, or well designed national or regional audits. An example of such a survey is NAP 3 in the UK, which was undertaken to study the major complications of central neuraxial blocks (Cook 2009).

 

Acknowledgements

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

We would like to thank: Karen Hovhannisyan (CARG Trials Search Co-ordinator) for designing the search strategy and retrieving articles that we were unable to access, and Jane Cracknell (Managing Editor CARG) for co-ordinating this review. We would also like to thank Mike Bennett (content editor), Nathan Pace (statistical editor), Maurizio Solca, Preethy J Mathew (external peer reviewers) and Janet Wale (Cochrane Consumer Network representative) for their help and editorial advice during the preparation of this systematic review.

We would like to acknowledge Gary Kantor's contribution to the protocol (Khan 2003). We would like to thank Drs Mike Bennett, Pramod Bapat and Filippo Bressan for their help and editorial advice during the preparation of the protocol for the systematic review.

We would also like to acknowledge the input of the following individuals in the preparation of this protocol: Dr Lee Fleisher, Baltimore, USA and Dr Andrew Smith, Lancaster, UK.

 

Data and analyses

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms
Download statistical data

 
Comparison 1. Arrhythmias

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Arrhythmias - by drug type582932Peto Odds Ratio (Peto, Fixed, 95% CI)0.19 [0.14, 0.26]

    1.1 Local anaesthetics
13550Peto Odds Ratio (Peto, Fixed, 95% CI)0.34 [0.18, 0.62]

    1.2 Calcium channel blockers
11381Peto Odds Ratio (Peto, Fixed, 95% CI)0.13 [0.04, 0.41]

    1.3 Sympathetic blockers
18742Peto Odds Ratio (Peto, Fixed, 95% CI)0.22 [0.12, 0.41]

    1.4 Centrally acting alpha agonists
3108Peto Odds Ratio (Peto, Fixed, 95% CI)0.05 [7.79, 3.18]

    1.5 Peripheral vasodilators
373Peto Odds Ratio (Peto, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.6 Narcotics
12620Peto Odds Ratio (Peto, Fixed, 95% CI)0.12 [0.07, 0.21]

    1.7 Miscellaneous
8458Peto Odds Ratio (Peto, Fixed, 95% CI)0.0 [0.0, 0.0]

 2 Arrhythmias - sympathetic blockers18742Peto Odds Ratio (Peto, Fixed, 95% CI)0.22 [0.12, 0.41]

    2.1 Beta blockers
14589Peto Odds Ratio (Peto, Fixed, 95% CI)0.23 [0.12, 0.44]

    2.2 Combined alpha and beta blockers
4103Peto Odds Ratio (Peto, Fixed, 95% CI)0.13 [0.01, 1.17]

    2.3 Alpha blockers
150Peto Odds Ratio (Peto, Fixed, 95% CI)0.0 [0.0, 0.0]

 3 Arrhythmias - high risk vs low risk patients582866Peto Odds Ratio (Peto, Fixed, 95% CI)0.20 [0.14, 0.27]

    3.1 High risk patients
9337Peto Odds Ratio (Peto, Fixed, 95% CI)0.18 [0.05, 0.59]

    3.2 Low risk patients
492529Peto Odds Ratio (Peto, Fixed, 95% CI)0.20 [0.14, 0.28]

 
Comparison 2. ECG evidence of myocardial ischaemia

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Myocardial ischaemia - by drug type29Odds Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 Local anaesthetics
4192Odds Ratio (M-H, Fixed, 95% CI)0.03 [0.00, 0.59]

    1.2 Calcium channel blockers
2130Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.3 Sympathetic blockers
11459Odds Ratio (M-H, Fixed, 95% CI)0.69 [0.25, 1.88]

    1.4 Peripheral vasodilators
483Odds Ratio (M-H, Fixed, 95% CI)1.5 [0.26, 8.82]

    1.5 Centrally acting alpha agonists
148Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.6 Narcotics
6366Odds Ratio (M-H, Fixed, 95% CI)0.31 [0.01, 8.31]

    1.7 Miscellaneous
6338Odds Ratio (M-H, Fixed, 95% CI)0.10 [0.00, 2.12]

 2 Myocardial ischaemia - high risk vs low risk patients291616Peto Odds Ratio (Peto, Fixed, 95% CI)0.36 [0.16, 0.80]

    2.1 High risk patients
12395Peto Odds Ratio (Peto, Fixed, 95% CI)0.67 [0.27, 1.67]

    2.2 Low risk patients
171221Peto Odds Ratio (Peto, Fixed, 95% CI)0.03 [0.01, 0.18]

 
Comparison 3. Adverse effects

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Local anaesthetics3227Peto Odds Ratio (Peto, Fixed, 95% CI)12.27 [4.03, 37.36]

 2 Beta blockers5259Peto Odds Ratio (Peto, Fixed, 95% CI)24.17 [8.88, 65.79]

 3 Combined alpha and beta blockers246Peto Odds Ratio (Peto, Fixed, 95% CI)6.43 [0.81, 50.98]

 4 Narcotics4218Peto Odds Ratio (Peto, Fixed, 95% CI)149.55 [35.07, 637.65]

 5 Miscellaneous280Peto Odds Ratio (Peto, Fixed, 95% CI)7.46 [0.99, 56.05]

 

Appendices

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms
 

Appendix 1. CENTRAL search strategy

Database: CENTRAL, The Cochrane Library, March 2010

Search strategy

 #1  MeSH descriptor Laryngoscopy, this term only

#2  MeSH descriptor Intubation, Intratracheal, this term only

#3  laryngoscop*:ti or (intubat* near (tracheal or endotracheal or intratracheal)):ti,ab or (heart rate or blood pressure or arrhythmia* or stroke):ti

#4  (h?emodynamic* near change*):ti,ab or ((cardiovascular or h?emodynamic) near respon*):ti,ab or (hearth near (isch?emia or failure)):ti,ab

#5  (#1 OR #2 OR #3 OR #4)

#6  MeSH descriptor Anesthetics, Local, this term only

#7  MeSH descriptor Analgesics, this term only

#8  (ganglion blocker* or alpha agonist* or  agiotensin converting enzyme inhibitor* or adrenergic agonist* or lignocaine or Verapamil or Diltiazem or nisoldipine or nivaldipine or nicardipine or nitrendipine or nifedipine or Esmolol or Pindolol or Labetalol or clonidine or dexmedatomidine or gunabenz or nitroglycerine or Fentanyl or Alfentanil or Sufentanil or Remifentanil or Morphine or Pethidine or Nalbuphine or Tramadol or Butorphenol or Buprenorphine or adenosine triphosphate or magnesium sulphate or gabapentin or dexamethasone):ti

#9  (#6 OR #7 OR #8)

#10 (#5 AND #9)

 

Appendix 2. MEDLINE search strategy

#1. (laryngoscop* or(intubat*adj6 (tracheal or endotracheal or intratracheal))).mp. or exp Laryngoscopy/ or exp Intubation, Intratracheal/

