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Epidural analgesia for cardiac surgery

  1. Vesna Svircevic1,*,
  2. Martijn M Passier1,
  3. Arno P Nierich2,
  4. Diederik van Dijk3,
  5. Cor J Kalkman1,
  6. Geert J van der Heijden4

Editorial Group: Cochrane Anaesthesia Group

Published Online: 6 JUN 2013

Assessed as up-to-date: 1 NOV 2012

DOI: 10.1002/14651858.CD006715.pub2


How to Cite

Svircevic V, Passier MM, Nierich AP, van Dijk D, Kalkman CJ, van der Heijden GJ. Epidural analgesia for cardiac surgery. Cochrane Database of Systematic Reviews 2013, Issue 6. Art. No.: CD006715. DOI: 10.1002/14651858.CD006715.pub2.

Author Information

  1. 1

    University Medical Center Utrecht, Department of Perioperative Care and Emergency Medicine, Utrecht, Netherlands

  2. 2

    Isala Clinics, Thoracic Anaesthesiology and Intensive care, Zwolle, Netherlands

  3. 3

    University Medical Center Utrecht, Division of Anesthesiology, Intensive Care and Emergency Medicine, Utrecht, Netherlands

  4. 4

    Academic Center for Dentistry Amsterdam (ACTA), Department of Social Dentistry, Amsterdam, Netherlands

*Vesna Svircevic, Department of Perioperative Care and Emergency Medicine, University Medical Center Utrecht, PO Box 85500, Mailstop E 03.511, Utrecht, 3508 GA, Netherlands. vesnasvircevic@hotmail.com. v.svircvic@umcutrecht.nl.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 6 JUN 2013

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Characteristics of included studies [ordered by study ID]
Bach 2002

MethodsRandomized controlled trial


Participants40 patients scheduled for elective coronary artery bypass grafting surgery. Exclusion criteria were impaired coagulation, allergies to local anaesthetics, corticoid medication, preoperative signs of infection, renal or liver failure, diabetes mellitus and an impaired left ventricular function (ejection fraction 50%)


InterventionsContinuous epidural infusion of bupivacaine 0.25% versus general anaesthesia group

The 13 patients received an epidural bolus of 10ml of bupivacaine 0.25% through the catheter followed by a continuous epidural infusion of bupivacaine 0.25% (Bupivacain 0.25%, Curasan Pharma AG, Kleinostheim, Germany) adjusted to body height for the whole observation period until 18h after surgery. The control group consists of 13 patients who received an intravenous dopexamine infusion beside general anaesthesia and 14 patients with general anaesthesia alone who received equal volumes of NaCl 0.9% intravenously as placebo in a time-matched fashion.


OutcomesInflammatory response

Mortality


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskOne day before surgery and after written informed consent was obtained, patients were randomly assigned to the study groups by drawing lots

Allocation concealment (selection bias)Unclear riskDrawing lots

Blinding (performance bias and detection bias)
All outcomes
High risk

Incomplete outcome data (attrition bias)
All outcomes
High riskOne patient of the control group was excluded during the study. He died 8h after surgery as a result of a non-occlusive ischaemia of the small intestine. All other patients who were initially included terminated the study.

Selective reporting (reporting bias)Low riskAppears to be free of other sources of bias

Bakhtiary 2007

MethodsRandomized controlled trial


Participants132 patients with symptomatic coronary artery disease were prospective enrolled in this study. All patients underwent elective OPCAB surgery and were randomized to receive either GA or combined GATEA. Patients with a history of atrial arrhythmias, those undergoing emergency operations, and patients requiring intraoperative inotropic support were excluded from this study.


InterventionsGeneral anaesthesia only or combined general anaesthesia with high thoracic epidural analgesia (66 patients in each group)

TEA: a continuous epidural infusion with ropivacaine 0.16% and sufentanil 1 g/mL at an hourly rate of 2 to 5 mL was started after a bolus dose of 6 mL to provide intraoperative analgesia. GA: propofol (1.5 mg/kg) and remifentanil (1 ug/kg) administered over 120 seconds. After loss of eyelash reflex, 0.1 mg/kg of cisatracurium was administered to facilitate tracheal intubation. Anaesthesia was maintained with continuous infusion of propofol (50-100 ug/kg/min) and remifentanil (0.1-0.3 ug/kg/min). Patients undergoing GA without TEA received intravenous metamizole (Novalgin; Aventis Pharma, Bad Soden, Germany), a peripheral analgesic derived from pyrazolone acid, 15 mg/kg, before skin incision. Intravenous piritramide, a-receptor agonist with a potency of 0.7 compared with morphine, 0.1 mg/kg, was administered after completion of coronary anastomosis and repeated during wound closure.


OutcomesMortality
Myocardial infarction
Supraventricular tachyarrhythmias


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskPatients were randomized to receive either GA or combined GATEA

Allocation concealment (selection bias)Unclear riskNot stated

Blinding (performance bias and detection bias)
All outcomes
High risk

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll pre-specified outcomes reported

Selective reporting (reporting bias)Low riskAppears to be free of other sources of bias. Sample size calculation not stated

Barrington 2005

MethodsRandomized controlled trial


Participants120 patients scheduled for elective coronary artery bypass grafting surgery

All patients scheduled for elective CABG surgery (using cardiopulmonary bypass (CPB)) were eligible. Exclusion criteria were emergency or repeat CABG surgery, combined valve and CABG surgery, aspirin ingestion within 6 days of surgery, a platelet count 150x109/L, an international normalized ratio 1.1, active neurological disease, and cutaneous disorders at the epidural insertion site.


InterventionsGeneral anaesthesia only or combined general anaesthesia with high thoracic epidural analgesia (ropivacaine 1%; 60 patients in each group)

epidural block was established with 5 mL of ropivacaine 1% and fentanyl 50 ug. If required, the block was extended with 2 mL of ropivacaine 1%.

GA was induced with midazolam (0.05 - 0.1 mg/kg), fentanyl (7-15 ug/kg for the GA group and 5-7 ug/kg for the HTEA group), propofol (20 mg increments as required), and rocuronium (0.6 mg/kg). GA was maintained with propofol 3-6 mg/kg/hr. Further doses of rocuronium 10 mg were given only for overt patient movement, with no additional rocuronium given after CPB.


OutcomesMortality
Myocardial infarction
Supraventricular tachyarrhythmias
Stroke

Respiratory complications


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskPatients were randomized the day before surgery to two groups. The random allocation sequence was computer-generated in permuted blocks of four and enclosed in sequentially numbered opaque sealed envelopes.

Allocation concealment (selection bias)Low riskOpaque sealed envelopes

Blinding (performance bias and detection bias)
All outcomes
High risk

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll patients were included in the intention to treat analysis; all pre-specified outcomes reported

Selective reporting (reporting bias)Low riskAppears to be free of other sources of bias. A formal sample size determination was not possible because primary endpoint data were not available at the time of study inception. The confidence intervals between groups were calculated post hoc to assess the precision of the data and the adequacy of sample size

Berendes 2003

MethodsRandomized controlled trial


Participants73 patients scheduled for coronary artery bypass who had left ventricular ejection fraction of 50% or more

Eligible patients had coronary artery disease with a left ventricular function of 50% or more and were scheduled for elective CABG. Exclusion criteria were any pre-existing endocrinological diseases, renal insufficiency, coagulation disorders or right and/or left ventricular dysfunction, concomitant disorders of heart valves, having undergone cardiac surgical procedures, acute myocardial infarction and heart failure.


InterventionsGeneral anaesthesia only (37 patients) or combined general anaesthesia with high thoracic epidural analgesia (36 patients) (bupivacaine and sufentanil)

correct position of the epidural was tested by 2 ml of bupivacaine 0.5% with epinephrine. Before induction high TEA was initiated by 6-12 mL of bupivacaine 0.5% and 15-25 ug sufentanil. General anaesthesia was induced in all patients with midazolam 0.1 mg/kg IV and pancuronium 0.1 mg/kg. The GA group received propofol 1.5-3 mg/kg/hr and sufentanil 1-2 ug/kg/hr. In the TEA group they received propofol 1.5-3 mg/kg/hr supported by repetitive injections of sufentanil 0.2-1 ug/kg.


