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Original article
Effect of remote ischaemic preconditioning on clinical outcomes in patients undergoing cardiac bypass surgery: a randomised controlled clinical trial
  1. Luciano Candilio1,
  2. Abdul Malik1,
  3. Cono Ariti2,
  4. Matthew Barnard3,
  5. Carmelo Di Salvo3,
  6. David Lawrence3,
  7. Martin Hayward3,
  8. John Yap3,
  9. Neil Roberts3,
  10. Amir Sheikh3,
  11. Shyam Kolvekar3,
  12. Derek J Hausenloy1,
  13. Derek M Yellon1
  1. 1The Hatter Cardiovascular Institute, University College London, London, UK
  2. 2The Nuffield Trust, London, UK
  3. 3The Heart Hospital, University College London Hospital, London, UK
  1. Correspondence to Dr Derek J Hausenloy, The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London WC1E 6HX, UK; d.hausenloy{at}ucl.ac.uk

Abstract

Objectives Remote ischaemic preconditioning (RIPC), using brief cycles of limb ischaemia/reperfusion, is a non-invasive, low-cost intervention that may reduce perioperative myocardial injury (PMI) in patients undergoing cardiac surgery. We investigated whether RIPC can also improve short-term clinical outcomes.

Methods One hundred and eighty patients undergoing elective coronary artery bypass graft (CABG) surgery and/or valve surgery were randomised to receive either RIPC (2–5 min cycles of simultaneous upper arm and thigh cuff inflation/deflation; N=90) or control (uninflated cuffs placed on the upper arm and thigh; N=90). The study primary end point was PMI, measured by 72 h area under the curve (AUC) serum high-sensitive troponin-T (hsTnT); secondary end point included short-term clinical outcomes.

Results RIPC reduced PMI magnitude by 26% (−9.303 difference (CI −15.618 to −2.987) 72 h hsTnT-AUC; p=0.003) compared with control. There was also evidence that RIPC reduced the incidence of postoperative atrial fibrillation by 54% (11% RIPC vs 24% control; p=0.031) and decreased the incidence of acute kidney injury by 48% (10.0% RIPC vs 21.0% control; p=0.063), and intensive care unit stay by 1 day (2.0 days RIPC (CI 1.0 to 4.0) vs 3.0 days control (CI 2.0 to 4.5); p=0.043). In a post hoc analysis, we found that control patients administered intravenous glyceryl trinitrate (GTN) intraoperatively sustained 39% less PMI compared with those not receiving GTN, and RIPC did not appear to reduce PMI in patients given GTN.

Conclusions RIPC reduced the extent of PMI in patients undergoing CABG and/or valve surgery. RIPC may also have beneficial effects on short-term clinical outcomes, although this will need to be confirmed in future studies.

Trial registration number ClinicalTrials.gov ID: NCT00397163.

  • CARDIAC SURGERY
  • MYOCARDIAL ISCHAEMIA AND INFARCTION (IHD)

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Introduction

Coronary artery bypass graft (CABG) surgery is the revascularisation strategy of choice for patients with multivessel coronary artery disease. Higher-risk patients are being operated on for a number of different reasons, including the aging population, the presence of comorbidities such as diabetes, obesity and hypertension, and the increasing incidence of concomitant valve surgery. These higher-risk patients are more susceptible to perioperative myocardial injury (PMI) and experience worse short-term and long-term clinical outcomes.1 Therefore, novel therapeutic interventions are required to protect the heart during CABG surgery in these higher-risk patients in order to improve patient morbidity and mortality.

In this regard, remote ischaemic preconditioning (RIPC), in which the application of one or more brief cycles of non-lethal ischaemia and reperfusion to an organ or tissue protects the heart against a lethal episode of acute ischaemia-reperfusion injury (IRI),2 ,3 has emerged as a non-invasive, low-cost therapeutic intervention for potentially reducing the extent of PMI (as measured by serum cardiac enzymes) in patients undergoing CABG and/or valve surgery.4–16 The majority of these clinical studies have reported beneficial effects using a standard single-limb RIPC protocol comprising three or four 5 min cycles of inflation and deflation of a cuff placed on either the upper arm or thigh to induce transient ischaemia. However, several recent studies have failed to demonstrate any reduction in PMI using this standard single-limb RIPC stimulus, suggesting that under certain conditions this RIPC stimulus may be ineffective.6 ,10 ,17

Whether increasing the intensity of the RIPC stimulus by simultaneously applying the RIPC protocol to the upper arm and thigh is more effective in patients undergoing CABG and/or valve surgery is unknown and is investigated in this study. Furthermore, whether RIPC can improve short-term clinical outcomes in this patient group is unknown and is explored here.