#2. ((h?emodynamic* adj3 change*) or((cardiovascular or h?emodynamic) adj3 respon*) or heart rate or blood pressure or arrhythmia* or stroke or (hearth adj3 (isch?emia or failure))).mp. or exp Blood Pressure/ or exp Heart Rate/ or Arrythmias, Cardiac/ or Myocardial Ischemia/ or Heart Failure/ or Stroke/

#3. #1 and #2

#4. Exp Anesthetics , Local/ or exp Calcium Channel Blockers/ or exp Adrenergic Agonists/ or exp Adrenergic alpha-Agonists/ or exp Vasodilator Agents/ or exp Analgesics Opioid/ or exp Analgesics/ or (local anesthetic* or calcium channel blocker* or sympathetic blocker* or ((alpha or beta) adj3 blocker*) or ganglion blocker* or alpha agonist* or vasodilator* or narcotic* or opioid* or analgesic* or agiotensin converting enzyme inhibitor* or adrenergic agonist* or lignocaine or Verapamil or Diltiazem or nisoldipine or nivaldipine  or nicardipine or nitrendipine or nifedipine or Esmolol or Pindolol or Labetalol or clonidine or dexmedatomidine or gunabenz or nitroglycerine or Fentanyl or Alfentanil or Sufentanil or Remifentanil or Morphine or Pethidine or Nalbuphine or Tramadol or Butorphenol or Buprenorphine or adenosine triphosphate or magnesium sulphate or gabapentin or dexamethasone).mp.

#5. #3 and #4

6. ((randomized controlled trial or controlled clinical trial).pt. or randomized.ab. or placebo.ab. or clinical trials as topic.sh. or randomly.ab. or trial.ti.) and humans.sh.

7. #5 and #6   

 

Appendix 3. EMBASE search strategy

Database: EMBASE via Ovid SP <1980 to 2010 Week 12>

Search Strategy:

1     exp Laryngoscopy/ or exp Intubation, Intratracheal/ or laryngoscop*.mp. or (intubat* adj6 (tracheal or endotracheal or intratracheal)).mp. (26819)

2     ((h?emodynamic* adj3 change*) or ((cardiovascular or h?emodynamic) adj3 respon*) or heart rate or blood pressure or arrhythmia* or stroke or (hearth adj3 (isch?emia or failure))).mp. (459212)

3     1 and 2 (3227)

4     (local anesthetic* or calcium channel blocker* or sympathetic blocker* or ((alpha or beta) adj3 blocker*) or ganglion blocker* or alpha agonist* or vasodilator* or narcotic* or opioid* or analgesic* or agiotensin converting enzyme inhibitor* or adrenergic agonist* or lignocaine or Verapamil or Diltiazem or nisoldipine or nivaldipine or nicardipine or nitrendipine or nifedipine or Esmolol or Pindolol or Labetalol or clonidine or dexmedatomidine or gunabenz or nitroglycerine or Fentanyl or Alfentanil or Sufentanil or Remifentanil or Morphine or Pethidine or Nalbuphine or Tramadol or Butorphenol or Buprenorphine or adenosine triphosphate or magnesium sulphate or gabapentin or dexamethasone).mp. (493050)

5     exp Calcium Channel Blocking Agent/ or exp Local Anesthetic Agent/ or exp Adrenergic Receptor Stimulating Agent/ or exp Alpha Adrenergic Receptor Stimulating Agent/ or exp Vasodilator Agent/ or exp Narcotic Analgesic Agent/ or exp Analgesic Agent/ (903481)

6     4 or 5 (1075322)

7     6 and 3 (2134)

8     (placebo.sh. or controlled study.ab. or random*.ti,ab. or trial*.ti,ab.) not (animals not (humans and animals)).sh. (745957)

9     7 and 8 (843)

 

Appendix 4. Study data extraction form

DATA EXTRACTION FORM

 


 

Study ID:

 



 


 

Authors:

 



 


 

Medline Journal ID:

 



 


 

Year of Publication:

 



 


 

Language:

 



 


 

Type of Study:                        RCT_______        CCT_______        Non-randomized_______

 



 


 

Comments on Study Design:

  



 

QUALITY OF STUDY

 

Selection bias assessment


Allocation was not concealed (e.g. quasi-randomization):     Yes _________           No_________

 

Allocation was not stated or was unclear:                              Yes _________           No_________

 

Adequate concealment (e.g. alteration using date of birth, open list of random numbers, table or envelopes):                                                                              Yes _________           No_________

 

Allocation was concealed (e.g. numbered, sealed opaque envelopes drawn NON consecutively; allocation through central office or pharmacy controlled; prenumbered or coded identical syringes; onsite computer system with locked unreadable computer file):    

                                                                                                Yes _________           No_________

 



 


Inclusion and exclusion criteria

were clearly defined in the text:  Yes _________      No________              Unclear __________



 

Performance bias assessment


Subject - Blinded                    Yes _________           No_________             Unclear_________

 

Outcome Assessor -Blinded   Yes _________           No_________             Unclear_________

 

Data analyser - Blinded          Yes _________           No_________             Unclear_________

 



 

Attrition bias assessment


Outcomes of patients who withdrew or were excluded after allocation were EITHER detailed separately OR included in an intention to treat analysis OR the text stated there were no withdrawals                            Yes _________           No_________             Unclear_________

 



 

Detection bias assessment


Outcome measures were              Yes _________      No_________             Unclear_________

clearly defined in the text:

Outcome assessors were blind     Yes _________      No_________             Unclear_________  to the allocation of patients:

The timing of the measurement   Yes _________      No_________             Unclear_________

of the outcomes was appropriate:



 

Risk of bias


LowMajority of above criteria met (> 75%) 

ModerateCriteria partially met (50-75%) 

HighMajority of above criteria not met (> 50% not met) 



 

METHODS

PARTICIPANTS:


Total number enrolled in Study

Number of males _________                   Number of females_________

 

Age group:      Mean age – Group 1 _________        Group 2_________     Group 3________

 

Participants at high risk for complications:

Pre-existing hypertension                                                        Yes _________           No_________

Pre-existing ischaemic heart disease                                       Yes _________           No_________

Pre-existing cerebral pathology                                               Yes _________           No_________

Cerebral aneurysm                                                                  Yes _________           No_________

History of stroke                                                                     Yes _________           No_________

History of cerebrovascular accident                                       Yes _________           No_________

Raised intracranial pressure                                                    Yes _________           No_________

Presence of major vascular disease                                        Yes_________           No_________

 



 

INDUCTION OF ANAESTEHSIA


DrugDose: mg kg-1/μg kg-1Comments

Thiopentone  

Propofol  

Ketamine  

Midazolam  

Inhalational agent  

More than one agent used  

Not mentioned  



 

ALTERATION TO ANAESTHESIA


Were any alterations to anaesthesia done in response to haemodynamic changes:

If yes, details:                         Yes _________           No_________             Unclear_________

 

  



 


 

INTERVENTION:
Drug nameDrug classDoseDuration of drug interventionRouteBolus/Infusion

(B) / (I)

Treatment Group 1:      

Treatment Group 2:      

Treatment Group 3:      



 


 ADVERSE EFFECTS OF DRUGS

 

 

 

 



 

 