OutcomesMortality
Respiratory complications

Left ventricular function

Postoperative complications


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer-generated block randomization

Allocation concealment (selection bias)Low riskAdministered through a sequential opaque envelope technique

Blinding (performance bias and detection bias)
All outcomes
Unclear riskParticipants, staff and research personnel unblinded to the intervention. The investigator collected data, but was not involved in patient care or management

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll pre-specified outcomes reported

Selective reporting (reporting bias)Low riskAppears to be free of other sources of bias

Brix-Christensen 1998

MethodsRandomized controlled trial


Participants16 patients scheduled for elective coronary artery bypass grafting surgery

Patients with diabetes mellitus or cancer were excluded


InterventionsLow dose opioid anaesthesia (epidural: bupivacaine 2 mg/mL and fentanyl 5 ug/mL at 5 ml/hr)) and general inhalational anaesthesia with fentanyl (8 patients in each group)

In the TEA group 8 mL of bupivacaine 0.5 % was injected 30 mins before surgery. Peroperative a continuous epidural infusion was given with bupivacaine 2 mg/ ml and fentanyl 5ug/mL at 5 mL/hr. General anaesthesia was induced with midazolam 0.15 mg/kg and fentanyl 5ug/kg. Muscle relaxation was achieved with pancuronium 0.1mg/kg. Anaesthesia was maintained with enflurane 0.4-0.8%. In the high dose fentanyl group anaesthesia was induced with midazolam 0.15 mg/kg and fentanyl 50 ug/kg. Anaesthesia was maintained with enflurane, midazolam and sufentanil.


OutcomesMortality

Cytokine response


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskPatients were randomly allocated into two groups

Allocation concealment (selection bias)Unclear riskNot stated

Blinding (performance bias and detection bias)
All outcomes
High risk

Incomplete outcome data (attrition bias)
All outcomes
Low riskThe peri- and postoperative courses were uneventful for all patients. All data addressed

Selective reporting (reporting bias)Low riskAppears to be free of other sources of bias

Caputo 2009

MethodsRandomized controlled trial


Participants74 patients undergoing off-pump coronary artery bypass surgery


InterventionsThe anaesthetic technique consisted of premedication with benzodiazepines, and induction with intravenous infusion of propofol at 3 mg/kg/hr combined with fentanyl (10 to 20 g/kg). Neuromuscular blockade was achieved with 0.1 to 0.15 mg/kg pancuronium bromide or vecuronium.

Intervention (36 patients): bilateral neuraxial block was established from T1 to T10 with an initial bolus of 5 mL bupivacaine 0.5% followed by another 5-mL bolus after 10 minutes. After induction of GA and when central haemodynamic status was stable, a continuous infusion of 0.125% bupivacaine and 0.0003% clonidine (150 g in 500 mL) was commenced at an initial rate of 10 mL/h

Control (38 patients): In the GA group, a patient-controlled analgesia intravenous morphine pump was started in the intensive care unit for 48 hours by using a 1 mg bolus dosing with a 5-minute lockout period


OutcomesMortality

Stroke

Myocardial infarction

Supraventricular arrhythmias


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskPatients were randomly assigned to receive either general anaesthesia only or general anaesthesia plus epidural. Random treatment allocations were generated by computer in advance of starting the study, using block randomization with varying block sizes. Allocation details were concealed in sequentially numbered opaque sealed envelopes.

Allocation concealment (selection bias)Low riskOpaque sealed envelopes

Blinding (performance bias and detection bias)
All outcomes
High risk

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll patients received the treatment allocated, all pre-specified outcomes reported

Selective reporting (reporting bias)Low riskAppears to be free of other sources of bias. Sample size calculation stated

Caputo 2011

MethodsTwo-centre, open, parallel-group, randomized controlled trial


Participants226 adults undergoing primary OPCAB surgery without the use of CPB and cardioplegic arrest


InterventionsIn both groups the induction with propofol at 0.5–1 mg/kg combined with fentanyl (10 –20g/kg). Neuromuscular blockade was achieved with 0.1–0.15 mg/kg pancuronium bromide or vecuronium. Anesthesia was maintained with either isoflurane at 0.8 –1.0 minimal anaesthetic concentration or intravenous propofol 3– 4 mg/kg/hr, at the discretion of the consultant anaesthetist. Patients in the GAE group had a thoracic epidural catheter sited in the operating theatre immediately before surgery at the T2–3 or T3–4 intervertebral space. Bilateral neuraxial block was established from T1 to T10 with an initial bolus of 5 mL bupivacaine, 0.5%, followed by another 5 mL bolus after 10 min. Determination of the spread of block was performed with ethyl chloride spray. After induction of GA and when central hemodynamic status was stable, a continuous infusion of 0.125% bupivacaine and 0.0003% clonidine (150 g in 500 mL) was commenced at an initial rate of 10 ml/hr.


OutcomesMortality
Myocardial infarction

Chest infections

Pain scores

Length of hospital stay

Arrhythmias

Stroke


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomized treatment allocations were generated using Stata version 8. They were stratified by consultant team with a 1:1 allocation using blocks of varying sizes.

Allocation concealment (selection bias)Low riskAllocation details were concealed in sequentially numbered, opaque sealed envelopes. These were prepared by the clinical trials and evaluation unit

Blinding (performance bias and detection bias)
All outcomes
High riskNot blinded

Incomplete outcome data (attrition bias)
All outcomes
Low riskThere were 18 protocol violations in patients allocated to GAE who received GA because the epidural could not be inserted

Selective reporting (reporting bias)Low riskAppears to be free of other sources of bias. Sample size calculation stated

de Vries 2002

MethodsRandomized controlled trial


Participants90 patients scheduled for elective minimally invasive direct coronary artery bypass surgery


Interventions30 patients had general anaesthesia and were extubated immediately after surgery (extubated group), 30 patients had a thoracic epidural (bupivacaine and sufentanil) and general anaesthesia and were extubated immediately after surgery (epidural group), and 30 patients had general anaesthesia and were ventilated after surgery (intubated group)

In the extubated group, at induction the patients received midazolam, 0.1 mg/kg, and sufentanil, 0.5 to 1 ug/kg. Anaesthesia was maintained with either isoflurane (0.5% to 0.8%) or propofol (3 to 5 mg/kg/hr) with incremental supplements of sufentanil (25 to 50 g) when the mean arterial pressure (MAP) exceeded baseline values by 20%.

In the epidural group, a thoracic epidural catheter was inserted at the T3-4 level before induction of anaesthesia. Anaesthesia was induced with midazolam, 0.1 mg/kg, and sufentanil, 0.5 to 1 g/kg. Through the epidural catheter, 8 to 10 mL of bupivacaine 0.25% with sufentanil, 25 ug/10 mL, were given 10 minutes before the start of surgery. Anaesthesia was maintained as in the extubated group. In the intubated group, induction of anaesthesia was performed with midazolam and sufentanil as previously reported.15 Briefly, midazolam, 0.1 mg/kg, and sufentanil, 1.5 ug/kg, were slowly infused over 5 minutes. Anaesthesia was maintained with continuous infusions of midazolam and sufentanil at a rate of 2 ug/kg/min for midazolam and 1 ug/kg/hr for sufentanil. In all groups, pancuronium, 0.1 mg/kg, was administered to facilitate endotracheal intubation.

In the extubated group and in the intubated group, postoperative analgesia was given on patient request with piritramide, 0.2 mg/kg intramuscularly. In the epidural group, a continuous infusion of bupivacaine 0.125% and sufentanil, 25 ug/50 mL, was given at 8 to 10 mL/hr. All groups received additional paracetamol suppositories, 1g 4 times daily.


OutcomesMortality
Myocardial infarction or ischaemia (ST segment analysis)
Haemodynamics: MAP and heart rate

Pain scores

Length of hospital stay


NotesMIDCAB surgery


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"90 patients were randomly divided into 3 groups"

Allocation concealment (selection bias)Unclear riskNot stated

Blinding (performance bias and detection bias)
All outcomes
High risk

Incomplete outcome data (attrition bias)
All outcomes
Low riskFive patients were excluded from analysis: three because of surgical reasons and in two patients the epidural technique failed

Selective reporting (reporting bias)Low riskAppears to be free of other sources of bias. Sample size calculation stated

El-Baz 1987

MethodsRandomized controlled trial


Participants60 patients, aged 34 to 76 years, after coronary artery bypass surgery (one to four grafts)


InterventionsIV opioids or low dose continuous opioid epidural analgesia (morphine 0.1 mg/mL at 1 mL/hr) with 30 patients in each group.

