Description of the condition
Coronary artery disease is the most common cardiac disease with approximately 500,000 new and 300,000 recurrent events each year in the United States alone (Boland 2002), making this disease one of the greatest public health concerns worldwide. In Brazil, 16,821 cardiac surgical procedures were performed in 2008 (Datasus 2009), and more than 30,000 patients undergo heart procedures in the United Kingdom each year (CQC 2012). In the United States, 405,000 inpatient coronary artery bypass graft (CABG) procedures were undertaken in 2007 (Hall 2010).
CABG is most commonly performed with the assistance of cardiopulmonary bypass ('on-pump’ CABG), in which a device, rather than the heart, pumps blood for circulation. However, an increasing number of cardiac surgical procedures are being performed 'off-pump', that is without cardiopulmonary bypass (Connolly 2000; Polomsky 2012; Taggart 2012). Coronary artery surgery aims to relieve symptoms but risks complications that might affect organs such as the lung (Freitas 2012; Staton 2005), kidney (Conlon 1999; Nezami 2012; van Straten 2010), brain (Bayram 2012; Kozora 2010; Selim 2007; Senay 2011) and heart itself (Hong 2012; Mair 2005; Onorati 2005). The individual response to surgery and clinical manifestations of postoperative complications appear to be influenced by gender, genetic factors (Wang 2005) and previous comorbidities (Khot 2003) such as renal dysfunction (Edwards 1998; Rosamond 2007).
Description of the intervention
Intravenous or inhalational techniques may be used to administer anaesthesia to patients undergoing CABG. Inhalational anaesthesia is achieved by means of volatile drugs administered by calibrated vaporizers that determine the concentration administered into the respiratory system; these drugs act on specific sites in the central nervous system after being absorbed into the bloodstream. Intravenous anaesthesia allows rapid onset and recovery. Continuous infusions of intravenous agents may be given using pumps, an approach that compares favourably with the inhalational technique.
How the intervention might work
Inhalation anaesthetics such as isoflurane, desflurane and sevoflurane have been shown to depress myocardial contractility in animal and human studies, and their haemodynamic effects have been observed in humans with or without heart disease (Pagel 2009). However, there is also evidence to suggest that inhalational anaesthetics may have cardioprotective properties (Pagel 2012). Two reviews of the MEDLINE and Science Citation Index databases, respectively, reported that sevoflurane and desflurane reduce biomarkers of cardiac injury in the postoperative period and that sevoflurane improves long-term outcomes (Landoni 2007; Yu 2006). Furthermore, a systematic review comparing inhalational with intravenous anaesthesia for CABG surgery found that the use of volatile agents was associated with lower serum troponin I concentrations (indicating a potential reduction in cardiac injury) and also a reduced length of hospital stay (Symons 2006).
Several experimental studies using a variety of protocols have shown that anaesthetic agents protect against ischaemia and reperfusion injury (Bland 1976; De Hert 2004; De Hert 2005; Freedman 1985). Several groups have reported that inhalational anaesthetics confer organ protection through this mechanism, and it has been proposed that there are similarities between pharmacological preconditioning afforded by halogenated anaesthetics and ischaemic preconditioning (Lorsomradee 2008).
Intravenous anaesthesia allows rapid onset and recovery; and continuous infusions of intravenous agents may be given using pumps, an approach that compares favourably with the inhalational technique. In total intravenous anaesthesia, the most frequently used anaesthetic is lipophilic hypnotic propofol, which also has antioxidant properties.
Despite the evidence that inhalational anaesthetics protect the myocardium, some studies have suggested otherwise (Felhahi 2004; Pouzet 2002). However, other studies have shown the superiority of inhalational anaesthetics over intravenous anaesthetics by using biomarkers of myocardial injury (Conzen 2003; De Hert 2005; Guarracino 2006; Tritapepe 2006).