PRIMARY OUTCOMES:Number of patientsMortalityMyocardial infarction following ischaemiaRupture of aneurysmAcute cerebral haemorrhageProlonged stay in OR, Recovery or ICU

Treatment Group 1:      

Treatment Group 2:      

Treatment Group 3:      



 


SECONDARYNumber of patients


OUTCOMES:Who had dysrhythmias

(Type of dysrhythmias)
ECG evidence of ischaemia 

Treatment Group 1:   

Treatment Group 2:   

Treatment Group 3:   



 


 DURATION OF FOLLOW-UP IN STUDY

 

  

Not clear____________

 



 

 


 

CHANGES IN PROTOCOL:



 

 


 

CONTACT WITH AUTHOR:



 

 


OTHER COMMENTS ON THIS STUDY:

 

 

 



 

 

 

Appendix 5. Summary of results where only a single study was available for a particular drug


Subgroup title

 
Study

 

 
Drug Participants total

 
Treatment ControlPeto Odds Ratio

Effect Estimate

 


EventsTotal

 
EventsTotal

 

Local anaesthetics arrhythmiasVictory 1995Bupivacaine404203201.40 [0.28 to 7.02] P = 0.68

 

Artru 1985Etidocaine308203101.52 [0.32 to 7.14] P = 0.60

 

Calcium channel blockers arrhythmiasMaekawa 1992Nisoldipine300201100.05 [0.00 to3.18] P = 0.16

 

Mikawa 1992aNivaldipine300201100.05 [0.00 to 3.18] P = 0.16

 

Mikawa 1994Manidipine300201100.05 [0.00 to 3.18] P = 0.16

 

Beta blockers  arrhythmiasMikawa 1991aPindolol300202100.04 [0.00 to 0.89] P = 0.04

 

Alpha blockersQuere 1990Urapidil50025025Not estimable

Centrally acting alpha agonists arrhythmiasMikawa 1993Guanabenz300201100.05 [0.00 to 3.18] P = 0.16

 

Miscellaneous

myocardial ischaemia
Puri 1998Magnesium sulphate300143160.13 [0.01 to 1.40] P = 0.09

 



 

 

Appendix 6. Drugs and doses in studies observing arrhythmias as outcome


Pharmacological groupStudy Drug used Dosage used Route

Local anaestheticsArtru 1985Etidocaine50mgs, 75mgsAerosol

Asfar 1990Lidocaine10, 4 and 2 %Spray,

Transtracheal,

IV

Denlinger 1974Lignocaine3mls of 4%Spray

Durrani 2000Lignocaine

Chloroprocaine
1.5 mgkg-1

4.5mgkg-1
IV

IV

Inada 1989Lignocaine100mgsIV

Kindler 1996Lignocaine1.5 mgkg-1IV

Pouttu 1988Lignocaine1 mgkg-1IV

Singh 1995Lignocaine1.5 mgkg-1IV

Sklar 1992Lignocaine40 mgInhalational

Splinter 1989Lignocaine1.5 mgkg-1IV

Sun 2009Lignocaine5mls of 2%Inhalational

Victory 1995Bupivacaine0.75%Via nebulizer

Wang 2003Lignocaine2 mgkg-1IV

Calcium channel blockersAbdel-Razek 1991Nifedipine10 mgSublingual

Atlee 2000Nicardipine30µgIV

Kale 1988Nifedipine10mgsSublingual

Maekawa 1992Nisoldipine5mgs, 10mgsOral

Maekawa 1993Nitrendipine5mgs, 10 mgOral

Mikawa 1990aDiltiazem

Diltiazem
0.2mgkg-1

0.3mgkg-1
IV

IV

Mikawa 1990bNicardipine15,30 µgskg-1IV

Mikawa 1992aNivaldipine2mgs 4mgsOral

Mikawa 1994Manidipine5mgs, 10 mgOral

Mikawa 1996Nicardipine

Diltiazem

Verapamil
30 µgskg-1

0.2mgkg-1

0.1mgkg-1
IV

IV

IV

Puri 1986Verapamil0.1mgkg-1IV

Sympathetic blockers

 beta blockers
Atlee 2000Esmolol1mgkg-1IV

Cucchiara 1986Esmolol500 ugkg-1min-1 x 4 min

300 ugkg-1min-1 x 8 min
IV

Jakobsen 1992 *Metoprolol100 mgsoral

Kindler 1996Esmolol1mgkg-1

2mgkg-1
IV

IV

Korpinen 1995aEsmolol2mgkg-1

3mgkg-1
IV

IV

Korpinen 1995bEsmolol2mgkg-1IV

Magnusson 1986Metoprolol15 mgIV

Maharaj 1983Practolol0.4 mgkg-1IV

Mallon 1990Esmolol100 mg

200 mg
IV

IV

Mikawa 1991aPindolol2mgkg-1

4mgkg-1
IV

IV

Oxorn 1990Esmolol100 mg

200 mg
IV

IV

Ryhanen 1977 *Practolol0.2 mgkg-1IV

Sharma 1995Esmolol100 mg

200 mg
IV

IV

Singh 1995Esmolol1.4 mgkg-1IV

White 2003Esmolol50 mgIV

Zargar 2002Esmolol

Metoprolol 
25 mg

4 mg
IV

IV

Sympathetic blockers,

Combined alpha and beta blockers
Amar 1991Labetalol0.15mgkg-1IV

Bernstein 1989Labetalol0.75mgkg-1

0.25mgkg-1
IV

IV

Inada 1989Labetalol5mgs, 10mgsIV

Maharaj 1983Labetalol0.5mgkg-1IV

Sympathetic blockers,

alpha blockers
Quere 1990Urapidil0.4mgkg-1 IV

Peripheral vasodilators Mahajan 1993Nitroglycerin2% ointmentTransdermal

Mikawa 1992bNitroglycerin1.5µg, 2.5µgIV

Singh 1995Nitroglycerin2µgskg-1IV

Centrally acting agonistsCarabine 1991Clonidine 1.25 µgskg-1

0.625µgskg-1
IV

IV

Mikawa 1993Gunabenz4mgs

6 mg
Oral

Oral

Montazeri 2011Clonidine0.3 mg kg-1Oral

NarcoticsAbdel-Razek 1991Fentanyl1.5 µgskg-1IV

Black 1984Alfentanil

Fentanyl
15,30 µgskg-1

 5 µgskg-1
IV

IV

Crawford 1987Alfentanil10,40 µgskg-1IV

Dahlgren 1981Fentanyl5 µgskg-1IV

Iyer 1988Fentanyl2,5,10,15  µgskg-1IV

Kay1987Sufentanil0.5 ,1.0 µgskg-1IV

Ko 1998Fentanyl2 µgskg-1IV

Korpinen 1995aAlfentanil0.03 µgskg-1IV

Korpinen 1995bAlfentanil15 µgskg-1IV

Lindgren 1987Fentanyl1,2,3 µgskg-1IV

Scheinin 1989Alfentanil1.5 µgskg-1

3 µgskg-1
IV

IV

Splinter 1989Fentanyl1.5 µgskg-1

3 µgskg-1
IV

IV

MiscellaneousAli 2009Gabapentin1200mgsOral

Bafna 2011Gabapentin600 mg

1000 mg
Oral

Oral

Kaya 2008Gabapentin800 mgOral

Koç 2007Gabapentin

Dexamethasone
800 mg

8 mgs
Oral

Memis 2006Gabapentin400 mg, 800mgOral

Mikawa 1991bATP0.05 mgkg-1

0.1 mgkg-1
IV

IV

Montazeri 2011Gabapentin800 mgOral

Puri 1998Magnesium sulphate50  mgskg-1IV

* Data of these studies was not included in analysis



 