General anaesthesia was induced with pentothal 3-4 mg/kg followed by succinylcholine 1-2 mg/kg. Anaesthesia was maintained with a nitrous-oxide-oxygen-halothane gas mixture. Pancuronium 0.1-0.2 mg/kg was used for muscle relaxation to facilitate control of ventilation.

The control group received morphine 2 mg/2 hr and as needed. The epidural group received a continuous epidural infusion of 0.1 mg morphine/hr, this was supplemented by 2 mg IV as needed.


OutcomesMortality
Respiratory function

Cardiovascular parameters

Pain relief


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Patients were randomly divided into two equal groups of 30 patients"

Allocation concealment (selection bias)Unclear riskNot stated

Blinding (performance bias and detection bias)
All outcomes
High risk

Incomplete outcome data (attrition bias)
All outcomes
Low riskAppears have no incomplete outcome data

Selective reporting (reporting bias)Low riskAppears to be free of other sources of bias

Fillinger 2002

MethodsRandomized controlled trial


Participants60 patients scheduled for elective coronary artery bypass

Patients scheduled for elective CABG surgery were considered eligible for inclusion in the study in the absence of any specific contraindication to the use of EAA (heparin or warfarin (Coumadin (Endo Laboratories Inc, Wilmington, DE)) anticoagulation, pre-existing coagulopathy, infection at insertion site, or septicaemia).


InterventionsGeneral anaesthesia with IV morphine or combined general anaesthesia with high thoracic epidural analgesia (bupivacaine 0.5% at 4-10 mL/hr) with 30 patients in each group.

On arrival in the operating room, intravenous sedation was initiated with incremental doses of fentanyl ≤2 ug/kg, and midazolam, 0≤.05 mg/kg. GA was induced in all patients with intravenous fentanyl (5 to 20 g/kg total), midazolam (0.1 mg/kg), thiopental (1 to 2 mg/kg), and pancuronium or vecuronium for muscle relaxation and tracheal intubation. Inhaled isoflurane was used for anaesthesia maintenance. Muscle relaxation was reversed at the end of the operation with neostigmine and glycopyrrolate.

For participants randomized to receive TEAA, a thoracic epidural catheter was inserted after vascular catheter placements and before induction of GA. After a negative epidural test dose of 3 mL of 1.5% lidocaine with 1:200,000 epinephrine, the epidural catheter was injected with preservative-free morphine, 20 ug/kg, and 0.5% bupivacaine, in 5 mg increments, to a total loading dose of 25 to 35 mg of bupivacaine. Then the epidural catheters were continuously infused with 0.5% bupivacaine with morphine, 25 ug/mL, at 4 to 10 mL/hr beginning after the induction of GA. Clinical signs of inadequate epidural analgesia (haemodynamic response to surgical stimulation) during surgery were managed with a 3 mL bolus of the infusion solution followed by an increase in the infusion rate of 1 mL/hr (to a maximum of 10 mL/hr).

After surgery: patients in the GA group received intravenous morphine for postoperative analgesia according to a standard CTICU protocol, whereas patients in the TEAA group received an epidural infusion of 0.125% bupivacaine with morphine, 25 ug/mL, at 4 to 10 mL/h.


OutcomesMortality
Myocardial infarction
Supraventricular tachyarrhythmias
Stroke
Respiratory (time to tracheal extubation)

Pain control

Duration of hospital stay


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputerized randomization

Allocation concealment (selection bias)Unclear riskNot stated

Blinding (performance bias and detection bias)
All outcomes
High riskParticipants, staff and research personnel unblinded to the intervention

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll pre-specified outcomes reported

Selective reporting (reporting bias)Low riskAppears to be free of other sources of bias

Hansdottir 2006

MethodsRandomized controlled trial


Participants113 patients undergoing elective cardiac surgery (CABG, cardiac valve procedures, combined CABG and valve procedures or the Maze procedure, with or without CABG), absence of contraindications to epidural anaesthesia, abnormal coagulation tests (i.e., partial thromboplastin time 45 sec or prothrombin time (international normalized ratio) 1.5 or a platelet count 80,000), or recent (1 week) treatment with thrombolytic or potent antiplatelet drugs (streptokinase, alteplase, clopidogrel, abciximab, tirofiban, integrelin). Aspirin treatment was not considered a contraindication to the placement of a thoracic epidural catheter.


InterventionsGeneral anaesthesia with postsurgical PCA with morphine or combined general anaesthesia with high thoracic epidural analgesia (bupivacaine 5 mg/mL at 0.05 mL/kg/hr)

All patients (58 patients in epidural group and 55 in the control group) received infusions of propofol and remifentanil to a target anaesthetic depth of 15-25 AAI using an auditory evoked response monitor. Tracheal intubation was facilitated with 0.5 mg/kg atracurium. After induction of anaesthesia and insertion of monitoring devices, patients in the PCTEA group received an epidural 0.1 mL/kg bolus dose followed by a continuous 0.05 mL/kg/hr infusion with bupivacaine (5 mg/mL). In the PCTEA group, postoperative pain treatment was achieved by epidural bolus doses of 2 mL of the mixture 1 mg/mL bupivacaine plus 2 g/mL fentanyl plus 2 g/mL adrenaline, a lockout interval of 20 min, and a background epidural infusion of 0.1 mL/kg/hr. An epidural 0.1 ml/kg loading dose of this mixture was given at the end of surgery. In the PCA group, postoperative pain treatment was achieved by intravenous PCA morphine with bolus doses of 0.01 mg/kg and a lockout interval of 6 min with no background infusion. A loading dose of 0.1 mg/kg morphine was given in the operating room when remifentanil infusion was stopped.


OutcomesMyocardial infarction
Supraventricular tachyarrhythmias
Stroke
Respiratory (lung volumes)

Pain and sedation scores

Length of hospital stay


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskPatients were randomly assigned the day before surgery to one of two regimens

Allocation concealment (selection bias)Low riskSealed envelopes

Blinding (performance bias and detection bias)
All outcomes
High risk

Incomplete outcome data (attrition bias)
All outcomes
Low risk113 patients were randomized, 110 patients received allocated treatment, and 97 patients were eventually analysed

Selective reporting (reporting bias)Low riskAppears to be free of other sources of bias. Sample size calculation stated

Heijmans 2007

MethodsRandomized controlled trial


Participants60 patients undergoing elective cardiac surgery

Exclusion criteria included left ventricular ejection fraction of less than 25%, hypothermic circulatory arrest, recent myocardial infarction, preoperative inotropic or intra-aortic balloon pump metabolic, or neurologic diseases. All patients were receiving chronic B-adrenoceptor blocking drugs


InterventionsAlfentanil or low dose remifentanil or high dose remifentanil or epidural (15 patients in the epidural and 45 patients in the control group)

A test dose of 2 mL of lidocaine 2% was given to test for the correct position of the catheter. A loading dose of 10 mL of bupivacaine 0.25% with 2.5 mg of morphine was infused over 1 hour.

In the present study, 4 groups of patients were compared as follows: group 1 (AG): a loading dose of alfentanil, 50 ug/kg, was infused over 4 minutes, and, thereafter, alfentanil was infused at a maintenance rate of 1 ug/kg/min throughout surgery; group 2 (HDRG): a loading dose of remifentanil, 2.5 ug/kg, was infused over 4 minutes, and, thereafter, remifentanil was infused at a maintenance rate of 0.5 ug/kg/min throughout surgery; group 3 (LDRG): a loading dose of remifentanil, 2.5 ug/kg, was infused over 4 minutes, and, thereafter, remifentanil was infused at a maintenance rate of 0.25 ug/kg/min; and group 4 (TEG): a loading dose of remifentanil, 2.5 ug/kg, was infused over 4 minutes, and, thereafter, remifentanil was infused at a maintenance rate of 0.125 ug/kg/min and via thoracic epidural infusion bupivacaine 0.375% plus morphine 0.2 mg/mL were administered at a rate of 1.5 mL/hr throughout surgery. The initial infusion setting for propofol on the Diprifusor was a plasma concentration of 2 ug/mL to be reached in 4 minutes.