Methods

Study design

This double-blinded randomised controlled clinical trial received local University College London Hospitals (UCLH) Ethics Committee approval and was conducted at the UCLH Heart Hospital (London, UK), in accordance with UCLH guidelines. Written informed consent was obtained from all patients recruited into the study. Randomisation was carried out using a computer-generated list of randomised numbers, and allocation concealment obtained using Sequentially Numbered Opaque Sealed Envelopes.

Randomisation, treatment allocation and delivery of RIPC or control protocols were performed by an unblinded investigator not involved in data collection or analysis. The investigator collecting and analysing the data, patients, cardiac surgeons and anaesthetists, operating theatre staff and staff on intensive care unit (ICU) and cardiac wards were all blinded to treatment allocation.

Inclusion and exclusion criteria

We recruited adult patients (>18 years of age) undergoing on-pump CABG and/or valve surgery at the UCLH Heart Hospital between December 2010 and July 2012. Patient exclusion criteria were cardiogenic shock or cardiac arrest in the current hospital admission; positive baseline serum hsTnT; pregnancy; significant peripheral arterial disease affecting upper and/or lower limbs; significant hepatic (INR>2.0), pulmonary (forced expiratory volume-1<40% predicted) or renal disease (estimated glomerular filtration rate <30 mL/min/1.73 m2); and concomitant therapy with glibenclamide or nicorandil, as these medications may interfere with RIPC.

Intervention

RIPC and control protocols were initiated after anaesthesia induction and completed prior to sternotomy. RIPC was delivered with one standard blood pressure cuff placed on the upper arm and another standard blood pressure cuff placed on the upper thigh. The cuffs were then simultaneously inflated to 200 mm Hg and left inflated for 5 min, then deflated to 0 mm Hg and left uninflated for 5 min. This cycle was repeated twice so that the total duration of the RIPC protocol was 20 min. If the systolic blood pressure was >185 mm Hg, the cuffs were inflated to 15 mm Hg above that level. For the control protocol, the two cuffs were placed on the upper arm and the upper thigh and left uninflated for 20 min.

Surgical procedure

Patients received premedication with oral temazepam 10–20 mg 1 h prior to surgery. Anaesthesia induction was achieved with different combinations of midazolam, etomidate, propofol, fentanyl and antinicotinic agents (rocuronium, vecuronium or pancuronium). The trachea was intubated and mechanical ventilation commenced with oxygen with or without air. Anaesthesia maintenance was achieved with volatile agents (isoflurane or sevoflurane) and propofol infusion with or without fentanyl. Arterial blood pressure, central venous pressure, leads I and III of the ECG and nasopharyngeal temperature were recorded continuously. An intravenous glyceryl trinitrate (GTN) infusion, initiated prior to sternotomy and continued until patient transfer to ICU, was administered at the discretion of the anaesthetist at a dose of 25–85 μg/kg/min (titrated to blood pressure). Standard non-pulsatile cardiopulmonary bypass (CPB) was employed using a membrane oxygenator and cardiotomy suction: following this, all coronary grafts were constructed during CPB using either intermittent cross-clamp fibrillation or blood cardioplegia. Following anastomosis of the grafts and/or valve replacement/repair, CPB was discontinued and protamine was used to achieve heparin reversal.

Study primary end point

The study primary end point was PMI, assessed by measuring the total 72-hour area under the curve (AUC) hsTnT. Blood samples for hsTnT were taken preoperatively and at 6, 12, 24, 48 and 72 h postsurgery: hsTnT was measured quantitatively by a one-step enzyme immunoassay based on electrochemiluminescence technology (Elecsys 2010, Roche, Switzerland). This assay can allow detection of concentrations <1.0 ng/L. These assays measure the upper range limit with a coefficient of variation <10%. The threshold level of ≥14 ng/L indicates significant myocardial necrosis.

Study secondary end points

These included the following:

  1. Acute kidney injury (AKI) score:18 Serum creatinine and urine output were measured preoperatively and 24, 48 and 72 h postsurgery. AKI was classified with the following grades:

    • Grade 1: serum creatinine rise of >26.4 µmol/L or 150%–200% of baseline and/or urine output <0.5 mL/kg/h for >6 contiguous hours.

    • Grade 2: serum creatinine rise of 200%–300% of baseline and/or urine output <0.5 mL/kg/h for >12 contiguous hours.

    • Grade 3: serum creatinine rise of >300% of baseline or serum creatinine >354 µmol/L with an acute rise of at least 44 µmol/L and/or urine output <0.3 mL/kg/h for >24 h or anuria for 12 h.