Appendix 7. Drugs and doses in studies observing myocardial ischaemia as outcome


Pharmacological GroupStudy Drug used Dosage used Route

Local anaesthetics 

 
Asfar 1990Lidocaine10, 4 and 2 %Spray,

Transtracheal,

IV

Singh 1995Lignocaine1.5 mgkg-1IV

Splinter 1989Lignocaine1.5 mgkg-1IV

Sun 2009Lignocaine5mls of 2%Inhalational

Calcium channel blockers

 
Kale 1988Nifedipine10mgsSublingual

Song 1997Nicardipine0.5,1,2,4mgIV

Sympathetic blocker, beta blockers

 
Cucchiara 1986Esmolol500 ug kg-1min-1 x 4 min

300 ug kg-1min-1 x 8 min
IV

De Brujin 1987Esmolol500 ug kg-1min-1IV

Ebert 1989Esmolol500µg kg min-1 + infusionIV

Girard 1986Esmolol500µg kg min-1 + infusionIV

Magnusson 1986Metoprolol15 mgIV

Mallon 1990Esmolol100 mg

200 mg
IV

Newsome 1986Esmolol500 µg kg min-1 + infusionIV

Oxorn 1990Esmolol100,200mgsIV

Sharma 1995Esmolol100 mg

200 mg
IV

IV

Singh 1995Esmolol1.4 mgkg-1IV

Stone 1988 *Atenalol

Oxprenalol
50 mg

20 mg
oral

oral

Zargar 2002Metaprolol 

Esmolol
4 mg

 25 mg
IV

IV

Sympathetic blocker, combined alpha and beta blockers

 
Stone 1988Labetalol100mgsoral

Centrally acting agonistsMontazeri 2011Clonidine0.3 mg kg-1IV

Peripheral vasodilatorsDavies 1981 *Hydralazine0.4 mgkg-1IV

Hart 1989Nitroglycerin1 µgskgmin-1IV

Mahajan 1993Nitroglycerin2% ointmentTransdermal

Singh 1995Nitroglycerin2µgskg-1IV

Thomson 1984Nitroglycerin0.5µgskg-1m-1IV

Narcotics

 
Chraemmer-Jorgensen 1992Alfentanil100 µgskg-1IV

Crawford 1987Alfentanil10,40 µgskg-1IV

Dahlgren 1981Fentanyl5 µgskg-1IV

Ebert 1989Fentanyl0.8 µgskg-1m-1IV

Lee 2011Hydromorphone

Fentanyl
0.03 mg kg -1

2 ug kg-1
IV

IV

Splinter 1989Fentanyl1.5 µg kg-1

3 µg kg-1
IV

IV

Miscellaneous

 
Ali 2009Gabapentin1200mgOral

Kaya 2008Gabapentin800 mgOral

Koç 2007Gabapentin800 mgOral

Memis 2006Gabapentin400, 800 mgOral

Montazeri 2011Gabapentin800 mgOral

Puri 1998Magnesium sulphate50  mg kg-1IV

·         Data of these studies was not included in the analysis



 

Appendix 8. Adverse effect of individual drugs


Pharmacological groupStudy Drugs Dosage  Adverse effect reported

Local anaesthetics Pouttu 1988Lignocaine1mg kg-1 IVOne patient had bradycardia and, heart rate less than 37 beats min -1

Splinter 1989 Lignocaine1.5mg kg-1 IVTinnitus in 48 % of patients

Wang 2003Lignocaine2 mg kg-1 IVRestlessness in two patients

Calcium channel blockers Maekawa 1993Nitrendipine5mgs, 10mgs oralFlushing in one patient

Beta blockers Mallon 1990Esmolol200mgs IVBradycardia, HR<50 beats min-1,and brochospasm in one patient

Singh 1995Esmolol1.4 mg kg -1 IVHypotension requiring treatment in one patient

Cucchiara 1986Esmolol500ugkg-1 IVBronchospasm and agitation in one patient

Sharma 1995Esmolol100, 200,mg bolus IVIncreased broncho motor tone and HR <70 beats min -1

in two patients

Miller 1991Esmolol100, 200,mg IVBronchospasm in four patients

Combined alpha and beta blocker Amar 1991Labetalol0.75 ug kg-1 IVTransient decrease in mean arterial pressure in two patients

Inada 1989Labetalol5mgs, 10 mg IVBronchospasm in one patient

Centrally acting alpha agonists Carabine 1991Clonidine1.25ugkg -1 IVBrady cardia of 45 beats min and hypotension in one patient

NarcoticsIyer 1988Fentanyl2,5,10 & 15ug kg -1 IVSignificant fall in BPin all patients receiving study drug

Splinter 1989Fentanyl1.5ug kg -1 IV,

13ug kg -1 IV
Respiratory depression in one patient

Crawford 1987Alfentanil40 ug kg -1  IV

 
40% fall in MAP and bradycardia resistant to IV fluid and IV atropine in one patient

Scheinin 1989Alfentanil75 ug kg -1 IV40% of patients had chest rigidity and difficulty in ventilation

Miscellaneous drugs Puri 1998Magnesium sulphate50 mg kg -1 IVWarmth in body and hypotension in three patients

Ali 2009Gabapentin800mgs oralTransient decrease in systolic blood pressure in one patient



 

Appendix 9. Studies with high risk patients observing arrhythmias as outcome


Subgroup titleStudies

n
Experimental groupControl groupPeto Odds Ratio (95% CI)

Comments
P value






  EventsTotalEventsTotal  

Local anaesthetics2016216Only one study with positive outcome

Calcium channel blockers1015015-

Sympathetic blockers –

Beta Blockers
22494510.5 (0.09 2.79)0.43

Combined alpha and beta blocker1120210Only one study with positive outcome

Peripheral vasodilators1 015  0 15 - 

Centrally acting alpha agonists0      

Narcotics21814140.05 (0.01 to 0.43)0.007

ACE inhibitors0      

Miscellaneous1 0 16 0 14  



 

Appendix 10. Studies with high risk patients observing myocardial ischaemia as outcome

 


Subgroup title  Studies

n
Experimental group Control groupPeto Odds Ratio (95% CI)P value






  EventsTotalEventsTotal  

Local anaesthetics0      

Calcium channel blockers11515  - 

Sympathetic blockers  beta blockers6510971210.84 (0.24 to 2.96)0.1

Combined alpha and beta blockers0      

Peripheral vasodilators35345360.68 (0.12 to 3.79)0.66

Centrally acting alpha blockers0      

Narcotics228 27 - 

ACE inhibitors0      

Miscellaneous1016314Only one study with positive outcome



  

 

Contributions of authors

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

Conceiving the review: Fauzia Khan (FK)

Coordinating the review: FK

Undertaking manual searches: FK, Hameed Ullah (HU)

Screening search results: FK and HU

Organizing retrieval of papers: HU

Screening retrieved papers against inclusion and exclusion criteria: FK and HU

Appraising quality of papers: FK and HU

Abstracting data from papers: FK and HU

Writing to authors for additional information: FK

Data management for review: HU

Entering data into Review Manager: HU and FK

Review Manager statistical data: HU

Statistical analysis: HU

Interpretation of data: HU and FK

Writing the review: FK

Performing previous work that was foundation of present review: FK

Guarantor of the review: FK

Responsible for reading and checking review before submission: FK

 

Declarations of interest

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

Fauzia Khan: none known

Hameed Ullah: none known

 

Sources of support

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms
 

Internal sources

  • Resources from the Department of Anaesthesiology, Aga Khan University, Pakistan.