At arrival in the ICU, a sedative-analgesic infusion of propofol, 0.5 mg/kg/hr, together with alfentanil, 0.1 ug/kg/min, in group 1 and remifentanil, 0.025 g/kg/ min, in groups 2, 3, and 4, were started for 4 hours. If necessary, propofol was increased to achieve the desired level of sedation (Ramsay sedation score 3, 4, or 5). Additionally, acetaminophen, 1 g, 4 times daily, was started as a basic analgesic. In the TEG group, the catheter was left in position 48 hours postoperatively and bupivacaine 0.125% and morphine, 0.2 mg/mL, were infused at a rate of 1.5 mL/hr. Fifteen minutes before cessation of the sedative analgesic infusion, pirinitramide, a synthetic morphine derivative (analgesic potency in comparison with morphine [1] is 0.7) 0.15 mg/kg, intravenously, was administered in the remifentanil groups 2 and 3, and placebo was administered to the AG in a blinded fashion.


OutcomesInfectious parameters (CRP, IL-6)

Mortality
Supraventricular tachyarrhythmias
Stroke


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"60 patients scheduled to undergo coronary artery bypass surgery were randomized"

Allocation concealment (selection bias)Unclear riskNot stated

Blinding (performance bias and detection bias)
All outcomes
Low riskThe study was blinded for the opioid infusion, except in the thoracic epidural group

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNot stated

Selective reporting (reporting bias)Low riskAppears to be free of other sources of bias. Sample size calculation not stated

Kendall 2004

MethodsRandomized controlled trial


Participants26 patients undergoing off pump coronary artery bypass grafting

Patients undergoing emergency surgery and those with unstable angina were excluded from the study. Patients with plasma creatinine values greater than 160 mmol/L were also excluded from the study. Patients taking anticoagulant therapy and those with any other contraindication to the insertion of a thoracic epidural were also excluded.


InterventionsGeneral anaesthesia: propofol or isoflurane or epidural: isoflurane with bupivacaine

In the propofol group (9 patients), anaesthesia was induced with fentanyl 10-15 ug/kg and propofol delivered by a DiprifusorTM pump (AstraZeneca, London, England), aiming for a target blood concentration in the range 4-8 ug/mL

In the isoflurane group (9 patients), anaesthesia was induced with etomidate 0.2 mg/kg and fentanyl 10-15 ug/kg. Anaesthesia was maintained with isoflurane in oxygen and air at an end-tidal concentration of 1%. This was discontinued at the end of the procedure, and a propofol infusion was started to provide sedation if required until the criteria for tracheal extubation were met

In the epidural group (8 patients), anaesthesia was as for the isoflurane group, with the exception that fentanyl was given in a dose of 1.5 ug/kg epidural: bupivacaine 0.1% with fentanyl
5 ug/ml was given, followed by an infusion of 0.1 ml/kg/hr, adjusted according to haemodynamic values


OutcomesMortality
Myocardial infarction (troponin levels, new Q waves, loss of R progression)

Prolonged intensive care stay (GT; 24 hr)

Duration of tracheal intubation

Return to operating room

Intraoperative haemodynamic parameters


NotesSurgery with the octopus


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskPatients were randomly allocated to one of three groups using a shuffled, sealed envelope technique

Allocation concealment (selection bias)Low riskSealed envelopes

Blinding (performance bias and detection bias)
All outcomes
High risk

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk"Three patients were excluded from the study and further analysis. Their treatment was re-randomized and reallocated,
providing 30 complete data sets for analysis"

Selective reporting (reporting bias)Low riskAppears to be free of other sources of bias. Sample size calculation not stated

Kilickan 2006

MethodsRandomized controlled trial


Participants80 patients scheduled for elective coronary artery bypass grafting

Exclusion criteria: contraindications for the epidural technique, contraindications to any of the intended drugs in the treatment protocol, alcohol abuse, cognitive impairment


InterventionsGeneral anaesthesia alone or general anaesthesia in combination with high thoracic epidural analgesia (40 patients in each group).

Anaesthesia was induced in all groups by 0.2 mg/kg midazolam, 10-15 ug/kg fentanyl and 0.1 mg/kg vecuronium. Anaesthesia was maintained with propofol 2-6 mg/kg/hr and 2 ug/kg fentanyl intermittently. In the TEA group, 1 hr before surgery a bolus of 20 mg of bupivacaine was administered and a continuous infusion was started (bupivacaine 0.25 % at 8 ml/hr).

Postoperatively, in the TEA group received an epidural infusion of bupivacaine 0.125%, 4-10 ml/hr. The control group received a standard analgesia protocol (morphine PCA)


OutcomesMortality
Bcl-2 immunoreactivity (rate of apoptosis)

Haemodynamic parameters (CI)

Reperfusion ventricular fibrillation


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk80 patients scheduled for elective CABG were randomized in two groups

Allocation concealment (selection bias)Low riskSealed envelopes

Blinding (performance bias and detection bias)
All outcomes
High risk

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll pre-specified outcomes reported

Selective reporting (reporting bias)Low riskAppears to be free of other sources of bias. Sample size calculation not stated

Kirno 1994

MethodsRandomized controlled trial


Participants20 patients undergoing coronary artery bypass grafting

All patients had a history of stable ischaemic heart disease with 2 or 3 vessel coronary artery disease and an ejection fraction of > 50%. Patients with co-existing valvular anomaly, arrhythmias or diabetes mellitus were not included.


InterventionsGeneral anaesthesia (fentanyl nitrous oxide) and general anaesthesia and epidural analgesia with 10 patients in each group.

Anaesthesia was induced with thiopental 3-5 mg/kg, followed by pancuronium 0.1 mg/kg IV. Fentanyl was given in incremental doses up to a total amount of 10-15 ug/kg before sternotomy. The patients were ventilated with 70% nitrous oxide in oxygen. In the TEA group 3-3.5 mL mepivacaine was given epidurally after induction.


OutcomesMortality

MAP

Regional myocardial oxygen consumption

Myocardial ischaemia

Haemodynamic parameters

Noradrenaline spillover (sympathetic nervous system activation)


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskThe patients were randomized into two groups

Allocation concealment (selection bias)Unclear riskNot stated

Blinding (performance bias and detection bias)
All outcomes
High risk

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll pre-specified outcomes reported

Selective reporting (reporting bias)Unclear riskNot stated

Lagunilla 2006

MethodsRandomized controlled trial


Participants50 patients submitted for scheduled coronary revascularization of, at least, the left anterior descending (LAD) coronary artery were enrolled in the study.

The exclusion criteria were as follows: patient refusal, urgent or emergency procedure, unstable haemodynamic status (myocardial infarction less than 2 weeks prior to surgery, requirement for inotropic drugs or for intra-aortic balloon contrapulsation), absence of normal sinus rhythm, neurologic or neuromuscular disorders, previous thoracic or cervical spine surgery or trauma, significant left main coronary artery stenosis, anticoagulation, haematologic disorders and infection at the puncture site.


InterventionsGeneral anaesthesia with a thoracic epidural with either ropivacaine or a saline solution with 25 patients in each group.

Thereafter, general anaesthesia was induced with midazolam 1 mg, remifentanil at 0.7 mg/kg/min, cisatracurium in a single bolus of 0.2 mg/kg and 2-3% inhaled sevoflurane in oxygen. All patients received the corresponding volume of plain saline or 0.3% ropivacaine, in a blind manner, accordingly to the group to which they had been randomized. Then, an epidural infusion of 0.3% ropivacaine at 5-7 ml/hr (reduced to 2-3 mL/h during grafting) was started in all patients. In the postoperative period, 0.2% ropivacaine with 5 mg/mL fentanyl was used for analgesia in all patients, employing a patient controlled system.


OutcomesMortality

Haemodynamic parameters

Intramyocardial oxygen partial pressure


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskPatients enrolled in the study were randomly assigned, randomization was performed using a computer-generated random sequence

Allocation concealment (selection bias)Unclear riskComputer-generated random sequence

Blinding (performance bias and detection bias)
All outcomes
Low riskPatients enrolled in the study were randomly assigned to receive either epidural saline or epidural 0.3% ropivacaine

Incomplete outcome data (attrition bias)
All outcomes
Low riskOne patient was excluded in the ropivacaine group due to a wet tap (no catheter placement). One patient in the saline group became unstable after anaesthesia induction and required inotropic support; this patient was subsequently withdrawn from the study.

