Advertisement

BMC Anesthesiology

, 19:175 | Cite as

Glucose-insulin-potassium improves left ventricular performances after aortic valve replacement: a secondary analysis of a randomized controlled trial

  • Marc LickerEmail author
  • John Diaper
  • Tornike Sologashvili
  • Christoph Ellenberger
Open Access
Research article
Part of the following topical collections:
  1. Perioperative medicine and outcome

Abstract

Background

Patients with left ventricular (LV) hypertrophy may suffer ischemia-reperfusion injuries at the time of cardiac surgery with impairment in left ventricular function. Using transesophageal echocardiography (TEE), we evaluated the impact of glucose-insulin potassium (GIK) on LV performances in patients undergoing valve replacement for aortic stenosis.

Methods

In this secondary analysis of a double-blind randomized trial, moderate-to-high risk patients were assigned to receive GIK (20 IU insulin with 10 mEq KCL in 50 ml glucose 40%) or saline over 60 min upon anesthetic induction. The primary outcomes were the early changes in 2-and 3-dimensional left ventricular ejection fraction (2D and 3D-LVEF), peak global longitudinal strain (PGLS) and transmitral flow propagation velocity (Vp).

Results

At the end of GIK infusion, LV-FAC and 2D- and 3D-LVEF were unchanged whereas Vp (mean difference [MD + 7.9%, 95% confidence interval [CI] 3.2 to 12.5%; P <  0.001) increased compared with baseline values. After Placebo infusion, there was a decrease in LV-FAC (MD -2.9%, 95%CI − 4.8 to − 1.0%), 2D-LVEF (MD -2.0%, 95%CI − 2.8 to − 1.3%, 3D-LVEF (MD -3.0%, 95%CI − 4.0 to − 2.0%) and Vp (MD − 4.5 cm/s, 95%CI − 5.6 to − 3.3 cm/s).

After cardiopulmonary bypass, GIK pretreatment was associated with preserved 2D and 3D-LVEF (+ 0.4%, 95% 95%CI − 0.8 to 1.7% and + 0.4%, 95%CI − 1.3 to 2.0%), and PGLS (− 0.9, 95%CI − 1.6 to − 0.2) as well as higher Vp (+ 5.1 cm/s, 95%CI 2.9 to 7.3), compared with baseline. In contrast, in the Placebo group, 2D-LVEF (− 2.2%, 95%CI − 3.4 to − 1.0), 3D-LVEF (− 6.0%, 95%CI − 7.8 to − 4.2), and Vp (− 7.6 cm/s, 95%CI − 9.4 to − 5.9), all decreased after bypass.

Conclusions

Administration of GIK before aortic cross-clamping resulted in better preservation of systolic and diastolic ventricular function in patients with LV hypertrophy undergoing aortic valve replacement.

Trial registration

ClinicalTrials.gov: NCT00788242, registered on November 10, 2008.

Keywords

Aortic valve stenosis Echocardiography Myocardial protection 

Abbreviations

AVR

aortic valve replacement

BGC

blood glucose concentration

CABGS

coronary artery bypass graft surgery

CPB

cardiopulmonary bypass

GIK

glucose-insuline-potassium

LVEF

left ventricular ejection fraction

PCVD

postcardiotomy ventricular dysfunction

PGLS

peak global longitudinal strain

TEE

transesophageal echocardiography

Vp

transmitral flow propagation velocity

Introduction

Currently, aortic valve replacement (AVR) remains the standard of care to treat patients with severe aortic valvular stenosis, although elderly and high-risk patients may now benefit from a lesser invasive transarterial vascular approach [1]. Low cardiac output syndrome occurs in 5 to 15% of patients undergoing open heart surgery and is a main cause of mortality [2]. Following AVR, patients with aortic stenosis are prone to develop myocardial injuries and contractile dysfunction owing to difficulties in protecting the hypertrophic heart with cardioplegic solutions [2, 3].

The term “postcardiotomy ventricular dysfunction” (PCVD) has been coined to define new onset or worsening heart failure that develops following weaning from cardiopulmonary bypass (CPB) and that requires support with inotropes [4]. Transesophageal echocardiography (TEE) coupled with haemodynamic monitoring allows the cardiac team to distinguish PCVD from other functional or structural abnormalities such as valve prosthesis/patient mismatch, myocardial ischemia or systolic anterior motion of the anterior mitral leaflet [5, 6].

In animal models of ischemia-reperfusion, there is strong evidence that the infusion of glucose-insulin-potassium (GIK) minimizes myocardial injuries [7, 8]. In patients undergoing open heart surgery, although the administration of GIK has been shown to improve cardiac output, few and conflicting results have been reported regarding functional ventricular performances [9, 10].

The aim of this study was to investigate the changes in left ventricular function using TEE, in moderate-to-high risk patients undergoing AVR.

Materials and methods

With ethical approval from the local ethics commission (CER 08–095), a randomized controlled blinded trial was conducted at the University Hospital of Geneva and was registered November 10, 2008 on ClinicalTrials.gov (NCT00788242). Written consent was obtained from each eligible participant. The trial was conducted in accordance with the Consolidated Standards of Reporting Trials (CONSORT) 2010 statement [11].