 

External sources

  • No sources of support supplied

 

Differences between protocol and review

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

1. Methods. Types of interventions.

ACE inhibitors and calcium channel blockers were added to the pharmacological groups.

2. Methods. Search methods for identification of studies.

a. The search period was extended to June 2011 and rerun in December 2012.

b. LILACS was not searched as it was not accessible to us.

3. Data collection and analysis

Exclusion criteria

a. Studies relating to haemodynamic responses and anaesthetic agents which form part of routine medications for example sedatives, induction agents, inhalational anaesthetics and muscle relaxants were not included

b. We excluded studies of haemodynamic response and tracheal intubation without use of muscle relaxants

c. We excluded studies of haemodynamic response and tracheal intubation which involved administration of induction agent with a controlled infusion pump

4. Criteria for assessing quality of studies

The recent Version 5.1.0. of the Cochrane Handbook for Systematic Reviews of Interventions (Chapter 8) was used for risk assessment, and 'Risk of bias' tables were generated (Higgins 2011).

5. Data collection

Interventions - codes were removed from the review as these were meant for data collection only

6. Authorship

Gary Kantor withdrew from the review after publication of the protocol (Khan 2003) and before the actual review was started

* Indicates the major publication for the study

References

References to studies included in this review

  1. Top of page
  2. Abstract
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies awaiting assessment
  20. Additional references
  21. References to other published versions of this review
Abdel-Razek 1991 {published data only}
  • Abdel-Razek A, El-Attar AM. Nifedipine versus fentanyl to prevent the pressor response to tracheal intubation. Middle East Journal of Anesthesia 1991;11:63-72. [PUBMED: 2067506]
  • Abdel-Razek A, El-Attar AM. Nifedipine versus fentanyl to prevent the pressor response to tracheal intubation. Middle East Journal of Anesthesia 1995;13:89-99. [PUBMED: 7565425]
Ali 2009 {published data only}
  • Ali AR, El Gohary M, Ashmawi HSE, El-Kerdawy HM, Essa HH. Efficacy of preoperative gabapentin in attenuation of neuroendocrine response to laryngoscopy and endotracheal intubation. Journal of Medical Science 2009;9:24-9.
Amar 1991 {published data only}
  • Amar D, Shamoon H, Frishman WH, Lazar EJ, Salama MD. Effects of labetalol on perioperative stress markers and isoflurane requirements. British Journal of Anaesthesia 1991;67:296-301. [PUBMED: 1911016]
Artru 1985 {published data only}
  • Artru AA, Strumwasser TA. Intratracheal aerosolized etidocaine to attenuate cardiovascular and cough responses to laryngoscopy and intubation. Annals of Emergency Medicine 1985;14:1069-73. [PUBMED: 4051271]
Asfar 1990 {published data only}
  • Asfar SN, Abdulla WY. The effect of various administration routes of lidocaine on hemodynamics and ECG rhythm during endotracheal intubation. Acta Anaesthesiologica Belgica 1990;41:17-24. [PUBMED: 2360387]
Atlee 2000 {published data only}
  • Atlee JL, Dhamee MS, Olund TL, George V. The use of esmolol, nicardipine, or their combination to blunt hemodynamic changes after laryngoscopy and tracheal intubation. Anesthesia and Analgesia 2000;90:280-5. [PUBMED: 10648307]
Bafna 2011 {published data only}
  • Bafna U, Goyal VK, Garg A. A comparison of different doses of gabapentin to attenuate the haemodynamic response to laryngoscopy and tracheal intubation in normotensive patients. Journal of Anaesthesiology Clinical Pharmacology 2011;27:43-6. [PUBMED: 21804705]
Bernstein 1989 {published data only}
  • Bernstein JS, Ebert TJ, Stowe DF, Schmeling WT, Nelson MA, Woods MP. Partial attenuation of hemodynamic responses to rapid sequence induction and intubation with labetalol. Journal of Clinical Anesthesia 1989;1:444-51. [PUBMED: 2696507]
Black 1984 {published data only}
Carabine 1991 {published data only}
Chraemmer-Jorgensen 1992 {published data only}
  • Chraemmer-Jørgensen B, Høilund-Carlsen PF, Bjerre-Jepsen K, Hertel S, Marving J, Strøm J, et al. Does alfentanil preserve left ventricular pump function during rapid sequence induction of anaesthesia?. Acta Anaesthesiologica Scandinavica 1992;36:362-8. [PUBMED: 1595343]
Crawford 1987 {published data only}
  • Crawford DC, Fell D, Achola KJ, Smith G. Effects of alfentanil on the pressor and catecholamine responses to tracheal intubation. British Journal of Anaesthesia 1987;59:707-12. [PUBMED: 3111508]
Cucchiara 1986 {published data only}
  • Cucchiara RF, Benefiel DJ, Matteo RS, DeWood M, Albin S. Evaluation of esmolol in controlling increases in heart rate and blood pressure during endotracheal intubation in patients undergoing carotid endarterectomy. Anesthesiology 1986;65:528-31. [PUBMED: 2877599]
Dahlgren 1981 {published data only}
Davies 1981 {published data only}
De Brujin 1987 {published data only}
  • De Brujin NP, Croughwell N, Reves JG. Hemodynamic effects of esmolol in chronically beat-blocked patients undergoing aortocoronary bypass surgery. Anesthesia and Analgesia 1987;66:137-41. [PUBMED: 2880530]
Denlinger 1974 {published data only}
Durrani 2000 {published data only}
  • Durrani M, Barwise JA, Johnson RF, Kambam JR, Janicki PK. Intravenous chloroprocaine attenuates hemodynamic changes associated with direct laryngoscopy and tracheal intubation. Anesthesia and Analgesia 2000;90:1208-12. [PUBMED: 10781481]
Ebert 1989 {published data only}