Why it is important to do this review
The outcome of this review will inform an approach that is likely to result in a large public health benefit. As the extent of cardioprotection is influenced by the choice of anaesthetic agent, identifying the best approach for patients undergoing on-pump or off-pump CABG will reduce complications and costs. While theoretical and laboratory evidence has suggested benefits with intravenous anaesthetics over inhalational anaesthetics, clear clinical benefits have not yet been demonstrated in the context of clinical trials.
To verify the efficacy and safe of intravenous versus inhalation anaesthesia in decreasing mortality and morbidity for patients undergoing on-pump or off-pump coronary artery bypass grafting (CABG).
Criteria for considering studies for this review
Types of studies
We will include randomized controlled trials (RCTs) and quasi-RCTs (RCTs in which allocation to treatment was obtained by alternation, use of alternate medical records, date of birth, or other predictable methods). We will exclude case series and case-control studies.
Types of participants
We will include adults (≥ 18 years old) undergoing on-pump or off-pump CABG, regardless of gender.
Patients having valve surgery and those who had central neuraxial blockade were excluded.
Those patients who were assigned to inhalation anaesthetic and those assigned to intravenous anaesthetic, whether or not they actually received the assigned treatment, will be considered in an intention-to-treat analysis.
We will also consider patients who receive intravenous anaesthetics for induction even when the patients were randomized to the volatile anaesthetic.
Types of interventions
- Intervention group: intravenous anaesthesia such as propofol or dexmedetomidine, etc.
- Control group: inhalation anaesthesia such as sevoflurane, isoflurane, desflurane, etc.
Types of outcome measures
a. Death within 24 hours of surgery
b. Death within 30 days of surgery
c. Death within 180 days of surgery
1. Renal insufficiency from the date of randomization, measured by neutrophil gelatinase-associated lipocalin (NGAL), 'Risk, Injury, Failure, Loss, End-stage' kidney disease (RIFLE), creatinine, cistatin or other.
2. Cardiac depression measured by haemodynamic variables.
3. Intraoperative awareness (as subsequently reported by the participant).
4. Length of stay in hospital.
5. Adverse postoperative outcomes:
- pneumonia, defined as an acute or chronic disease marked by inflammation of the lungs determined by clinical examination or x-ray, or both;
- stroke, defined as a sudden loss of brain function measured by magnetic resonance imaging (MRI) or computed tomography (CT);
- arrhythmia, defined as any abnormality in the rhythm of the heart measured by electrocardiogram or echocardiography;
- nausea and vomiting measured by frequency and severity;
- pain measured by any validated tool such as the visual analogue scale (VAS);
- brain injury measured by the Cerebral Performance Category (CPC) or other equivalent validated scales;
- heart failure, defined as the inability of the heart to pump blood, measured by clinical signs, x-ray, electrocardiogram or echocardiography;
- myocardial infarction, defined as sudden chest pain, shortness of breath, nausea and anxiety, determined by electrocardiogram, echocardiography, and various blood markers such as creatine kinase-MB and troponin;
- blood transfusion, defined as the need to receive blood products and determined by volume administered by body weight.
6. Hospital costs (descriptive narrative) analysed from any of the following perspectives: the insurer, hospital, individual, or society, as provided by the included studies.
Search methods for identification of studies
We will search the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, current issue), MEDLINE (OvidSP) (1966 to present), EMBASE (OvidSP) (1980 to present), LILACS (BIREME interface) (1982 to present), and ongoing trials databases such as http://www.controlled-trials.com/ and http://clinicaltrials.gov. We will combine the optimal MEDLINE, EMBASE and LILACS sensitive strategies for identification of RCTs (Dickersin 1994) with the following phrases and their synonyms: coronary diseases and coronary artery bypass grafting and intravenous anaesthesia and inhalation anaesthesia. The full search strategy can be found in Appendix 1.
We will not impose any language restrictions.
Searching other resources
We will scrutinize the references of the identified relevant studies for additional citations.