Selective reporting (reporting bias)Low riskAppears to be free of other sources of bias. Sample size calculation stated

Liem 1992

MethodsRandomized controlled trial


Participants54 patients scheduled for elective coronary artery bypass surgery

To be admitted to the study they were required to have normal or only moderately impaired left ventricular (LV) function (ejection fraction greater than 40%) as assessed by preoperative LV cineangiography and a LV end-diastolic pressure of less than 18 mmHg. Patients who had a myocardial infarction in the 7 days preceding surgery. Pre-existing haemorrhagic diathesis, or valvular heart disease were excluded from the study.


InterventionsHigh thoracic epidural with bupivacaine 0.375% plus sufentanil 5 ug/mL in combination with general anaesthesia midazolam/N2O and general anaesthesia with midazolam/fentanyl (27 patients in each group).

IV anaesthesia in the GA group was induced over a period of 10 minutes with midazolam, 0.1 mg/kg, sufentanil, 5 ug/kg, and pancuronium, 0.1 mg/kg. Anaesthesia was maintained with an infusion of midazolam, 0.1 mg/kg/hr, and sufentanil, 2.5 ug/kg/hr. Pancuronium, 0.025 mg/kg, was administered every hour.

Epidural analgesia in the TEA group was induced, over a period of 10 minutes, with a mixture of 0.375% bupivacaine plus sufentanil, 1:200,000 (i.e., 5 ug/mL) in a dose of 0.05 mL/cm body length. Continuous epidural analgesia was then started with 0.125% bupivacaine plus sufentanil, 1:1,000,000 (i.e., 1 ug/mL) at an infusion rate of 0.05 mL/cm body length/hour. Just before induction of GA, measurements were taken (point 2). IV anaesthesia was induced with etomidate, 0.2 mg/kg, midazolam, 0.1 mg/kg, and pancuronium, 0.1 mg/kg. IV anaesthesia was maintained with an infusion of midazolam, 0.1 mg/kg/hr, and after the establishment of cardiopulmonary bypass (CPB), a bolus of midazolam, 0.05 mg/kg, was administered IV; pancuronium, 0.025 mg/kg, was administered every hour.


OutcomesMortality
Myocardial infarction
Haemodynamic parameters
Respiratory complications

VAS scores

Time to awakening

Arrythmias (tachycardia)

Adrenergic responses


NotesAll three articles


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskOn the day before surgery, the patients were assigned randomly to either a TEA or a GA group

Allocation concealment (selection bias)Unclear riskNot stated

Blinding (performance bias and detection bias)
All outcomes
High risk

Incomplete outcome data (attrition bias)
All outcomes
Low riskRe-sternotomy was necessary in two patients (1 in each group). In one TEA group patient, the epidural catheter was dislocated. These patients were excluded from the study

Selective reporting (reporting bias)Low riskAppears to be free of other sources of bias

Loick 1999

MethodsRandomized controlled trial


Participants70 patients scheduled for elective coronary artery bypass grafting

Seventy-two patients scheduled for elective CABG fulfilled the study criteria and were selected for the investigation. Disorders of the intestine and liver, gastritis, ulcera ventriculi and duodeni, autonomic neuropathy, and diabetes mellitus (patients receiving insulin or oral hypoglycaemic drugs) were exclusion criteria


InterventionsGeneral anaesthesia with clonidine IV or general anaesthesia with thoracic epidural analgesia with 25 patients in epidural group and 45 in the control group (with and without clonidine).

Anaesthesia was induced with sufentanil (1-2 mg/kg) and propofol (1-2 mg/kg). Pancuronium (0.1 mg/kg) was used to facilitate tracheal intubation. Anaesthesia was maintained by a continuous infusion of sufentanil (1-2 ug/kg/hr) and propofol (1-3 mg/kg/hr) throughout the surgical procedure. On the day of surgery, after insertion of the invasive catheters, the patients received 8-12 mL of bupivacaine 0.375% and 16-24 ug of sufentanil into the epidural space. In the clonidine group, patients received a standardized opioid-based general anaesthesia supplemented with IV clonidine. In the control group, patients received a standardized opioid-based general anaesthesia without any supplement. Postoperative pain management consisted of an IV application of 1 g of paracetamol four times daily. Additionally, patients in the clonidine and control groups were allowed to administer a bolus of 2 mg of piritramide IV on demand by a patient-controlled analgesia device with a lockout time of 20 min. Patients in the TEA group received a continuous infusion of 2-3 mL of bupivacaine 0.75% via the epidural catheter. If the patient was < 65 yr of age, the bupivacaine solution contained 1 ug/mL sufentanil, but this drug was not given to older patients. If pain relief was not sufficient, patients administered an additional 2 mL of bupivacaine with a lockout interval of 20 min. IV piritramide was supplemented for additional pain relief.


OutcomesMortality
Myocardial infarction and ischaemia

Haemodynamics, lactate, cortisol plasma levels, and cardiac enzymes


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"The patients were randomly allocated to one of the following three study groups"

Allocation concealment (selection bias)Unclear riskNot stated

Blinding (performance bias and detection bias)
All outcomes
High risk

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNot stated

Selective reporting (reporting bias)Low riskAppears to be free of other sources of bias

Lundstrom 2005

MethodsRandomized controlled trial


ParticipantsA total of 50 patients undergoing elective coronary artery bypass grafting

The criteria for inclusion in the study were age greater than 18 years, sinus rhythm on the ECG preoperatively, and written and oral informed consent. The criteria for exclusion from the study were oral anticoagulation and coagulopathy


InterventionsConventional IV anaesthesia (24 patients) or general anaesthesia combined with thoracic epidural anaesthesia followed by postoperative epidural analgesia (26 patients) with bupivacaine

Epidural analgesia was induced with 8 to 10 mL of bupivacaine, 5 mg/mL. Anaesthesia was induced with IV midazolam, 3 to 5 mg, fentanyl, 0.3 mg, and a dose of pancuronium, 0.1 mg/kg. Anaesthesia was maintained with isoflurane and a continuous epidural infusion of bupivacaine, 1.25 mg/mL, with morphine, 25 ug/mL and 5 mL/h. Top-up bolus doses of 4 mL of bupivacaine, 5 mg/mL, were administered hourly during the operation. The administration of fentanyl was restricted to the dose given at the induction of general anaesthesia. Postoperatively, the epidural infusion continued, and bolus doses of 4 mL of 0.25% bupivacaine were administered as needed Anaesthesia was induced with midazolam, 3 to 5 mg, fentanyl, 15 to 30 ug/kg, and pancuronium, 0.1 mg/kg, which were administered at induction only and not repeated. Anaesthesia was maintained with isoflurane. Analgesia in the CON group was provided with intermittent IV morphine boluses (2.5 to 5 mg) until the morning of the first postoperative day when morphine, 5 to 10 mg, orally were given as needed. Postoperatively, all patients received oral paracetamol, 1 g every 6 h.


OutcomesMortality
Respiratory complications: episodic hypoxaemia


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Patients were randomly assigned to receive either conventional IV anaesthesia (CON) or general anaesthesia combined with TEA. The randomization list was generated from a table of random numbers."

Allocation concealment (selection bias)Unclear riskNot stated

Blinding (performance bias and detection bias)
All outcomes
High risk

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll pre-specified outcomes reported

Selective reporting (reporting bias)Low riskAppears to be free of other sources of bias. Sample size calculation stated

Moore 1995

MethodsRandomized controlled trial


Participants18 patients undergoing elective coronary artery bypass grafting

They had no history of metabolic or endocrine disease and had a normal bleeding time


InterventionsGeneral anaesthesia alone or combined with thoracic epidural analgesia with 9 patients in each group

Bupivacaine 0.5% was given in 2 mL increments to achieve a adequate block, followed by an infusion of 0.375% bupivacaine at 5-8 mL/hr. General anaesthesia was induced by all patients with sufentanil 10 ug/kg, followed by a sleep-dose of thiopentone. Pancuronium 0.1 mg/kg was given and ventilation was with nitrous oxide in 50% oxygen. Post-OK analgesia was with 0.25 % bupivacaine at 5-8 mL/hr, increments of 2.5 mg papaveretum IV was given in the control group.