  2. Inotrope requirement,19 measured every 24 h over the 72 h postoperative period as dosages (µg/kg/min) of Embedded Image

  3. Length of ICU and hospital stay, calculated as the total duration in days of length of stay on ICU and in hospital.

  4. Incidence of postoperative atrial fibrillation (AF): This was the incidence of new-onset AF in the first 72 h after surgery detected by continuous telemetry and ECG (performed by a blinded staff nurse on a daily basis and immediately after the detection of AF on the telemetry, and then analysed by a blinded investigator) and requiring intervention with pharmacological treatment and/or direct current cardioversion.

  5. Major adverse cardiovascular events at 6 weeks: This was the rate of death, non-fatal myocardial infarction, coronary artery revascularisation and stroke at 6 weeks postoperatively.

Study safety end points

The main study safety end point was skeletal muscle injury from the RIPC protocol (measured by total creatine kinase (CK)-AUC over the first 72 postoperative hours) and any adverse events relating to the RIPC protocol.

Statistical analysis and sample size estimation

Data are presented as mean (SD) or median (IQR). Comparison between treatment groups was made using unpaired Student t test for approximately normally distributed variables or Wilcoxon–Mann–Whitney test for non-normal data. For outcomes collected at different time points, a repeated measures linear regression model was used to estimate the difference at each time point and 95% CIs. Categorical data were analysed using Fisher's exact test. The post hoc analysis of associations between RIPC and GTN was performed using an interaction test in a linear regression model. We hypothesised that RIPC would reduce hsTnT-AUC by a standardised difference of 0.6. At 90% power and significance at the two-sided 5% level, this required a sample size of 60 subjects, which we increased by 33% to accommodate withdrawal or missing data points. A sample size of at least 80 patients per intervention group was determined based on the following assumptions: (a) the largest published study to date on RIPC in PMI,6 (b) a power of at least 90%, (c) an SD of 0.2 µg/L and (d) type I error rate of 5%.

Analysis was by intention to treat. No adjustment for multiplicity has been applied for secondary outcomes or post hoc analyses. Data were analysed using Stata V.12.1.

Results

We assessed 340 patients for eligibility (see figure 1), of whom 180 patients were enrolled into the study and randomised to receive either RIPC (N=90) or control (N=90): a total of 178 patients were included for final analysis. No significant difference was found between the two treatment groups with respect to baseline patient characteristics (table 1). With regards to the details of surgery, the only evidence of a difference between the two groups was the percentage of patients receiving intravenous GTN, which was higher in the control group (65 vs 53 patients; table 2).

Table 1

Patient baseline characteristics

Table 2

Details of surgical procedure

Figure 1

Study profile. RIPC, remote ischaemic preconditioning; eGFR, estimated glomerular filtration rate; PAD, peripheral arterial disease; FEV, forced expiratory volume.

In all patients, the RIPC protocol was completed within an interval period not longer than 45 min prior to sternotomy. There were no untoward consequences or side effects with the RIPC protocol.

RIPC reduced the extent of PMI

The primary end point of total 72 h AUC hsTnT was reduced by 25.6% in patients randomised to receive RIPC compared with control (−9.30 μg/L, 95% CI −15.618 to −2.987, p=0.004; figure 2, table 3). Moreover, baseline preoperative hsTnT levels were <0.02 μg/L and were not significantly different between RIPC and control groups (−0.003 μg/L, 95% CI −0.009 to 0.003), p=0.308; figure 2, table 3). In patients randomised to RIPC, the mean hsTnT was significantly reduced at 6, 12, 24, 48 and 72 h postsurgery compared with control (figure 2, table 3).

Table 3

Summary of study end points

Figure 2

Serum hsTnT levels. Values are mean±SEM. hsTnT, high-sensitivity troponin-T; RIPC, remote ischaemic preconditioning.

RIPC protected kidney function during surgery

The incidence of AKI was decreased in RIPC-treated patients, with 10 new cases of postoperative AKI in the preconditioned group, compared with 19 new cases in the control group, that is, 10.0% versus 21.0% of new cases, which corresponded to a relative reduction of AKI 48% (p=0.063: table 3).

RIPC reduced the incidence of AF and shortened ICU stay

RIPC reduced the incidence of new onset of postoperative AF in the first 72 h postsurgery by 54% (10 RIPC vs 22 control; p=0.03) and decreased the length of ICU stay (RIPC 2.0 days (IQR 1.0 to 4.0) vs control 3.0 days (IQR 2.0 to 4.5); p=0.04) (table 3).