We will contact specialists in the area and the main authors of included trials for information on unpublished data.
We will contact pharmaceutical companies for further details of published and unpublished trials.
Data collection and analysis
Selection of studies
Two authors (MPM and MAM) will independently screen the trials identified by the literature search. We will resolve disagreements by consulting with the other authors (NM and RED) and consult with them for quality assurance of the processes.
Data extraction and management
Two authors (MPM and MAM) will independently extract data. We will resolve any discrepancies by discussion. We will use a standard data extraction form to extract the following information: characteristics of the study (design, methods of randomization); participants; interventions; outcomes (types of outcome measures, adverse events) (see Appendix 2). We will then check for errors before entering the data into RevMan.
Assessment of risk of bias in included studies
We will independently assess study quality (NM and RED) using the risk of bias approach for Cochrane reviews (Higgins 2011). We will use the following five separate criteria.
Random sequence generation
Was the allocation sequence adequately generated, for example with random number tables, computer-generated random numbers? We will record this as 'low risk of bias' (the method used is either adequate or unlikely to introduce confounding), 'uncertain risk of bias' (there is insufficient information to assess whether the method used is likely to introduce confounding), or 'high risk of bias' (the method used (for example quasi-randomized trials) is likely to introduce confounding).
Was allocation adequately concealed and in a way that would not allow either the investigators or the participants to know or influence allocation to an intervention group before an eligible participant was entered into the study (for example using central randomization or sequentially numbered, opaque, sealed envelopes held by a third party)? We will record this as 'low risk of bias' (the method used (for example central allocation) is unlikely to induce bias in the final observed effect), 'uncertain risk of bias' (there is insufficient information to assess whether the method used is likely to induce bias in the estimate of effect), or 'high risk of bias' (the method used (for example open random allocation schedule) is likely to introduce bias in the final observed effect).
Were the study participants and personnel blinded from knowledge of which intervention a participant received? We will note where there has been partial blinding (for example where it has not been possible to blind participants but where outcome assessment was carried out without knowledge of group assignment). We will record this as 'low risk of bias' (blinding was performed adequately, or the outcome measurement is not likely to be influenced by lack of blinding), 'uncertain risk of bias' (there is insufficient information to assess whether the type of blinding used is likely to introduce bias in the estimate of effect), or 'high risk of bias' (no blinding or incomplete blinding, and the outcome or the outcome measurement is likely to be influenced by lack of blinding).
Incomplete outcome data
Were incomplete outcome data adequately addressed? Incomplete outcome data essentially include: attrition, exclusions, and missing data. If any withdrawals occurred, were they described and reported by treatment group with reasons given? We will record whether or not there were clear explanations for withdrawals and dropouts in the treatment groups. An example of an adequate method to address incomplete outcome data is the use of an intention-to-treat analysis (ITT). This item will be recorded as 'low risk of bias' (the underlying reasons for missingness are unlikely to make treatment effects depart from plausible values, or proper methods have been employed to handle missing data), 'uncertain risk of bias' (there is insufficient information to assess whether the missing data mechanism in combination with the method used to handle missing data is likely to introduce bias in the estimate of effect), or 'high risk of bias' (the crude estimate of effects (for example complete case estimate) will clearly be biased due to the underlying reasons for missingness, and the methods used to handle missing data are unsatisfactory).
Are reports of the study free from any suggestion of selective outcome reporting? This will be interpreted as no evidence that statistically non-significant results might have been selectively withheld from publication, for example selective under-reporting of data or selective reporting of a subset of data. We will record this as 'low risk of bias' (the trial protocol is available and all of the trial’s prespecified outcomes that are of interest in the review have been reported, or similar), 'uncertain risk of bias' (there is insufficient information to assess whether the magnitude and direction of the observed effect is related to selective outcome reporting), or 'high risk of bias' (not all of the trial’s prespecified primary outcomes have been reported, or similar).