OutcomesMortality

Plasma catacholamines

Plasma cortisol

Serum insulin and growth hormone

Haemodynamic parameters


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskPatients were allocated by selection of a sealed envelope

Allocation concealment (selection bias)Low riskSealed envelopes

Blinding (performance bias and detection bias)
All outcomes
Unclear riskNot stated

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskOne patient had a severe haemorrhage and data from this patient were not presented

Selective reporting (reporting bias)Low riskAppears to be free of other sources of bias. Sample size calculation not stated

Nygard 2004

MethodsRandomized controlled trial


Participants163 patients scheduled for elective coronary artery bypass grafting

Patients scheduled for elective CABG were screened for participation in the study. Inclusion criterion was sinus rhythm. Exclusion criteria were off-pump surgery; implanted pacemaker; use of amiodarone within 4 months of enrolment; a history of amiodarone toxicity; known thyroid disease, liver disease, or uncontrolled heart failure; a resting heart rate of less than 50 beats/min in the absence of medical therapy known to slow the heart rate; anticoagulant medication with warfarin; coagulopathy; pregnancy; and use of antiarrhythmic drugs other than alfa1-receptor antagonists, calcium channel antagonists, and digoxin.


InterventionsGroup E (44 patients) had perioperative TEA, group E and A had TEA and amiodarone (35 patients), group A had amiodarone (36 patients), and group C served as control (48 patients).

On arrival in the operating room, epidural analgesia was induced with 8 to 10 mL of bupivacaine, 5 mg/mL. Anaesthesia was induced with intravenous (IV) midazolam, 3 to 5 mg, fentanyl, 0.3 mg, and pancuronium, 0.1 mg/kg. Anaesthesia was maintained with isoflurane in oxygen and a continuous epidural infusion of bupivacaine, 1.25 mg/mL, with morphine, 25 ug/mL, 5 mL/h. Additional bolus doses of 4 mL of bupivacaine, 5 mg/mL, were given hourly during the operation. Fentanyl was restricted to the dose given at induction of anaesthesia. Postoperatively, the epidural infusion was continued for 4 days. In groups A and C, anaesthesia was induced with midazolam, 3 to 5 mg, fentanyl, 15 to 30 ug/kg, and pancuronium, 0.1 mg/kg. Anaesthesia was maintained with isoflurane in oxygen. Postoperative analgesia in the non-TEA groups was provided with intermittent IV morphine boluses (2.5 to 5 mg) until the morning of the first postoperative day when 5 to 10 mg of oral morphine was given as needed.


OutcomesMortality

Supraventricular tachyarrhythmias


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskPatients were randomly assigned to four groups; randomization was 1:1:1:1

Allocation concealment (selection bias)Unclear riskThe randomization list was generated from a computerized table of random numbers

Blinding (performance bias and detection bias)
All outcomes
High risk

Incomplete outcome data (attrition bias)
All outcomes
Low riskOf the 196 patients included, 163 were evaluated: 18 patients had surgery cancelled, and 4 patients had a change in surgical procedure. One withdrew consent preoperatively, and 6 withdrew consent postoperatively. One patient had a stroke before surgery, and in 1 patient placement of the epidural catheter was unsuccessful. Two patients were excluded because of protocol violations.

Selective reporting (reporting bias)Low riskAppears to be free of other sources of bias. Sample size calculation stated

Onan 2011

MethodsA prospective randomized study


Participants30 patients with documented 3-vessel coronary artery disease who were scheduled for elective coronary artery bypass graft surgery


InterventionsIn both groups, anesthesia was induced with midazolam (0.1-0.2 mg/kg), fentanyl (7-10 g/kg), and rocuronium (0.6 mg/kg). The patients in the GA TEA group received a 20-mg bolus of 0.25% bupivacaine through the epidural catheters 1 hour before surgery. During the intraoperative period, 0.25% bupivacaine was infused at a rate of 20 mg/hr. The patients received a continuous epidural infusion of 0.125% bupivacaine, 4 to 10 mL/h, after surgery to attain sensory blockade.


OutcomesImmunoreactivity

(Mortality)
(Myocardial infarction)

Graft blood flow


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"The patients were assigned randomly into 2 groups"

Allocation concealment (selection bias)Unclear riskNot clear

Blinding (performance bias and detection bias)
All outcomes
High riskNot blinded

Incomplete outcome data (attrition bias)
All outcomes
Low riskData appear to be completed

Selective reporting (reporting bias)Low riskAppears to be free of other sources of bias. Sample size calculation stated

Priestley 2002

MethodsRandomized controlled trial


Participants100 patients scheduled for elective coronary artery bypass grafting

All patients presenting for elective CABG were eligible for inclusion unless they had one or more of the following exclusion criteria: contraindications to the epidural technique (e.g., pre-existing coagulopathy, anticoagulation (i.e., full therapeutic doses of standard or low-molecular-weight heparin, warfarin, thrombolytic drugs, or potent antiplatelet drugs), or systemic or local infection); arthritis of the thoracic or cervical spine with a history of associated neurologic deficit; coexisting surgery (e.g., valvular, carotid, or aortic surgery); contraindications to any of the intended drugs in the treatment protocol; significant alcohol or other substance abuse; cognitive impairment; or other reason for inability to comply with treatment as assessed by the investigators.


InterventionsHigh (T1 to T4) thoracic epidural anaesthesia (TEA) with ropivacaine 1% (4 mL bolus, 3-5 mL/h infusion), with fentanyl (100 ug bolus, 15-25 ug/hr infusion) and a propofol infusion (6 mg/kg/hr) in 50 patients. Another 50 patients (the general anaesthesia group) received fentanyl 15 ug/kg and propofol (5 mg/kg/hr), followed by IV morphine patient-controlled analgesia.

On the day of surgery, after monitoring devices were inserted, an epidural bolus of 4 mL ropivacaine 1% and fentanyl 100 ug was administered, with supplemental ropivacaine 1% given as necessary to obtain blockade. After the bolus, an epidural infusion was commenced with ropivacaine 1% and fentanyl 5 ug/mL, and this continued for 48 h at 3-5 mL/hr. General anaesthesia (GA) in the TEA group consisted of IV fentanyl 2 ug/kg plus propofol 15 mg/kg/hr until consciousness was lost, followed by a propofol infusion at 6 mg/kg/hr, which continued until wiring of the sternum was completed. The GA group received fentanyl 15 ug/kg in divided doses from the induction of anaesthesia to sternotomy, in addition to propofol 15 mg/kg/hr until loss of consciousness, followed by a propofol infusion of 5 mg/kg/h (the larger fentanyl dose allowed a slightly smaller propofol dose than in the TEA group) until sternal closure. During cardiopulmonary bypass (CPB), a morphine infusion was commenced at 40 ug/kg/hr.

All patients received pancuronium 0.1 mg/kg for muscle relaxation


OutcomesMortality
VAS pain score
Stroke
Respiratory parameters: spirometry results

Time to extubation

Length of hospital stay

Mobilization goals


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskBlock randomization using sealed envelopes was used; patients at high risk were randomized separately

Allocation concealment (selection bias)Low riskSealed envelopes

Blinding (performance bias and detection bias)
All outcomes
High risk

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNot stated

Selective reporting (reporting bias)Low riskAppears to be free of other sources of bias. Sample size calculation stated

Rein 1989

MethodsRandomized controlled trial


Participants16 male patients requiring aorta-coronary bypass with extra-corporal circulation


InterventionsGeneral anaesthesia alone or general anaesthesia combined with thoracic epidural analgesia (8 patients in each group)

All patients received morphine-scopolamine as premedication. General anaesthesia was obtained by the administration of thiopentone, pancuronium, nitrous oxide, diazepam and oxygen. The control group received fentanyl 54 ug/kg , the study group received fentanyl 14 ug/kg. TEA at T4-T5, initial dose of 50 mg bupivacaine, followed by 20 mg/hr during surgery. Postoperatively the control patients received morphine, the TEA patients were treated with epidural bupivacaine at 20 mg/hr.