From January 1, 2009 to December 31, 2013, adult patients with severe aortic valve stenosis and/or coronary artery disease scheduled for elective AVR and/or coronary artery bypass surgery (CABGS) were enrolled if they had a Parsonnet score higher than 7. Exclusion criteria were the presence of poorly controlled diabetes mellitus, liver disease (Child-Pugh C stage), dementia, cerebrovascular disease or contraindications for TEE.

Results regarding clinical outcomes and the incidence of PCVD (main study endpoints) in the whole population have been reported previously as well as the effects of GIK on TEE parameters (secondary endpoints) in the CABGS subpopulation [12, 13]. In the current report and as preplanned, we analyzed the effects of GIK infusion on TEE parameters before and after CPB in patients who underwent isolated AVR (without CABGS), in whom TEE was completed with good quality imaging.

The randomization and blinding process as well as perioperative care has been described elsewhere in detail [12]. In short, patients were randomized in two groups (1:1), receiving an unlabeled coded solution (NaCl 0.9%, in Placebo group or Actrapid, Novo Nordisk 20 IU and potassium chloride 10 mEq in 50 ml of 40% glucose, in GIK group) over 60 min upon anesthetic induction (Fig. 1). A standard anesthesia technique was applied that included inhaled sevoflurane for myocardial preconditioning and intrathecal morphine analgesia to minimize the administration of opiates and facilitate early extubation. All surgical procedures were performed via sternotomy, under normothermic nonpulsatile CPB. Weaning from CPB was standardized and guided by TEE and hemodynamic measurements [14].
Fig. 1

Time line of study protocol describing the study interventions (saline vs glucose-insuline-potassium), surgical/anesthetic events and data collection

The primary outcome variable was the left ventricular ejection fraction (LVEF) as measured by two- and three dimensional (2D and 3D) echocardiography, peak global longitudinal strain (PGLS) and transmitral flow propagation velocity (Vp). Secondary study endpoints included other TEE parameters as well as hemodynamic parameters. TEE data acquisition was performed intraoperatively by two experienced echocardiographers at three time points, before drug infusion, 20 min after drug infusion and at the end of surgery (Fig. 1) using an iE33 ultrasound system (Philips Medical System, Einthoven, Netherland). The acquisition process has previously been described in detail [13]. In short, a comprehensive TEE examination was performed. 2D-LVEF was assessed using the Simpson’s method of discs. 3D-LVEF was assessed from a full volume scan of the left ventricle (with 4 R-wave triggered sub-volumes) using the QLAB 3D-advanced quantification software package. Speckle-tracking analysis to assess PGLS was performed with the cardiac motion quantification software (CMQ-Advanced; Philips Healthcare, Einthoven, Netherland). Transmitral flow propagation velocity (Vp) was determined from the mid-esophageal 4-chamber view using the color M-mode. Intraobserver and interobserver variabilities for 2-D/3D LVEF, PGLS and Vp were studied off-line in randomly selected patients (n = 10).

Details on the statistical analysis have been given previously [13]. Summary descriptive statistics are expressed as frequencies (and percentages, %), medians (and interquartile range, IQR 25–75%), and means (and standard deviations, SD). Two-sided unpaired t tests, Wilcoxon rank-sum tests, chi-squared tests, and repeated-measures two-way analysis of variance (ANOVA) was used to estimate between and within group differences when appropriate. Inter- and intra-observer variabilities in echocardiographic measurements were assessed using the Pearson’s correlation coefficient. Statistical tests were conducted using STATA 14 software (Stata Corp, College Station, TX, USA).

Results

The Consolidated Standards of Reporting Trials (CONSORT) diagram is shown in Fig. 2. From a total of 295 screened patients, 212 were randomized into GIK and Placebo groups (110 and 112, respectively). Among those undergoing isolated AVR, 63 and 44 were allocated to Placebo and GIK groups, respectively. After exclusion of cases with unavailable or poor quality TEE (N = 15), 92 patients remained for final analysis (Placebo, N = 54 and GIK, N = 38).
Fig. 2

Consolidated Standards of Reporting Trials flow diagram. AVR, aortic valve replacement; CABGS, coronary artery bypass graft surgery; GIK, glucose-insuline-potassium; TEE, transesophageal echocardiography

As shown in Tables 1, the two groups were well balanced in baseline preoperative variables and surgical characteristics. Intraoperatively, BGC were similar in the two groups, with no difference regarding the need for glucose infusion (GIK, 4 (7%) vs Placebo 3 (4%), respectively, P = 0.689) and insulin being added more frequently in the GIK group (24 (44%) vs 14 (20%) in Placebo, P = 0.004). Strong intra-rater and inter-rater reproducibility for all TEE parameters was reported as correlation coefficients with 95%CI (Table 2).
Table 1

Clinical and surgical characteristics of patients undergoing aortic valve replacement and receiving Saline or Glucose-Insulin Potassium (GIK) infusion

Characteristics

Placebo

GIK

P value

(N = 54)

(N = 38)

Demographics

 Age, yearsa

73.2

(9.6)

71.7

(9.8)

0.464b

 Body Mass indexa

29.5

(6.1)

27.7

(4.5)

0.128b

 Sex, male

33

(61.1)

20

(52.6)

0.418

Comorbidities

 Bernstein-Parsonnet scorea

21.8

(7.5)

20.8

(8.3)

0.547b

 Hypertension

47

(87.0)