We will consider trials which are classified as low risk of bias in sequence generation, allocation concealment, blinding, incomplete data and selective outcome reporting as low bias-risk trials. We will record this information for each included trial in ’Risk of bias’ tables in RevMan 5 (RevMan 5.1) and summarize the risk of bias for each study in a summary ’Risk of bias’ figure and graph.
Measures of treatment effect
(a) Binary outcomes
For dichotomous data, we will use the relative risk (RR) as the effect measure with 95% confidence interval (CI).
(b) Continuous outcomes
For continuous data, we will present the results as mean differences (MD) with 95% CIs. When pooling data across studies we will estimate the MD if the outcomes are measured in the same way between trials. We will use the standardized mean difference (SMD) to combine trials that measure the same outcome but use different methods.
Unit of analysis issues
The unit of analysis will be each patient recruited into the trials.
Dealing with missing data
An intention-to-treat analysis (ITT) is one in which all the participants in a trial are analysed according to the intervention to which they were allocated, whether they received the intervention or not. We will impute an outcome for a dropout rate of 5%. We will assume that participants who dropped out present the worst outcome. For each trial we will report whether or not the investigators stated if the analysis was performed according to the ITT principle. If participants were excluded after allocation, we will report any details provided in full. Therefore, we will perform the analysis on an ITT basis (Newell 1992) whenever possible. Otherwise, we will adopt the per protocol analysis.
Assessment of heterogeneity
We will look for clinical heterogeneity by examination of the study details then test for statistical heterogeneity between trial results using the Chi
• 0 to 40%, might not be important;
• 30% to 60%, may represent moderate heterogeneity;
• 50% to 90%, may represent substantial heterogeneity;
• 75% to 100%, considerable heterogeneity.
If substantial heterogeneity exists we will not combine the studies but will provide a descriptive summary of results.
Assessment of reporting biases
Apart from assessing the risk of selective outcome reporting, considered under assessment of risk of bias in included studies, we will assess the likelihood of potential publication bias using funnel plots provided that there are at least 10 trials. When small studies in a meta-analysis tend to show larger treatment effects, other causes will be considered including: selection biases, poor methodological quality, heterogeneity, artefactual and chance.
We will use Review Manager (RevMan 5.1), the statistical program of The Cochrane Collaboration. We will use the random-effects model unless there are fewer than three trials, in which case we may use the fixed-effect model. If there is significant clinical or methodological heterogeneity, we will not perform any statistical analysis to synthesize the results.
We will consider costs only as a narrative description in the discussion section.
Subgroup analysis and investigation of heterogeneity
In the case of excessive clinical heterogeneity (I
- different type of inhalation anaesthetics (such as isoflurane, sevoflurane, desflurane);
- different type of intravenous anaesthetics (such as propofol, dexmedetomidine);
- comorbidities (diabetes, hypertension, endocrinopathies, etc.);
- age (≥ 18 to 60 years old versus > 60 years old).
If there are an adequate number of studies, we will perform a sensitivity analysis for the primary outcome (that is death) to evaluate the effect on the results of studies with a high risk of bias.
Summary of findings tables
We will use the principles of the GRADE system (Guyatt 2008) to assess the quality of the body of evidence associated with specific outcomes (death-related anaesthesia and cardiac depression) in our review and construct a summary of findings (SoF) table using the GRADE software. The GRADE approach appraises the quality of a body of evidence based on the extent to which one can be confident that an estimate of effect or association reflects the item being assessed. The assessment of the quality of a body of evidence considers within study risk of bias (methodologic quality), the directness of the evidence, heterogeneity of the data, precision of effect estimates and risk of publication bias.
We would like to thank Jane Cracknell; Mark Neuman (content editor); Nathan Pace (statistical editor); Monty Mythen, Stefan De Hert and R Peter Alston (peer reviewers) for their help and editorial advice during the preparation of this protocol for the systematic review.