  • Ebert JP, Pearson JD, Gelman S, Harris C, Bradley EL. Circulatory responses to laryngoscopy: the comparative effect of placebo, fentanyl and esmolol. Canadian Journal of Anesthesia 1989;36:301-6. [PUBMED: 2566391]
Girard 1986 {published data only}
Hart 1989 {published data only}
  • Hart AP, Camporesi EM, Sell TL, Croughwell N, Silva R, Jones RH, et al. The effect of nitroglycerin on response to tracheal intubation. Assessment by radionuclide angiography. Anesthesia and Analgesia 1989;68:718-23. [PUBMED: 2500040]
Inada 1989 {published data only}
  • Inada E, Cullen DJ, Nemeskal AR, Teplick R. Effect of labetalol or lidocaine on the hemodynamic response to intubation: A controlled randomized double-blind study. Journal of Clinical Anesthesia 1989;1:207-13. [PUBMED: 2697239]
Iyer 1988 {published data only}
  • Iyer V, Russell WJ. Induction using fentanyl to suppress the intubation response in the cardiac patient: what is the optimal dose?. Anaesthesia and Intensive Care 1988;16:411-7. [PUBMED: 3232799]
Jakobsen 1992 {published data only}
  • Jakobsen CJ, Blom L. Effect of preoperative metoprolol on cardiovascular and catecholamine response and bleeding during hysterectomy. European Journal of Anaesthesiology 1992;9:209-15. [PUBMED: 1600972]
Kale 1988 {published data only}
Kay1987 {published data only}
Kaya 2008 {published data only}
Kindler 1996 {published data only}
  • Kindler CH, Schumacher PG, Schneider MC, Urwyler A. Effects of intravenous lidocaine and/or esmolol on hemodynamic responses to laryngoscopy and intubation: a double-blind, controlled clinical trial. Journal of Clinical Anesthesia 1996;8:491-6. [PUBMED: 8872690]
Ko 1998 {published data only}
  • Ko S, Kim D, Han Y, Song H. Small-does fentanyl: optimal time of injection for blunting the circulatory responses to tracheal intubation. Anesthesia and Analgesia 1998;86:658-61. [PUBMED: 9495433]
Koç 2007 {published data only}
  • Koç S, Memis D, Sut N. The preoperative use of gabapentin, dexamethasone, and their combination in varicocoele surgery: a randomised controlled trial. Anesthesia and Analgesia 2007;105:1137-42. [PUBMED: 17898401]
Korpinen 1995a {published data only}
Korpinen 1995b {published data only}
  • Korpinen R, Saarnivaara L, Siren K, Sarna S. Modification of the haemodynamic responses to induction of anaesthesia and tracheal intubation with alfentanil, esmolol and their combination. Canadian Journal of Anaesthesia 1995;48:298-304. [PUBMED: 7788827]
Lee 2011 {published data only}
  • Lee SH, Lee CJ, Kim TH, Shin BS, Lee SY, Joo EY, et al. Novel use of hydromorphone as a pretreatment agent: a double-blind, randomized, controlled study in adult Korean surgical patients. Current Therapeutic Research 2011;72:36-48.
Lindgren 1987 {published data only}
  • Lindgren L, Sarnivara L, Klemola UM. Protection by fentanyl against cardiac dysrhythmias during induction of anaesthesia. European Journal of Anaesthesiology 1987;4:229-33. [PUBMED: 3653018]
Maekawa 1992 {published data only}
  • Maekawa N, Mikawa K, Hasegawa M, Kaetsu H, Goto R, Yaku H, et al. Partial attenuation to the cardiovascular responses to tracheal intubation with oral nisoldipine. Journal of Clinical Anaesthesia 1992;4:297-300. [PUBMED: 1358133]
Maekawa 1993 {published data only}
Magnusson 1986 {published data only}
  • Magnusson J, Thulin T, Werner O, Jarhult J, Thomson D. Haemodynamic effects of pretreatment with metoprolol in hypertensive patients undergoing surgery. British Journal of Anaesthesia 1986;58:251-60. [PUBMED: 3511930]
Mahajan 1993 {published data only}
Maharaj 1983 {published data only}
  • Maharaj RJ, Thompson M, Brock-Utne JG, Williamson R, Downing JW. Treatment of hypertension following endotracheal intubation. A study comparing the efficacy of labetalol, practolol and placebo. South African Medical Journal 1983;63:691-4. [PUBMED: 17408055]
Mallon 1990 {published data only}
  • Mallon JS, Hew E, Wald R, Kapala D. Bolus doses of esmolol for the prevention of postintubation hypertension and tachycardia. Journal of Cardiothoracic Anesthesia 1990;4:27-30.
Memis 2006 {published data only}
  • Memis D, Turan A, Karamanlioqlu B, Seker S, Türe M. Gabapentin reduces cardiovascular responses to laryngoscopy and tracheal intubation. European Journal of Anaesthesia 2006;23:686-90. [PUBMED: 16805934]
Mikawa 1990a {published data only}
Mikawa 1990b {published data only}
Mikawa 1991a {published data only}
  • Mikawa K, Maekawa N, Goto R, Kaetsu H, Hasegawa M, Yaku H, et al. Effects of pindolol on the cardiovascular response to tracheal intubation. British Journal of Anaesthesia 1991;67:416-20. [PUBMED: 1931398]
Mikawa 1991b {published data only}
  • Mikawa K, Maekawa N, Kaetsu H, Goto R, Yaku H, Obora H. Effects of adenosine triphosphate on the cardiovascular response to tracheal intubation. British Journal of Anaesthesia 1991;67:410-5. [PUBMED: 1931397]
Mikawa 1992a {published data only}
  • Mikawa K, Maekawa N, Hasegawa M, Kaetsu H, Goto R Hideaki Y, et al. Effects of Nilvadipine on the cardiovascular responses to tracheal intubation. Journal of Clinical Anaesthesia 1992;4:292-6. [PUBMED: 1358132]
Mikawa 1992b {published data only}
  • Mikawa K, Hasegawa M, Suzuki T, Maekawa N, Kaetsu H, Goto R, et al. Attenuation of hypertensive response to tracheal intubation with nitroglycerin. Journal of Clinical Anesthesia 1992;4:367-71. [PUBMED: 1389189]
Mikawa 1993 {published data only}
  • Mikawa K, Maekawa N, Hasegawa M, Kaetsu H, Goto R, Yaku H, et al. Attenuation of the cardiovascular and catecholamine responses to tracheal intubation with oral guanabenz. Anesthesia and Analgesia 1993;76:585-91. [PUBMED: 8095779]
Mikawa 1994 {published data only}
Mikawa 1996 {published data only}