Other end points

Total CK release was not statistically different between control and RIPC patients (32 543±27 087 µg/L control vs 36 312±19 496 μg/L RIPC; 3769.6 difference (CI −4647.0 to 12186.2); p=0.38), demonstrating that the multilimb RIPC stimulus was not associated with a significant skeletal muscle injury (table 3). There was no difference in total inotrope requirement or major adverse cardiac events at 6 weeks in patients randomised to RIPC compared with control (table 3).

Post hoc subgroup analysis

We performed a post hoc subgroup analysis to examine the effect of administering an intravenous GTN infusion during surgery on the magnitude of PMI. Interestingly, we found that the total 72 h AUC hsTnT was reduced by 39% in those control patients who had been administered intraoperative intravenous GTN compared with those control patients who had not (GTN 30.8±17.6 μg/L vs no GTN 50.5±34.2 μg/L (−19.7 difference (CI −29.7 to −9.8); p<0.001; figure 3A; table 4), suggesting that intraoperative intravenous GTN itself can reduce PMI.

Table 4

Effect of intravenous glyceryl trinitrate (GTN) on plasma hsTnT levels in control and RIPC patients

Figure 3

(A) Serum high-sensitivity troponin-T release in a subgroup of patients receiving intravenous GTN intraoperatively. Values are mean±SEM. (B) Serum high-sensitivity troponin-T release in a subgroup of patients not receiving intravenous GTN intraoperatively. Values are mean±SEM. hsTnT, GTN, glyceryl trinitrate; high-sensitivity troponin-T; RIPC, remote ischaemic preconditioning.

We also investigated whether administering an intravenous GTN infusion during surgery affected the cardioprotective efficacy of RIPC. RIPC did not reduce the magnitude of PMI in those patients who had been administered intraoperative intravenous GTN compared with those RIPC patients who had not (RIPC+GTN 26.7±13.9 μg/L vs RIPC+no GTN 27.9±20.10 μg/L (−1.2 difference (CI −9.9 to −7.6); p=0.793, figure 3B; table 4), suggesting that the beneficial effect of RIPC on PMI was absent in the presence of intraoperative intravenous GTN.

Discussion

In an unselected prospective cohort of 180 adult patients undergoing elective CABG and/or valve surgery, we have demonstrated that a shortened RIPC protocol can reduce the amount of PMI by 26%. In addition, there is a possibility that RIPC may also improve short-term clinical outcomes with a 54% reduction in the incidence of postoperative AF, a 48% decrease in the incidence of AKI and a shortening of ICU stay by 1 day. However, the effect of RIPC on these outcome measures will have to be repeated in future studies.

A number of small clinical trials have investigated the effect of a standard single-limb RIPC protocol on the magnitude of PMI in patients undergoing cardiac surgery, the majority of which have demonstrated beneficial effects on PMI magnitude.4 ,5 ,7 This has also been confirmed by a number of recent meta-analyses.20 One clinical study has even suggested reduced mortality in preconditioned patients.21 However, several recent studies have failed to demonstrate beneficial effects of RIPC in this patient group.6 ,10 ,17 One potential explanation for these differences may relate to the RIPC stimulus itself, which may not be sufficient to elicit cardioprotection under certain conditions: the majority of clinical studies have used a standard single-limb RIPC protocol comprising either three or four 5 min cycles of inflation/deflation of a cuff placed on either the upper arm or thigh. In our study, we used a more intense RIPC protocol comprising two 5 min cycles of simultaneous upper arm and thigh cuff inflation and deflation, which can be delivered far more rapidly, requiring only 20 min, compared with 40 min using the standard single-limb four-cycle RIPC protocol. This allowed the multilimb RIPC protocol to be delivered after the induction of anaesthesia and well before sternotomy. Another potential explanation could be the timing of delivery of the RIPC stimulus: two of the negative studies that failed to report any beneficial effects with RIPC administered the protocol after sternotomy had taken place,6 ,10 whereas in the vast majority of clinical studies the RIPC stimulus is initiated and completed prior to sternotomy.