Appendix 1. Search strategy for MEDLINE (OvidSP)
1 exp Myocardial Revascularization/ or (myocard* adj4 revascular*).af. or Internal Mammary Artery Implantation.mp.
2 exp Anesthesia, Inhalation/ or exp Anesthesia, Intravenous/ or exp Isoflurane/ or exp Propofol/ or Hydrocarbons, Fluorinated/ or Halothane/ or (isoflurane or sevoflurane or sevorane or halothane or ftorotan* or narcotan or ultane or 1,1,1-trifluoro-2-chloro-2-bromoethane or fluothan* or enfluran* or etran or ethrane or enlirane or enfran or propofol* or 2,6?diisopropylphenol or disoprofol or diprivan or ici?35?868 or recofol or aquafol).mp. or (an?esth* adj3 (insufflation or inhalation or intravenous)).ti,ab.
3 1 and 2
4 ((randomized controlled trial or controlled clinical trial).pt. or randomized.ab. or placebo.ab. or drug therapy.fs. or randomly.ab. or trial.ab. or groups.ab.) not (animals not (humans and animals)).sh.
5 3 and 4
Appendix 2. Data extraction form
1. General Information
2. Study Eligibility
3. Population and setting
5. Risk of Bias assessment
Provide overall data and, if available, comparative data for each intervention or comparison group.
7. Intervention groups
Copy and paste table for each intervention and comparison group
Intervention Group 1: Intravenous anaesthesia
Control group Group 2: Inhalation anaesthesia
Primary outcome 1a. death-related anaesthesia (at perioperative and/or at first postoperative day); 1b. death (at one month); 1c. mortality rate (at six months).
Primary outcome 2. cardiac depression measured by haemodynamic instability variables.
Secondary outcome 1. renal insufficiency from the date of randomization measured by neutrophil gelatinase-associated lipocalin (NGAL), rifle, creatinine, cistatin or other.
Secondary outcome 2. intraoperative awareness (as subsequently reported by the participant).
Secondary outcome 3. adverse postoperative outcomes, such as nausea and vomiting, pain, brain damage, heart failure, myocardial infarction, blood transfusion (analysed separately).
Secondary outcome 4. length of stay in hospital.
Secondary outcome 5. economic analysis (by narrative description).
10. Other information
Contributions of authors
Conceiving the review: Norma SP Módolo (NSPM)
Co-ordinating the review: Regina El Dib (RED)
Undertaking manual searches: Marília P Módolo (MPM), Marcos Marton (MM)
Screening search results: MPM, MM and Rodrigo Leal Alves (RLA)
Organizing retrieval of papers: MPM, MM and RLA
Screening retrieved papers against inclusion criteria: MPM and MM
Appraising quality of papers: NSPM and RED
Abstracting data from papers: MPM, MM, NSPM and RED
Writing to authors of papers for additional information: Leandro Globbo Braz (LGB)
Providing additional data about papers: LGB
Obtaining and screening data on unpublished studies: LGB
Data management for the review: NSPM and RED
Entering data into Review Manager (RevMan 5.1): NSPM and RED
RevMan statistical data: RED
Other statistical analysis not using RevMan: RED
Interpretation of data: NSPM and RED
Statistical inferences: NSPM and RED
Writing the review: NSPM, MPM, MM, LGB, RLA and RED
Securing funding for the review: NSPM
Performing previous work that was the foundation of the present study: NSPM
Guarantor for the review (one author): NSPM
Person responsible for reading and checking review before submission: NSPM and RED
Declarations of interest
Norma SP Módolo: none known
Marília P Módolo: none known
Marcos A Marton: none known
Leandro G Braz: none known
Rodrigo L Alves: none known
Regina El Dib: paid scientific advisor for Evidence-Based Medicine and director of the Systematic Review Unit of the Botucatu Medical School (FMB/UNESP)