  • Mikawa K, Nishina K, Maekawa N, Obara H. Comparison of nicardipine, diltiazem and verapamil for controlling the cardiovascular responses to tracheal intubation. British Journal of Anaesthesia 1996;76:221-6. [PUBMED: 8777101]
Miller 1991 {published data only}
  • Miller DR, Martineau RJ, Hull KA, Hill J. Bolus administration of esmolol for controlling the hemodynamic response to laryngoscopy and intubation: The Canadian multicentre trial. Canadian Journal of Anaesthesia 1991;38:849-58. [: PMID 1683818]
Montazeri 2011 {published data only}
  • Montazeri K, Kashefi P, Honarmand A, Safavi M, Hirmanpour A. Attenuation of the pressor response to direct laryngoscopy and tracheal intubation: oral clonidine vs. oral gabapentin premedication. Journal of Research in Medical Sciences 2011;16:377-86. [PUBMED: 22247722]
Newsome 1986 {published data only}
  • Newsome LR, Roth JV, Hug CC Jr, Nagle D. Esmolol attenuates hemodynamic responses during fentanyl-pancuronium anesthesia for aortocoronary bypass surgery. Anesthesia and Analgesia 1986;65:451-6. [PUBMED: 3485937]
Oxorn 1990 {published data only}
Pouttu 1988 {published data only}
Puri 1986 {published data only}
  • Puri GD, Singh SP, Singh H, Batra YK. Attenuation of pulse rate and blood pressure-response to laryngoscopy and intubation with verapamil. Indian Journal of Medical Research 1986;84:548-51. [PUBMED: 3557578]
Puri 1998 {published data only}
  • Puri GD, Marudhachalam KS, Chari P, Suri RK. The effect of magnesium sulphate on haemodynamics and its efficacy in attenuating the response to endotracheal intubation in patients with coronary artery disease. Anesthesia and Analgesia 1998;87:808-11. [PUBMED: 9768774]
Quere 1990 {published data only}
  • Quere JF, Ozier Y, Bringier J, Morot B, Conseiller C. Does urapidil attenuate the blood pressure response to tracheal intubation for general anaesthesia. Drugs 1990;40:80-1. [PUBMED: 2092977]
Ryhanen 1977 {published data only}
  • Ryhanen P, Saarela E, Saukkonen J, Hollmen A. Circulatory responses to laryngoscopy and endotracheal intubation in patients with and without cardiovascular disease. Effect of prophylactic practolol. Annales Chirurgiae et Gynaecologiae 1977;66:294-8. [PUBMED: 603221]
Scheinin 1989 {published data only}
  • Scheinin B, Scheinin M, Vuorinen J, Lindgren L. Alfentanil obtunds the cardiovascular and sympathoadrenal responses to suxamethonium-facilitated laryngoscopy and intubation. British Journal of Anaesthesia 1989;62:385-92. [PUBMED: 2495811]
Sharma 1995 {published data only}
  • Sharma S, Ghani AA, Win N, Ahmad M. Comparison of two bolus doses of esmolol for attenuation of haemodynamic response to tracheal intubation. Medical Journal of Malaysia 1995;50:372-6. [PUBMED: 8668059]
Singh 1995 {published data only}
  • Singh H, Vichitvejpaisal P, Gaines GY, White PF. Comparative effects of lidocaine, esmolol, and nitroglycerin in modifying the hemodynamic response to laryngoscopy and intubation. Journal of Clinical Anesthesia 1995;7:5-8. [PUBMED: 7772359]
Sklar 1992 {published data only}
  • Sklar BZ, Lurie S, Ezri T, Krichelli D, Savir I, Soroker D. Lidocaine inhalation attenuates the circulatory response to laryngoscopy and endotracheal intubation. Journal of Clinical Anesthesia 1992;4:382-5. [PUBMED: 1389192]
Song 1997 {published data only}
  • Song D, Singh H, White PF, Gadhiali M, Griffin JD, Klein KW. Optimal dose of Nicardipine for maintenance of hemodynamic stability after tracheal intubation and skin incision. Anesthesia and Analgesia 1997;85:1247-51. [PUBMED: 9390588]
Splinter 1989 {published data only}
  • Splinter WM, Cervenko F. Haemodynamic responses to laryngoscopy and tracheal intubation in geriatric patients: effects of fentanyl, lidocaine and thiopentone. Canadian Journal of Anaesthesia 1989;36:370-6. [PUBMED: 2758537]
Stone 1988 {published data only}
  • Stone JG, Foex P, Sear JW, Johnson LL, Khambatta HJ, Triner L. Myocardial ischemia in untreated hypertensive patients: effect of a single dose of a beta adrenergic blocking agent. Anesthesiology 1988;68:495-500. [PUBMED: 2895596]
Sun 2009 {published data only}
  • Sun HL, Wu TJ, Ng CC, Chien CC, Huang CC, Chie WC. Efficacy of oropharyngeal lidocaine instillation on hemodynamic responses to orotracheal intubation. Journal of Clinical Anesthesia 2009;21:103-7. [PUBMED: 19329013]
Thomson 1984 {published data only}
  • Thomson IR, Mutch WA, Culligan JD. Failure of intravenous nitroglycerin to prevent intraoperative myocardial ischaemia during fentanyl-pancuronium anesthesia. Anesthesiology 1984;61:385-93. [PUBMED: 6435481]
Victory 1995 {published data only}
  • Victory RA, Gajraj NM, Pace NA, Ostman LP. Nebulized bupivacaine attenuates the heart rate responses following tracheal intubation. Journal of Clinical Anaesthesia 1995;7:9-13. [PUBMED: 7772369]
Wang 2003 {published data only}
  • Wang YM, Chung KC, Lu HF, Huang YW, Lin KC, Yang LC, et al. Lidocaine: the optimal timing of intravenous administration in attenuation of increase of intraocular pressure during tracheal intubation. Acta Anaesthesiologica Sinica 2003;41:71-5. [PUBMED: 12934420]
White 2003 {published data only}
  • White PF, Wang B, Tang J, Wender RH, Naruse R, Sloninsky A. The effect of intraoperative use of esmolol and nicardipine on recovery after ambulatory surgery. Anesthesia and Analgesia 2003;97:1633-8. [PUBMED: 14633533]
Zargar 2002 {published data only}
  • Zargar JA, Naqash IA, Gurcoo SA. Comparative evaluation of the effect of metoprolol and esmolol on rate pressure product and ECG changes during laryngoscopy and endotracheal intubation in controlled hypertensives patients. Indian Journal of Anaesthesia 2002;46:365-8.