37

(97.4)

0.083

 Pulmonary Hypertension

2

(3.7)

3

(7.9)

0.645c

 Hypercholesterolemia

37

(68.5)

29

(76.3)

0.413

 Diabetes mellitus

17

(31.5)

13

(34.2)

0.783

 Vascular disease

23

(42.6)

15

(39.5)

0.765

 Chronic Obstructive Lung Disease

6

(11.1)

2

(5.3)

0.463c

 Previous cardiac surgery

3

(5.6)

1

(2.6)

0.640c

Preoperative blood parameters

 Hemoglobin, g/dLa

12.5

(2.1)

12.4

(2.0)

0.747b

 Creatinine clearance, ml/min a

81.1

(34.6)

75.4

(30.0)

0.418b

Surgical data

 CPB time, mina

97.1

(37.5)

102.2

(47.8)

0.564b

 Aortic clamping time, mina

74.3

(29.0)

76.5

(32.0)

0.730b

Intraoperative fluids and blood

 Crystalloids and colloids, mla

3′213

(1214)

2′897

(850)

0.170b

 Blood transfusion

31

(57.4)

26

(68.4)

0.284

 Fresh frozen plasma

12

(22.2)

9

(23.7)

0.869

 Platelets

8

(14.8)

4

(10.5)

0.362

Blood glucose (mMol/L)

 Start of surgerya

6.7

(1.5)

6.7

(1.6)

0.980b

 Before bypassa

7.4

(1.6)

7.6

(2.9)

0.621b

 During Bypassa

7.4

(1.7)

7.1

(2.5)

0.556b

 End of surgerya

7.6

(1.9)

6.8

(2.1)

0.158b

Data given as number (percentage) unless otherwise indicated. Chi-squared tests were used for statistical tests unless otherwise indicated. a Data given as mean (standard deviation); b student t test. c Fisher exact test

AVR aortic valve replacement, CABG coronary artery bypass grafting, CPB cardiopulmonary bypass

Table 2

Interobserver and intraobserver variability for measurements of transesophageal echocardiographic data

Measurements

Interobserver

Correlation

Coefficient

95% Confidence Interval

Intraobserver

Correlation

Coefficient

95% Confidence Interval

Vp

0.742

0.488–0.945

0.791

0.477–0.944

FAC

0.956

0.890–0.983

0.883

0.723–0.953

2D-LVEF

0.890

0.739–0.956

0.923

0.812–0.970

3D-LVEF

0.819

0.591–0.926

0.840

0.595–0.973

PGLS

0.856

0.571–0.908

0.899

0.671–0.943

Vp, transmitral flow propagation velocity; FAC, fractional area change; 2D-LVEF-, two-dimensional left ventricular ejection fraction; 3D-LVEF-, three-dimensional left ventricular ejection fraction; PGLS, peak global longitudinal strain

At baseline, patients presented similarly increased LV posterior wall thickness (1.19 ± 0.23 mm and 1.21 ± 0.19 mm in Placebo and GIK groups, respectively; P = 0.543) whereas LV-FAC, 2DLVEF, 3D-LVEF and Vp were lower in the GIK group compared with the Placebo group (Table 3).
Table 3

Echocardiographic parameters in patients undergoing aortic valve replacement and receiving Placebo or Glucose-Insulin Potassium (GIK) infusion

Parameter

Start surgery

After GIK

End Surgery

P-value

Preload

 End diastolic area (cm2)

  All patients

13.9

(3.3)

13.2

(3.0)

12.6

(3.4)

< 0.001

  Placebo group

13.6

(2.7)

12.9

(2.4)

12.3

(2.9)

< 0.001

  GIK group

14.3

(4.5)

13.5

(3.8)

13.0

(4.1)

0.001

    

Baseline difference

0.362

    

Effect modification by GIK

0.949

Systolic function

 LV FAC (%)

  All patients

47.1

(6.2)

45.4

(8.4)

44.7

(7.8)

0.033

  Placebo group

48.4

(6.1)

45.5

(8.5)

42.7

(8.5)

< 0.001

  GIK group

45.2

(6.0)

45.2

(8.4)

47.5

(5.8)

0.052

    

Baseline difference

0.016

    

Effect modification by GIK

< 0.001

3D-LVEF (%)

 All patients

47.5

(6.4)

46.2

(5.5)

44.1

(6.4)

< 0.001

 Placebo group

49.3

(5.4)

46.3

(5.2)

43.3

(6.8)

< 0.001

 GIK group

44.9

(6.9)

46.0

(5.9)

45.2

(5.7)

0.236

    

Baseline difference

< 0.001

    

Effect modification by GIK

< 0.001

2D-LVEF (%)

 All patients

43.7

(5.3)

42.5

(5.4)

42.5

(5.9)

0.006

 Placebo group

44.7

(4.5)

42.7

(5.3)

42.5

(6.5)

< 0.001

 GIK group

42.2

(6.1)

42.4

(5.7)

42.6

(5.0)

0.722

    

Baseline difference

0.023

    

Effect modification by GIK

0.002

PGLS (%)

 All patients

−12.3

(2.5)

−12.6

(2.1)

0.151

 Placebo group

−12.6

(2.3)

−12.6

(1.9)

0.985

 GIK group

−11.8

(2.7)