OutcomesTranscapillary fluid balance

Postoperative haemodynamics

(Mortality)


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"16 male patients were allocated at random to two groups"

Allocation concealment (selection bias)Unclear riskNot stated

Blinding (performance bias and detection bias)
All outcomes
Unclear riskNot stated

Incomplete outcome data (attrition bias)
All outcomes
Low riskOne patient died 9 hr postoperatively and was excluded from the final analyses

Selective reporting (reporting bias)Unclear riskNot stated

Royse 2003

MethodsRandomized controlled trial


Participants76 patients receiving elective coronary artery bypass grafting with cardiopulmonary bypass


InterventionsHigh thoracic epidural analgesia with ropivacaine and fentanyl (37 patients) or IV morphine analgesia (39 patients)

Acetaminophen, indomethacin, and tramadol were allowed as supplemental analgesia in both groups

Epidural at T1-2 or T2-3. Eight mL of 0.5% ropivacaine with 20 ug of fentanyl was administered prior to induction of anaesthesia. Thereafter, ropivacaine 0.2% with fentanyl 2 ug/mL was infused at a rate of 5 to 14 mL per hour, adjusted to attain a sensory blockade of T1 to T10, and was ceased at 6:00 am on postoperative day 3. Anaesthesia consisted of midazolam (3 to 5 mg), fentanyl (200 ug), and a target-controlled infusion of propofol. For the control group anaesthesia consisted of midazolam (3 to 5 mg), propofol (2 to 4 g/mL), and a 2-stage target controlled alfentanil infusion (2 ug/mL, reduced to 0.05 ug/mL after cardiopulmonary bypass, and ceased after sternal wiring. Nurses were permitted to administer boluses of morphine in the intensive care unit until the patient was awake. This was followed by demand patient controlled intravenous morphine (1 mg bolus with 5 minute lockout period), which was continued until 6:00 am on postoperative day 3.


OutcomesPain

Physiotherapy cooperation

Depression and post-traumatic stress

Somatosensory sensitization

Lung function

Intraoperative haemodynamics

(Mortality)
(Myocardial infarction)


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskEighty patients undergoing elective CABG were randomized

Allocation concealment (selection bias)Unclear riskNot described

Blinding (performance bias and detection bias)
All outcomes
High risk

Incomplete outcome data (attrition bias)
All outcomes
Low risk4 patients were withdrawn: 1 patient withdrew itself from the study after randomization, deciding not to participate in research, and 2 patients failed epidurals and 1 patient from the control group requested the epidural

Selective reporting (reporting bias)Low riskAppears to be free of other sources of bias. Sample size calculation not stated

Scott 2001

MethodsRandomized controlled trial


Participants408 patients undergoing elective coronary artery bypass grafting with a normal coagulation screen and an ejection fraction of > 35%


InterventionsGeneral anaesthesia alone (202 patients) or general anaesthesia combined with thoracic epidural analgesia (bupivacaine and clonidine) in 206 patients

All patients received target-controlled infusions (TCIs) of propofol and alfentanil for anaesthesia and analgesia, respectively. In Group GA, TCI of alfentanil continued for 24 hr and was then converted to a patient-controlled analgesia (PCA) IV morphine pump for another 48 h by using 1 mg bolus dosing with a 3 min lockout period. Patients in Group TEA had a thoracic epidural catheter sited in the operating theatre immediately before surgery at the T2-3 or T3-4 interspace with an initial bolus of 5 mL bupivacaine 0.5% followed by another 5 mL bolus after 10 min. After induction of GA and when central haemodynamic status was stable, a continuous infusion of 0.125% bupivacaine and 0.0006% clonidine (300 ug in 500 mL) commenced at an initial rate of 10 mL/hr. In Group TEA, the epidural infusion continued for 96 hr. “Top-up” bolus doses up to a maximum of 4 mL of 0.25% bupivacaine were administered either when the patient complained of pain.


Outcomes(Mortality)
Myocardial infarction
Supraventricular arrhythmias
Stroke or cerebrovascular accident
Pulmonary complications

Acute confusion

Significant bleeding

Renal failure

Incidence of major organ complications


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Patients were randomized to one of two regimens...by using cards drawn from a sealed envelope"

Allocation concealment (selection bias)Low riskSealed envelope

Blinding (performance bias and detection bias)
All outcomes
High risk

Incomplete outcome data (attrition bias)
All outcomes
Low risk12 subjects had insufficient data

Selective reporting (reporting bias)Low riskAppears to be free of other sources of bias. Sample size calculation stated. Interim analysis performed and presented after 120 patients

Sharma 2010

MethodsRandomized controlled trial


ParticipantsSixty patients scheduled for elective OPCAB


InterventionsPatients in both the groups received general anaesthesia as per hospital protocol. Intravenous propofol (1-1.5 mg/kg) for induction of anesthesia along with fentanyl citrate (2-3 µgm/kg), midazolam (0.04 mg/kg) and vecuronium bromide (0.1 mg/kg) while isoflurane (1- 2 MAC) in air and oxygen mixture was used for maintenance of anesthesia. An epidural catheter was placed at C7-T1 /T1 -T2 level. Intrathecal placement was ruled out by using 3 mL of 2% lignocaine as a test dose. Once on the operation table, the patient was administered a bolus dose of 8-10 mL of bupivacaine (0.25%), inducing sensory block till at least T4. After confirming the block by loss of sensation to cold and pin prick, general anesthesia was administered. Bupivacaine infusion (0.125%) with 1µg/mL fentanyl citrate) at the rate of 5 mL/hr was commenced and continued till 3rd postoperative day for providing intra- and postoperative analgesia.


OutcomesPostoperative spirometric values

Postoperative PaO2/FiO2 ratio and PaCO2 values

Painscores

(Mortality)


NotesOnly obese patients (BMI > 30 kg/m2) were included


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"Patients were randomized into two groups of 30 each."

Allocation concealment (selection bias)Unclear riskNot clear

Blinding (performance bias and detection bias)
All outcomes
High risk

Incomplete outcome data (attrition bias)
All outcomes
Low riskData appear to be completed

Selective reporting (reporting bias)Unclear riskAppears to be free of other sources of bias. Sample size calculation not stated

Stenseth 1994

MethodsRandomized controlled trial


Participants28 male patients < 65 years and with an ejection fraction of > 50% undergoing cardiac surgery. They were all ASA III with double or triple vessel disease


InterventionsGeneral anaesthesia with high dose fentanyl (10 patients), general anaesthesia with low dose fentanyl and thoracic epidural analgesia (18 patients).

Epidural at T4-5 or T5-6. 10 mL 0.5% bupivacaine, top up doses of 4 mL 0.5% bupivacaine during surgery. GA with thiopentone, pancuronium. High dose fentanyl was 20-30 ug/kg, low dose fentanyl was 5 ug/kg. HF received morphine IV on demand, both epidural groups received a continuous epidural infusion of bupivacaine 0.5 % at 3 mL/hr with additional top ups of 4 mL every hour.


Outcomes(Mortality)
(Myocardial infarction)

Hypertension

Tachycardia

Other haemodynamic parameters

Use of vasoactive drugs


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk30 male patients gave informed consent and were randomized into one of three groups

Allocation concealment (selection bias)Unclear riskNot stated

Blinding (performance bias and detection bias)
All outcomes
High risk

Incomplete outcome data (attrition bias)
All outcomes
Low riskTwo patients were excluded from the final analysis due to surgical problems

Selective reporting (reporting bias)Low riskAppears to be free of other sources of bias. Sample size calculation not stated

Stenseth 1996

MethodsRandomized controlled trial


Participants52 male patients age < 65 years and with an ejection fraction of > 50%. They were all in NYHA class III and presented with double- or triple-vessel disease


InterventionsHigh dose fentanyl general anaesthesia and an epidural group receiving low dose fentanyl general anaesthesia + thoracic epidural analgesia with bupivacaine 0.5% (26 patients in each group)

Patients allocated to the epidural group had an epidural catheter inserted at level T4- T5 or T5-T6. Epidural group patients received an epidural injection of 10 mL of bupivacaine 5 mg/mL. Top up bolus doses of 4 mL bupivacaine 5 mg/mL were given hourly during the operation. General anaesthesia consisted of thiopentone, diazepam, nitrous oxide and pancuronium (with no difference between the groups) in addition to fentanyl. The control group patients received a total of 55 ug/kg of fentanyl, the epidural group a total of 15 ug/kg. Control group patients received morphine IV on demand for pain relief during the first 20 hr after surgery. During the next 2 days daily paracetamol 3.2 g and codeine 240 mg (Paralgin forte) were given rectally as basal analgesia, which was supplemented with morphine IV as needed. Epidural group patients received a continuous epiduraI infusion of bupivacaine 5 mg/ml, 3 ml/h with additional top up doses of 4 mL bupivacaine every 4 hr and supplementation with IV morphine when needed. They received morphine epidurally 4-6 mg 3-4 times a day for the next 2 days, supplemented with bupivacaine 5 mg/mL and morphine IV when needed. For both groups, supplementation was most often needed in association with physiotherapy and mobilization.
From the 3rd postoperative day all patients received only Paralgin forte on request