References to studies awaiting assessment

  1. Top of page
  2. Abstract
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies awaiting assessment
  20. Additional references
  21. References to other published versions of this review
Adams 1987 {published data only}
  • Adams HA, von Bormann B, Bachmann B, Ratthey K, Hempelmann G. The endocrine stress-reaction to orotracheal intubation and topical anesthesia with lidocaine. Anaesthesist 1987;36:468-73. [PUBMED: 3688417]
Ay 1999 {published data only}
  • Ay B, Ati Z, Tezcan H, Bekiroglu N, Gogus FY. Can alfentanil or diltiazem prevent myocardial ischemia due to tracheal intubation?. Marmara Medical Journal 1999;12:7-10.
Bhawna 2012 {published data only}
  • Bhawna R, Gupta K, Agarwal S, Jain M, Chauhan H. Oral pregabalin premedication for attenuation of hemodynamic pressor response of airway instrumentation during general anaesthesia: A dose response study. Indian Journal of Anaesthesia 2012;56(1):49-54. [PUBMED: 22529420]
Cao 1995 {published data only}
  • Cao JS, Huang HB, Cheng HZ, Cheng MS, Wang LS. Inhibitory effect of combination of nicardipine and fentanyl on circulatory response to endotracheal intubation. Chinese Journal of Anesthesiology 1995;15:503-5.
Chao 1990 {published data only}
  • Chao JS, Cheng MS. Clinical observation of the using nitroglycerine through nose to prevent the adverse-effect during tracheal intubation. Chinese Journal of Anesthesiology 1990;10:233-4.
Do 2012 {published data only}
  • Do H, Kim SY, Heo S, Park S. The effect of intravenous labetalol administration on hemodynamic responses during desflurane inhalation. Korean Journal of Anesthesiology 2012;62(3):245-50. [PUBMED: 22474551]
Eerola 1971 {published data only}
  • Eerola R, Salmenpera A, Scharlin M. The effect of topical analgesia of the larynx on electrocardiographic changes during induction. Annals of Clinical Research 1971;3:204-6. [PUBMED: 5093152]
El-Tahan 2012 {published data only}
  • el-Tahan MR, Mowafi HA, Al Shiekh IH, Khidr AM, Al-Juhaiman RA. Efficacy of dexmedetomidine in suppressing cardiovascular and hormonal responses to general anaesthesia for caesarian delivery: a dose response study. International Journal of Obstetric Anaesthesia 2012;21:2221-9. [PUBMED: 22681971]
Fujii 1995 {published data only}
  • Fujii Y, Tanaka H, Saitoh Y, Toyooka H. Effects of calcium channel blockers on circulatory response to tracheal intubation in hypertensive patients: nicardipine versus diltiazem. Canadian Journal of Anaesthesia 1995;42:785-8. [PUBMED: 7497558]
Gupta 2011 {published data only}
  • Gupta K, Sharma D, Gupta PK. Oral premedication with pregabalin or clonidine for hemodynamic stability during laryngoscopy and laparoscopic cholecystectomy: A comparative evaluation. Saudi Journal of Anaesthesia 2011;5(2):179-84. [PUBMED: 21804800]
Heinrichs 1989 {published data only}
  • Heinrichs W, Fauth U, Tzanova I, Karim S, Halmágyi M. The effect of nifedipine and fentanyl on changes in the circulatory reaction to endotracheal intubation. Anaesthesist 1989;38:466-75. [PUBMED: 2686488]
Hoda 2011 {published data only}
  • Hoda A, Khan FA. Effect of one minimum alveolar concentration sevoflurane with and without fentanyl on hemodynamic response to laryngoscopy and tracheal intubation. Journal of Anaesthesiology Clinical Pharmacology 2011;27(4):522-6. [PUBMED: 22096288]
Hu 1990 {published data only}
  • Hu XG, Wang MD. Lightening the cardiovascular responses by drooping nitroglycerine in nose during tracheal intubation. Chinese Journal of Anesthesiology 1990;10:301-2.
Hu 1993 {published data only}
  • Hu YP, Pu HZ, Lu LH, Pan HQ, Lu XA. Comparison of captopril and nifedipine on preventing cardiovascular effects of the aged hypertensive patients induced by tracheal intubation. Chinese Journal of Anesthesiology 1993;13:133-5.
Ishikawa 2012 {published data only}
  • Ishikawa K, Shirakawa K, Nagao M, Yamaguchi S. Comparison of remifentanil and landiolol on hemodynamic and catecholamine responses to tracheal intubation. Dokkyo Journal of Medical Sciences 2012;39(1):1-8.
Pan 1997 {published data only}
  • Pan NL, Wang RM, Du XM, Pan XM, Liu JW, Zhou PZ. Influences of sufentanil on hemodynamics, blood sugar, cortisol and insulin during intratracheal intubation. Chinese Journal of Anesthesiology 1997;17:160-1.
Perez 1991 {published data only}
  • Perez JM, Olmedilla L, Jimeno C. Effect of intravenous bolus of nitroglycerin on the hemodynamic consequences of laryngoscopy and tracheal intubation. Revista Espanola de Anestesiologia Reanimacion 1991;38:234-7.
Roelofse 1987 {published data only}
  • Roelofse JA, Shipton EA, Joubert JJ, Grotepass FW. A comparison of labetalol, acebutolol, and lidocaine for controlling the cardiovascular responses to endotracheal intubation for oral surgical procedures. Journal of Oral and Maxillofacial Surgery 1987;45:835-41. [PUBMED: 3477619]
Sulaiman 2012 {published data only}
  • Sulaiman S, Karthekeyan RB, Vakamudi M, Sundar AS, Ravullapalli H, Gandham R. The effects of dexmedetomidine on the attenuation of stress response to endotracheal intubation in patients undergoing elective off pump coronory artery bypass grafting. Annals of Cardiac Anaesthesia 2012;15(1):39-43. [PUBMED: 22234020]
Tang 1995 {published data only}
  • Tang LY, Luo HY, Gao CS. Clinical study of preventive effects of low-dose fentanyl and different doses of lidocaine on hemodynamic responses to endotracheal intubation for patients over 60 years. Chinese Journal of Anesthesiology 1995;15:36-7.
Wang 1995 {published data only}
  • Wang ML, Zeng BX, Liu JJ, Zhan XM. Protective effect of clonidine on stress response to endotracheal intubation. Chinese Journal of Anesthesiology 1995;15:134-6.
Xu 1994 {published data only}
  • Xu GZ, Liu HW, Fu W, Wang JK, Sheng ZR. The effect of tramadol on cardiovascular responses during tracheal intubation. Chinese Journal of Anesthesiology 1994;14:27-9.
Ye 1993 {published data only}
  • Ye T, Luo A, Ren H, Xu J, Gao M. Preliminary report on cardiovascular responses to urapidil during intubation and extubation. Chinese Medical Science Journal 1993;8:240-2. [PUBMED: 8032072]
Zhang 1992 {published data only}
  • Zhang SL, Yu RY, Zhang JZ, Zhang YQ, Zu FP. The effect of magnesium sulphate on the prevention in circulatory responses by tracheal intubation. Chinese Journal of Anesthesiology 1992;13:300-2.
Zhao 1994 {published data only}
  • Zhao YL, Cheng T, Fan YL, Qi TH, Chen BL. Fentanyl and urapidil used in preventing cardiovascular reaction during tracheal intubation of old patients. Chinese Journal of Anesthesiology 1994;14:281-3.
Zhao 1996 {published data only}
  • Zhao K. Effects of nifedipine on stress responses to endotracheal intubation, a randomised placebo-controlled clinical study. Chinese Journal of Anesthesiology 1996;16:73.
Zhao 1998 {published data only}
  • Zhao WH, Lu ZH, He RZ, Gao CR. Effects of esmolol on haemodynamics during tracheal intubation. Chinese Journal of Anesthesiology 1998;18:363-4.
Zsigmond 1988 {published data only}
  • Zsigmond EK, Barabas E, Korenaga GM. Esmolol attenuates tachycardia caused by tracheal intubation: a double-blind study. International Journal of Clinical Pharmacology, Therapy, and Toxicology 1988;26:225-31. [PUBMED: 2900819]

Additional references

  1. Top of page
  2. Abstract
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies awaiting assessment
  20. Additional references
  21. References to other published versions of this review
Bruder 1992
  • Bruder N, Ortega D, Granthill C. Consequences and prevention methods of hemodynamic changes during laryngoscopy and intratracheal intubation. Annales Françaises d'Anesthésie et de Réanimation 1992;11:57-71. [PUBMED: 135981]
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