−12.6

(2.4)

0.014

    

Baseline difference

0.157

    

Effect modification by GIK

0.076

LV systolic strain rate (s−1)

 All patients

−1.04

(0.29)

−1.07

(0.24)

0.174

 Placebo group

−1.07

(0.26)

−1.07

(0.25)

1.000

 GIK group

−0.99

(0.32)

−1.07

(0.23)

0.053

    

Baseline difference

0.202

    

Effect modification by GIK

0.094

Diastolic function

 E-wave velocity (cm/s)

  All patients

58.8

(14.2)

56.9

(13.6)

58.2

(16.3)

0.505

  Placebo group

59.8

(13.5)

56.3

(13.4)

56.2

(17.8)

0.229

  GIK group

57.2

(15.3)

57.7

(14.0)

61.0

(13.7)

0.286

    

Baseline difference

0.391

    

Effect modification by GIK

0.136

A-wave velocity (cm/s)

 All patients

59.5

(16.0)

58.4

(15.4)

58.8

(19.2)

0.707

 Placebo group

57.9

(14.3)

58.0

(14.1)

63.1

(20.6)

0.047

 GIK group

61.8

(18.0)

58.9

(17.3)

52.8

(15.2)

< 0.001

    

Baseline difference

0.249

    

Effect modification by GIK

< 0.001

E/A ratio

 All patients

1.06

(0.43)

1.05

(0.41)

1.09

(0.54)

0.660

 Placebo group

1.12

(0.48)

1.03

(0.38)

0.99

(0.62)

0.274

 GIK group

0.99

(0.34)

1.08

(0.46)

1.22

(0.39)

< 0.001

    

Baseline difference

0.161

    

Effect modification by GIK

0.007

Pressure half-time (ms)

 All patients

55.0

(14.9)

53.8

(13.7)

51.3

(13.9)

0.210

 Placebo group

54.6

(14.3)

54.4

(14.4)

51.0

(13.4)

0.851

 GIK group

55.6

(15.9)

52.9

(12.8)

51.7

(14.8)

0.082

    

Baseline difference

0.757

    

Effect modification by GIK

0.235

Isovolemic relaxation time (ms)

 All patients

88.3

(37.0)

89.0

(35.7)

83.6

(33.5)

0.133

 Placebo group

90.8

(37.9)

87.4

(36.2)

84.5

(37.6)

0.229

 GIK group

84.7

(35.7)

91.2

(35.4)

82.4

(27.0)

0.126

    

Baseline difference

0.440

    

Effect modification by GIK

0.213

S-wave velocity (LUPV) (cm/s)

 All patients

30.8

(9.3)

29.7

(9.7)

27.6

(9.5)

0.015

 Placebo group

31.7

(9.6)

29.4

(9.8)

26.7

(9.5)

0.011

 GIK group

29.4

(8.8)

30.2

(9.5)

28.9

(9.5)

0.336

    

Baseline difference

0.247

    

Effect modification by GIK

0.015

D-wave velocity (LUPV) (cm/s)

 All patients

23.2

(6.8)

22.1

(6.7)

22.3

(10.5

0.397

 Placebo group

22.8

(6.9)

22.8

(7.6)

23.8

(11.8)

0.652

 GIK group

23.8

(6.8)

21.2

(4.9)

20.3

(6.7)

0.005

    

Baseline difference

0.520

    

Effect modification by GIK

0.065

A-wave velocity (LUPV) (cm/s)

 All patients

11.8

(4.2)

11.8

(4.3)

9.8

(4.8)

< 0.001

 Placebo group

12.4

(4.2)

12.1

(4.8)

7.9

(4.4)

< 0.001

 GIK group

10.8

(4.0)

11.3

(3.6)

12.4

(4.1)

0.076

    

Baseline difference

0.066

    

Effect modification by GIK

< 0.001

S/D ratio

 All patients

1.42

(0.59)

1.44

(0.62)

1.42

(0.68)

0.871

 Placebo group

1.46

(0.49)

1.38

(0.53)

1.35

(0.69)

0.429

 GIK group

1.35

(0.71)

1.52

(0.73)

1.52

(0.66)

0.119

    

Baseline difference

0.385

    

Effect modification by GIK

0.080

Early lateral velocity (cm/s)

 All patients

10.2

(2.9)

9.5

(2.7)

8.2

(2.3)

<  0.001

 Placebo group

10.4

(2.9)

9.5

(2.7)

7.4

(2.2)

< 0.001

 GIK group

9.8

(2.9)

9.6

(2.7)

9.3

(2.1)

0.274

    

Baseline difference

0.387

    

Effect modification by GIK

< 0.001

Late lateral velocity (cm/s)

 All patients

9.0

(2.5)

8.7

(2.2)

7.5

(2.2)

< 0.001

 Placebo group

9.0

(2.7)

8.9

(2.2)

7.8

(2.4)

0.002

 GIK group

8.9

(2.2)

8.4

(2.2)

6.9

(1.7)

< 0.001

    

Baseline difference

0.815

    

Effect modification by GIK

0.236

Early septal velocity (cm/s)

 All patients

6.1

(1.6)

5.7

(1.5)

4.9

(1.4)

< 0.001

 Placebo group

6.0

(1.5)

5.6

(1.5)

4.5

(1.2)