Outcomes(Mortality)
(Myocardial infarction)

Extubation time

Spirometry results after surgery


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk54 male patients were randomized into two groups

Allocation concealment (selection bias)Unclear riskNot stated

Blinding (performance bias and detection bias)
All outcomes
High risk

Incomplete outcome data (attrition bias)
All outcomes
Low riskTwo patients were excluded from the analysis because of the suffered complications

Selective reporting (reporting bias)Low riskAppears to be free of other sources of bias. Sample size calculation not stated

Svircevic 2011

MethodsTwo centre, randomized controlled trial


Participants656 patients scheduled for elective cardiac surgery, including off-pump procedures


InterventionsNot known


OutcomesMortality
Myocardial infarction

Pulmonary complications

Length of hospital stay

Arrhythmias

Stroke


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskThe random allocation sequence was concealed and computer-generated in permuted unequal blocks, accessible through an Internet site

Allocation concealment (selection bias)Low riskThe random allocation sequence was concealed

Blinding (performance bias and detection bias)
All outcomes
High riskNot blinded

Incomplete outcome data (attrition bias)
All outcomes
Low riskOne patient was excluded because his surgery was cancelled, and one patient withdrew his consent after randomization

Selective reporting (reporting bias)Low riskAppears to be free of other sources of bias. Sample size calculation stated

Tenling 1999

MethodsRandomized controlled trial


Participants28 patients scheduled for coronary artery bypass grafting. Inclusion criteria were stable angina pectoris with a left ventricular ejection fraction of more than 40%


InterventionsPerioperative and postoperative TEA ( bupivacaine) was added to general anaesthesia (GA) in 14 patients, and 14 patients receiving GA alone served as controls

Epidural at T3-4 or T4-5. Epidural analgesia was induced with 8 to 12 mL of bupivacaine, 5 mg/mL. The block was maintained with an infusion of bupivacaine, 5 mg/mL, 4 to 8 mL/hr, until the patient arrived at the intensive care unit. Anaesthesia was induced with fentanyl, 5 to 10 ug/kg; thiopental, 1.5 to 2.5 mg/kg; and pancuronium, 0.1 mg/kg. In the TEA group, fentanyl was restricted to the dose administered at induction. From then on, analgesia was achieved with TEA. The GA group was administered small doses of fentanyl as needed (1 to 2 mg total). In both groups, anaesthesia was maintained with inhaled isoflurane, 0.5 to 1.0 minimal alveolar concentration.
In the GA group, postoperative analgesia was achieved with titrated doses of ketobemidone, 1 to 3 mg
intravenously, according to standard procedures. The TEA group
received a continuous infusion of bupivacaine, 2 mg/mL, and sufentanil, 1 ug/mL epidurally (3 to 7 mL/hr), from arrival at the ICU until the end of the study on the day after surgery.


OutcomesMortality
Respiratory: ventilation/perfusion mismatch, atelectasis, time to extubation


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"After giving their informed consent, 30 patients scheduled for CABG were randomized to receive either general anaesthesia (GA group) or GA with TEA (TEA group). Randomization was achieved with sealed envelopes"

Allocation concealment (selection bias)Low riskSealed envelopes

Blinding (performance bias and detection bias)
All outcomes
High risk

Incomplete outcome data (attrition bias)
All outcomes
Low riskTwo patients were excluded from the analyses

Selective reporting (reporting bias)Low riskAppears to be free of other sources of bias. Sample size calculation stated

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Chae 1998No adequate sequence generation

Dohle 2001No adequate sequence generation and no allocation concealment

Fawcett 1997No adequate sequence generation

Greisen 2012Not randomized

Jakobsen 2012No relevant outcomes reported

Jideus 2001Not randomized

Kessler 2005No adequate sequence generation

Liang 2012Comparison between epidural anesthesia perioperatively and postoperatively

Liem 1992aNo relevant outcomes reported

Liem 1992bNo relevant outcomes reported

Mehta 1998No adequate sequence generation and no allocation concealment

Olivier 2005No comparison to general anaesthesia

Stenseth 1995No relevant outcomes reported

Thorelius 1996No adequate sequence generation

 
Comparison 1. Thoracic epidural analgesia versus general anaesthesia for mortality

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

 1 Mortality two weeks292877Peto Odds Ratio (Peto, Fixed, 95% CI)0.84 [0.33, 2.13]

    1.1 All studies
292877Peto Odds Ratio (Peto, Fixed, 95% CI)0.84 [0.33, 2.13]

 2 Mortality six months2170Peto Odds Ratio (Peto, Fixed, 95% CI)1.35 [0.08, 22.83]

 
Comparison 2. Thoracic epidural analgesia versus general anaesthesia for myocardial infarction

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

 1 Myocardial infarction two weeks152127Peto Odds Ratio (Peto, Fixed, 95% CI)0.76 [0.49, 1.19]

 2 Myocardial infarction six months2170Peto Odds Ratio (Peto, Fixed, 95% CI)0.41 [0.06, 3.03]

 
Comparison 3. Thoracic epidural analgesia versus general anaesthesia for respiratory complications

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

 1 Respiratory complications two weeks132011Risk Ratio (M-H, Random, 95% CI)0.66 [0.45, 0.98]

 
Comparison 4. Thoracic epidural analgesia versus general anaesthesia for supraventricular tachycardias (SVTs)

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

 1 SVTs two weeks132250Risk Ratio (M-H, Random, 95% CI)0.65 [0.50, 0.86]

 2 SVTs six months2170Peto Odds Ratio (Peto, Fixed, 95% CI)0.76 [0.39, 1.51]

 
Comparison 5. Thoracic epidural analgesia versus general anaesthesia for stroke

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

 1 Stroke two weeks91791Peto Odds Ratio (Peto, Fixed, 95% CI)0.50 [0.21, 1.18]

 
Comparison 6. Thoracic epidural analgesia versus general anaesthesia for mortality - sensitivity analysis

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

 1 Low risk of bias studies101794Peto Odds Ratio (Peto, Fixed, 95% CI)0.83 [0.25, 2.70]

 
Summary of findings for the main comparison. Epidural analgesia for cardiac surgery

Studies: randomized clinical trials

Patient or population: adult patients undergoing cardiac surgery
Intervention: thoracic epidural anaesthesia
Comparison: general anaesthesia

OutcomesIllustrative comparative risks*Relative
effect
(95% CI)
Number of
participants
(studies)
Quality of the
evidence

(GRADE)

Assumed riskCorresponding risk

GATEA

respiratory complications144 per 1000100 per 1000

(79 to 141)
0.66 (0.45, 0.98)2011 (14)++OO1

supraventricular arrhythmias372 per 1000242 per 1000

(186 to 208)
0.65 (0.50, 0.86)2250 (15)++OO2

mortality7 per 10006 per 1000

(2 to 16)
0.84 (0.33, 2.13)2877 (31)+++O3

myocardial infarction44 per 100033 per 1000

(22 to 52)
0.76 (0.49, 1.19)2127 (17)+OOO4

stroke15 per 10008 per 1000

(3 to 18)
0.50 (0.21, 1.18)1791 (10)+OOO5

*The basis for the assumed risk (e.g. the mean control group risk) is provided in footnotes. The corresponding risk is based on the assumed risk in the comparison group and the effect estimate of the intervention.
CI: Confidence interval;

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

 1 Narrow confidence intervals, however high variability in effect estimates (I2 = 42%) and the definition of this endpoint was variable among the studies, for this reason the quality of evidence was down graded
2 There was substantial variability in effect estimates (I2 = 67%)
3 Large number of participants with narrow confidence intervals and small variability in effect estimates (I2 = 0%)
4 Large number of participants and small variability in effect estimates, but with wide confidence intervals indicating imprecision in results
5 The wide confidence intervals indicate imprecision in results