A further possible reason for failing to observe RIPC cardioprotection in patients undergoing cardiac surgery may be due to concomitant therapy, including intravenous GTN: in a post hoc subgroup analysis of data, we investigated the effect of intraoperative intravenous GTN on PMI, in relation to the cardioprotective effect of RIPC. Interestingly, we found that control patients given intravenous GTN during surgery sustained 39% less PMI than control patients who did not receive intravenous GTN. Furthermore, in preconditioned patients administered intravenous GTN during surgery, RIPC had no beneficial effect on PMI, whereas in preconditioned patients not given intravenous GTN, RIPC significantly reduced the amount of PMI. It is well established in the published literature that nitric oxide donors such as GTN are highly effective mediators of cardioprotection in both the preclinical and the clinical settings.22 ,23 These findings suggest that RIPC may not be able to elicit cardioprotection in the presence of intravenous GTN, as the myocardium may have already been protected by the GTN itself. In contrast to our findings, a recently published retrospective analysis by Kleinbongard et al21 has suggested that intravenous GTN had no effect on RIPC cardioprotection in patients undergoing CABG surgery. Therefore, it will be important to investigate whether GTN is cardioprotective and whether RIPC cardioprotection is attenuated when it is present in a suitably powered prospective randomised controlled clinical trial.

In our study, the incidence of postoperative AF was reduced by 55% in RIPC-treated patients: new-onset AF occurs in 30%–50% of patients following cardiac surgery24 and is associated with increased rates of death, thromboembolic events, left ventricular failure, prolonged hospitalisation, reduced quality of life and poor exercise capacity.24 The aetiology of postoperative AF is multifactorial, with acute myocardial IRI being one contributory factor.24 Therefore, RIPC may have decreased the incidence of postoperative AF by protecting the myocardium against acute IRI. However, Rahman et al6 failed to demonstrate any effect of RIPC on AF incidence following cardiac surgery. An ongoing large multicentre RICO trial is currently investigating the effects of RIPC on the incidence of postoperative AF in patients with CABG (ClinicalTrials.gov: NCT01107184).25

AKI can affect up to 30% of patients postcardiac surgery, necessitating dialysis in 1%–2% of cases and ultimately leading to an eightfold increase in death rate.26 A number of clinical studies have investigated the effect of RIPC on postoperative renal function in patients undergoing cardiac surgery, where once again IRI plays a significant pathogenic role.26 However, the results have been controversial:6 ,10 ,11 ,27 ,28 our study is the largest to report a potential renoprotective effect with RIPC in patients undergoing cardiac surgery and found both an improved postoperative urine output and a reduced AKI incidence of 48% in preconditioned patients, although this did not reach statistical significance.

Finally, our study is the first to report beneficial effects of RIPC on the length of ICU stay following cardiac surgery: we found that RIPC shortened the duration of ICU stay by 1 day, a finding that may well be related to reduced PMI magnitude and decreased postoperative AF and AKI incidence.

One important limitation of our study was the blinding of the RIPC protocol in the anaesthetic room, which, because of the nature of the intervention, was difficult to achieve in an optimal manner. However, it is important to note that all data were collected by a research investigator blinded to the treatment allocation. Another limitation of our study was not adjusting for multiple comparisons and therefore, we restricted the number of comparisons we performed to the minimum in order to reduce the risk of a type I error. However, despite doing this, the effect of RIPC on clinical outcomes should be treated as ‘hypothesis generating’ and there is a possibility that the results may have arisen by chance, and therefore the clinical outcome data will need to be confirmed in future studies.

In summary, we have demonstrated that RIPC applied by simultaneous multilimb IRI can reduce the magnitude of PMI and has the potential to improve short-term clinical outcomes in an unselected cohort of adult patients undergoing elective CABG and/or valve surgery. However, the effect of RIPC on short-term clinical outcomes will have to be confirmed in future studies. Large multicentre randomised controlled clinical trials are currently being undertaken to evaluate the potential effects of RIPC on long-term clinical outcomes in patients undergoing CABG with or without valve surgery (ERICCA trial,29 ClinicalTrial.gov identifier: NCT01247545 and RIPHeart trial,30 ClinicalTrials.gov identifier: NCT01067703).

Key messages

  • What is known on this subject?

  • Remote ischaemic preconditioning (RIPC) may reduce perioperative myocardial injury in patients undergoing coronary artery bypass graft (CABG) surgery. Whether it can improve clinical outcomes in this patient group is unknown and is investigated in our study.

  • What might this study add?

  • We find that RIPC may improve short-term clinical outcomes as evidenced by reduced incidences of postoperative atrial fibrillation, acute kidney injury and a shortened ICU stay.

  • How might this impact on clinical practice?

  • RIPC may improve morbidity and mortality in patients undergoing CABG surgery and it, therefore, has the potential to change clinical practice.

Acknowledgments

We express our gratitude to the staff and patients at the UCLH Heart Hospital.

References

Footnotes

  • DJH and DMY are joint senior authors.

  • Contributors All authors contributed to this study.

  • Funding This research study was funded by British Heart Foundation (grant numbers RG/03/007 and FS/10/039/28270), the Rosetrees Trust and supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval UCLH Ethics Committee.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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