< 0.001

 GIK group

6.3

(1.6)

5.9

(1.6)

5.6

(1.4)

0.010

    

Baseline difference

0.445

    

Effect modification by GIK

0.019

Late septal velocity (cm/s)

 All patients

5.8

(1.9)

5.5

(1.8)

4.5

(1.7)

< 0.001

 Placebo group

5.6

(2.0)

5.3

(1.9)

4.8

(1.8)

0.003

 GIK group

6.0

(1.8)

5.7

(1.6)

4.1

(1.4)

< 0.001

    

Baseline difference

0.342

    

Effect modification by GIK

0.003

E/e’ ratio

 All patients

6.2

(2.4)

6.4

(2.5)

7.6

(3.1)

< 0.001

 Placebo group

6.2

(2.2)

6.4

(2.8)

8.2

(3.7)

< 0.001

 GIK group

6.3

(2.6)

6.4

(2.0)

6.8

(1.7)

0.342

    

Baseline difference

0.828

    

Effect modification by GIK

0.026

Flow Propagation Velocity (cm/s)

 All patients

42.6

(7.3)

41.3

(6.7)

40.2

(7.0)

0.014

 Placebo group

44.0

(6.9)

39.5

(5.9)

36.3

(6.1)

< 0.001

 GIK group

40.6

(7.6)

43.8

(7.0)

45.7

(3.9)

< 0.001

    

Baseline difference

0.030

    

Effect modification by GIK

< 0.001

Data given as mean (standard deviation)

Repeated-measures two-way analysis of variance (ANOVA) with Greenhouse-Geisser correction was used to estimate trend differences between and within group differences

LV FAC, left ventricular fractional area change; 3D-LVEF, three-dimensional left ventricular ejection fraction; 2D-LVEF, two-dimensional left ventricular ejection fraction; PGLS, peak global longitudinal strain; LUPV, left upper pulmonary vein

Throughout the three study periods, GIK infusion produced strong interaction effects on LVFAC, 2D-LVEF, 3D-LVEF and Vp (p <  0.001). At the end of GIK infusion, LV-FAC and 2D- and 3D-LVEF were unchanged whereas Vp (mean difference [MD + 7.9%, 95% confidence interval [CI] 3.2 to 12.5%; P <  0.001) increased compared with baseline values (Table 3). After Placebo infusion, we observed decreases in LV-FAC (MD -2.9%, 95%CI − 4.8 to − 1.0%), 2D-LVEF (MD -2.0%, 95%CI − 2.8 to − 1.3%, 3D-LVEF (MD -3.0%, 95%CI − 4.0 to − 2.0%) and Vp (MD − 4.5 cm/s, 95%CI − 5.6 to − 3.3 cm/s) compared with baseline values.

After separation from CPB, mean transprosthetic pressure gradients were comparable in the two groups (6 mmHg [2] in Placebo and 7 mmHg [2] in GIK, P = 0.463).

Compared with baseline values, LVFAC, 2D-LVEF and 3D-LVEF, all decreased at the end of surgery in the Placebo group, [MD] -5.7%, P <  0.001; MD -2.2%, P <  0.001; MD -6.0%, P <  0.001, respectively) whereas these indices of systolic LV function improved or remained unchanged in the GIK group (MD + 2.3%; P = 0.017, MD, + 0.4%, P = 0.503, MD + 0.4%, P = 0.671, respectively) (Fig. 3). Patients receiving GIK presented minor changes in PGLS (MD -0.9, P = 0.014) and LV strain rate (MD -0.08, P = 0.053). In the Placebo group, there was no change in PGLS and LV strain rate from pre-bypass to post-bypass condition.
Fig. 3

Hemodynamic and echocardiographic changes from baseline after study drug administration and at the end of surgery in patients undergoing aortic valve replacement and receiving Placebo or Glucose-Insulin Potassium (GIK) infusion

In the GIK group, the E/A ratio and Vp were higher at the end of surgery compared with baseline (MD + 19.5%, P < 0.001; MD + 5.1 cm/s, P < 0.001, respectively) and compared with the Placebo group. As indicators of cardiac preload, the E/e’ ratio was increased at the end of surgery, compared with baseline, in the Placebo group (MD 32.2%, 95%CI 16.3 to 48.1%, P < 0.001) whereas this cardiac filling parameter remained unchanged in the GIK group.

After weaning from CPB, GIK pretreated patients less frequently required norepinephrine (11 [29.0%] vs 44 (81.5%], in the Placebo group), dobutamine (5 [13.2%] vs 29 [53.7%] in the Placebo group), epinephrine (1 [2.6%] vs 7 (13.0%], in the Placebo group), or a combination of at least two inotropes (4 [10.5%] vs 32 [59.3%] in the Placebo group).

Discussion

In this randomized controlled trial including patients undergoing isolated AVR for aortic stenosis, we demonstrated that the infusion of GIK, − in addition to usual cardioprotective techniques -, prevented the early impairment in LV systolic and diastolic function following separation from CPB and resulted in lesser requirement of cardiovascular drug support. The extent of the benefit was similar to that seen in patients undergoing CABGS [13].

Patients included in this trial are likely to correspond to recent evolution of real-world cardiac surgery. Using the Parsonnet score, the increased operative risk profile was mainly related to hypertension (91% of patients), advanced age (61% ≥70 years) hyperlipidemia (72%) and diabetes mellitus (33%), all factors known to be implicated in promoting LV hypertrophy and impaired LV function. The development of valvular aortic stenosis was another trigger for structural remodeling of the LV as characterized by cardiomyocytes hypertrophy and apoptosis, decreased coronary flow reserve, reduced capillary density, as well as intercellular matrix fibrosis [3, 15]. In the hypertrophied LV, the relative deficient microcirculation hinders the delivery of the cardioplegic solution particularly to the subendocardium, therefore compromising intra-operative myocardial preservation and rendering the heart more susceptible to ischemia-reperfusion injuries following weaning from CPB as manifested by early deterioration of LV performances and release of myocardial biomarkers [3, 5, 15].

In both groups, standardized cardioprotective strategies were applied including antegrade administration of cold blood cardioplegia and pre-ischemic exposure to volatile anesthetics. Although no clear benefit has so far been demonstrated by varying the composition of cardioplegia or its delivery (retrograde vs antegrade), many cardiac teams have adopted the infusion of cold oxygenated blood as it provides effective buffering and uniform capillary flow through the myocardium [16, 17, 18]. Anesthetic preconditioning may also enhance cardioprotection by modulating mitochondrial electron pathways and ATP level through protein kinase C and KATP channels [19, 20].

Besides standard 2D TEE examination, additional imaging techniques including 3D echocardiography and speckle tracking have been used to improve the reliability of the TEE assessment. Three dimensional echocardiography has shown an excellent agreement with magnetic resonance imaging in assessing LV function [21] whereas quantification of systolic longitudinal fiber shortening is particularly valuable in patients with LV hypertrophy since the subendocardial longitudinal fibers are more sensitive to ischemia and wall stress [22]. Abnormal patterns of deformation have been documented in the setting of preserved LVEF and changes in GLS parameters have been shown to detect early functional improvement associated with LV remodeling shortly after AVR [23].

In patients with aortic stenosis undergoing AVR, two previous randomized controlled trials have evaluated the potential cardioprotective effects of perioperative infusion of GIK and reported opposing results. Using speckle tracking echocardiography, Duncan et al. failed to demonstrate any clinically relevant improvement in longitudinal myocardial strain in patients treated by hyperinsulinemic normoglycemic clamp [24]. In contrast, in the Hypertrophy, Insulin, Glucose, and Electrolytes (HINGE) trial, Howell et al. reported a lower incidence of low cardiac output syndrome (− 70% compared with usual care group) with lesser requirement for inotropes and non-significant changes in biomarkers of myocardial injury [25]. Different patient’s populations, as well as different timing and dosing of GIK could partly explain these discrepant results. Compared with the HINGE trial, patients enrolled in Duncan’s study presented lesser degree of LV hypertrophy and well-preserved systolic LV function (mean LVEF of 62%); in addition, insulin was frequently administered in the Control group to maintain a tight glycemic control. In our trial, patients were even sicker, they had lower LVEF (mean value of 47%) compared with the HINGE trial and Duncan’s study (59% and 66%, respectively) providing more opportunity for testing cardioprotection in the intervention arm. Moreover, we limited the GIK infusion only to the pre-bypass period, in contrast with previous studies where GIK was given over the whole surgical period including bypass and post-bypass times. The hypertrophied heart is highly dependent on glucose uptake and accelerated glycolysis to fuel energy metabolism since the hypertrophied cardiomyocytes are reprogrammed with gene expression and metabolic profiles similar to the fetal hearts [26]. Under such conditions, pre-ischemic administration of GIK is expected to shift substrate utilization from fatty acids to glucose and therefore to promote more efficient oxygen utilization for synthesis of adenosine triphosphate (ATP) compounds. Besides metabolic modulation, insulin, − the key component of the GIK cocktail -, exerts other cardiovascular protective effects by improving intracellular calcium homeostasis [27] and coronary blood flow [28] as well as via phosphatidylinositol 3′-kinase-protein kinase B-endothelial nitric oxide synthase (PI3K-Akt-eNOS)-dependent signaling mechanism [8].

This study has several limitations that have already been highlighted previously [13]. Indeed, there were baseline differences in LV function between the two groups and the functional assessment was exclusively focused on the LV function. Using longitudinal strain and strain rate, various changes have been reported immediately after AVR, namely improved LV function coupled with decreased RV function that could explain the development of postoperative low cardiac output syndrome [29]. Moreover, in a similar surgical population, Maslow et al. reported that treatment with inotropes resulted in increased cardiac output that was more correlated to RV ejection fraction than to LVEF improvements [30]. Finally, we ignore whether the enhanced post-bypass LV function in GIK-treated patients may translate into better long-term clinical outcome owing to favorable LV remodeling. Repeated echocardiographic examinations over 6 to 12 months postoperative follow up period would disclose whether the GIK-related effect similar mitigates myocardial stunning or if it minimizes myocardial injuries and promotes ventricular functional recovery [31].

Conclusions

The addition of GIK therapy to standard cardioprotective techniques in moderate-to-high risk patients with severe aortic valve stenosis, resulted in better preservation of LV systolic and diastolic function and lesser requirement of cardiovascular drug support in the early period following AVR. Further evidence is required to ascertain myocardial recovery along with improved long term survival and clinical outcome.

Notes

Acknowledgements

None.

Authors’ contributions

ML and CE conceived and designed the study, performed all statistical analysis and drafted the manuscript. TS and JD discussed the design of the study, supervised the collection of the clinical data and corrected the initial version of the manuscript. All authors read and approved the final manuscript.

Funding

The study was supported by the APSI Funds of the department of Anesthesiology, Pharmacology & Intensive Care of the University Hospital of Geneva. The funding body had no influence on the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.

Ethics approval and consent to participate

This study approved by the institutional review board at the University Hospital of Geneva (CER: 08–095). Written consent was obtained from each eligible participant.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References

  1. 1.
    Baumgartner H, Falk V, Bax JJ, De Bonis M, Hamm C, Holm PJ, Iung B, Lancellotti P, Lansac E, Rodriguez Munoz D, et al. 2017 ESC/EACTS guidelines for the management of valvular heart disease. Eur Heart J. 2017;38(36):2739–91.CrossRefPubMedGoogle Scholar
  2. 2.
    Lomivorotov VV, Efremov SM, Kirov MY, Fominskiy EV, Karaskov AM. Low-cardiac-output syndrome after cardiac surgery. J Cardiothorac Vasc Anesth. 2017;31(1):291–308.CrossRefPubMedGoogle Scholar
  3. 3.
    Rader F, Sachdev E, Arsanjani R, Siegel RJ. Left ventricular hypertrophy in valvular aortic stenosis: mechanisms and clinical implications. Am J Med. 2015;128(4):344–52.CrossRefPubMedGoogle Scholar
  4. 4.
    Mebazaa A, Pitsis AA, Rudiger A, Toller W, Longrois D, Ricksten SE, Bobek I, De Hert S, Wieselthaler G, Schirmer U, et al. Clinical review: practical recommendations on the management of perioperative heart failure in cardiac surgery. Crit Care. 2010;14(2):201.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Barber RL, Fletcher SN. A review of echocardiography in anaesthetic and peri-operative practice. Part 1: impact and utility. Anaesthesia. 2014;69(7):764–76.CrossRefPubMedGoogle Scholar
  6. 6.
    Licker M, Cikirikcioglu M, Inan C, Cartier V, Kalangos A, Theologou T, Cassina T, Diaper J. Preoperative diastolic function predicts the onset of left ventricular dysfunction following aortic valve replacement in high-risk patients with aortic stenosis. Crit Care. 2010;14(3):R101.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    LaDisa JF Jr, Krolikowski JG, Pagel PS, Warltier DC, Kersten JR. Cardioprotection by glucose-insulin-potassium: dependence on KATP channel opening and blood glucose concentration before ischemia. Am J Physiol Heart Circ Physiol. 2004;287(2):H601–7.CrossRefPubMedGoogle Scholar
  8. 8.
    Yao H, Han X, Han X. The cardioprotection of the insulin-mediated PI3K/Akt/mTOR signaling pathway. Am J Cardiovasc Drugs. 2014;14(6):433–42.CrossRefPubMedGoogle Scholar
  9. 9.
    Fan Y, Zhang AM, Xiao YB, Weng YG, Hetzer R. Glucose-insulin-potassium therapy in adult patients undergoing cardiac surgery: a meta-analysis. Eur J Cardiothorac Surg. 2011;40(1):192–9.CrossRefPubMedGoogle Scholar
  10. 10.
    Bothe W, Olschewski M, Beyersdorf F, Doenst T. Glucose-insulin-potassium in cardiac surgery: a meta-analysis. Ann Thorac Surg. 2004;78(5):1650–7.CrossRefPubMedGoogle Scholar
  11. 11.
    Schulz KF, Altman DG, Moher D. CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. BMC Med. 2010;8:18.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Ellenberger C, Sologashvili T, Kreienbuhl L, Cikirikcioglu M, Diaper J, Licker M. Myocardial protection by glucose-insulin-potassium in moderate- to high-risk patients undergoing elective on-pump cardiac surgery: a randomized controlled trial. Anesth Analg. 2018;126(4):1133–41.CrossRefPubMedGoogle Scholar
  13. 13.
    Licker M, Reynaud T, Garofano N, Sologashvili T, Diaper J, Ellenberger C. Pretreatment with glucose-insulin-potassium improves ventricular performances after coronary artery bypass surgery: a randomized controlled trial. J Clin Monit Comput. 2019.Google Scholar
  14. 14.
    Licker M, Diaper J, Cartier V, Ellenberger C, Cikirikcioglu M, Kalangos A, Cassina T, Bendjelid K. Clinical review: management of weaning from cardiopulmonary bypass after cardiac surgery. Ann Card Anaesth. 2012;15(3):206–23.CrossRefPubMedGoogle Scholar
  15. 15.
    Halkos ME, Chen EP, Sarin EL, Kilgo P, Thourani VH, Lattouf OM, Vega JD, Morris CD, Vassiliades T, Cooper WA, et al. Aortic valve replacement for aortic stenosis in patients with left ventricular dysfunction. Ann Thorac Surg. 2009;88(3):746–51.CrossRefPubMedGoogle Scholar
  16. 16.
    Lotto AA, Ascione R, Caputo M, Bryan AJ, Angelini GD, Suleiman MS. Myocardial protection with intermittent cold blood during aortic valve operation: antegrade versus retrograde delivery. Ann Thorac Surg. 2003;76(4):1227–33 discussion 1233.CrossRefPubMedGoogle Scholar
  17. 17.
    Ovrum E, Tangen G, Tollofsrud S, Oystese R, Ringdal MA, Istad R. Cold blood versus cold crystalloid cardioplegia: a prospective randomised study of 345 aortic valve patients. Eur J Cardiothorac Surg. 2010;38(6):745–9.CrossRefPubMedGoogle Scholar
  18. 18.
    Braathen B, Tonnessen T. Cold blood cardioplegia reduces the increase in cardiac enzyme levels compared with cold crystalloid cardioplegia in patients undergoing aortic valve replacement for isolated aortic stenosis. J Thorac Cardiovasc Surg. 2010;139(4):874–80.CrossRefPubMedGoogle Scholar
  19. 19.
    Jovic M, Stancic A, Nenadic D, Cekic O, Nezic D, Milojevic P, Micovic S, Buzadzic B, Korac A, Otasevic V, et al. Mitochondrial molecular basis of sevoflurane and propofol cardioprotection in patients undergoing aortic valve replacement with cardiopulmonary bypass. Cellular Physiol Biochem. 2012;29(1–2):131–42.CrossRefGoogle Scholar
  20. 20.
    Uhlig C, Bluth T, Schwarz K, Deckert S, Heinrich L, De Hert S, Landoni G, Serpa Neto A, Schultz MJ, Pelosi P, et al. Effects of volatile anesthetics on mortality and postoperative pulmonary and other complications in patients undergoing surgery: a systematic review and meta-analysis. Anesthesiology. 2016;124(6):1230–45.CrossRefPubMedGoogle Scholar
  21. 21.
    Grossgasteiger M, Hien MD, Graser B, Rauch H, Gondan M, Motsch J, Rosendal C. Assessment of left ventricular size and function during cardiac surgery. An intraoperative evaluation of six two-dimensional echocardiographic methods with real time three-dimensional echocardiography as a reference. Echocardiography. 2013;30(6):672–81.CrossRefPubMedGoogle Scholar
  22. 22.
    Stanton T, Marwick TH. Assessment of subendocardial structure and function. J Am Coll Cardiol Img. 2010;3(8):867–75.CrossRefGoogle Scholar
  23. 23.
    Iwahashi N, Nakatani S, Kanzaki H, Hasegawa T, Abe H, Kitakaze M. Acute improvement in myocardial function assessed by myocardial strain and strain rate after aortic valve replacement for aortic stenosis. J Am Soc Echocardiogr. 2006;19(10):1238–44.CrossRefPubMedGoogle Scholar
  24. 24.
    Duncan AE, Kateby Kashy B, Sarwar S, Singh A, Stenina-Adognravi O, Christoffersen S, Alfirevic A, Sale S, Yang D, Thomas JD, et al. Hyperinsulinemic Normoglycemia does not meaningfully improve myocardial performance during cardiac surgery: a randomized trial. Anesthesiology. 2015;123(2):272–87.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Howell NJ, Ashrafian H, Drury NE, Ranasinghe AM, Contractor H, Isackson H, Calvert M, Williams LK, Freemantle N, Quinn DW, et al. Glucose-insulin-potassium reduces the incidence of low cardiac output episodes after aortic valve replacement for aortic stenosis in patients with left ventricular hypertrophy: results from the hypertrophy, insulin, glucose, and electrolytes (HINGE) trial. Circulation. 2011;123(2):170–7.CrossRefPubMedGoogle Scholar
  26. 26.
    Shao D, Tian R. Glucose transporters in cardiac metabolism and hypertrophy. Comprehensive Physiology. 2015;6(1):331–51.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Ranasinghe AM, McCabe CJ, Quinn DW, James SR, Pagano D, Franklyn JA, Bonser RS. How does glucose insulin potassium improve hemodynamic performance? Evidence for altered expression of beta-adrenoreceptor and calcium handling genes. Circulation. 2006;114(1 Suppl):I239–44.PubMedGoogle Scholar
  28. 28.
    McNulty PH, Pfau S, Deckelbaum LI. Effect of plasma insulin level on myocardial blood flow and its mechanism of action. Am J Cardiol. 2000;85(2):161–5.CrossRefPubMedGoogle Scholar
  29. 29.
    Duncan AE, Sarwar S, Kateby Kashy B, Sonny A, Sale S, Alfirevic A, Yang D, Thomas JD, Gillinov M, Sessler DI. Early left and right ventricular response to aortic valve replacement. Anesth Analg. 2017;124(2):406–18.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Maslow AD, Regan MM, Schwartz C, Bert A, Singh A. Inotropes improve right heart function in patients undergoing aortic valve replacement for aortic stenosis. Anesth Analg. 2004;98(4):891–902 table of contents.CrossRefPubMedGoogle Scholar
  31. 31.
    Lamb HJ, Beyerbacht HP, de Roos A, van der Laarse A, Vliegen HW, Leujes F, Bax JJ, van der Wall EE. Left ventricular remodeling early after aortic valve replacement: differential effects on diastolic function in aortic valve stenosis and aortic regurgitation. J Am Coll Cardiol. 2002;40(12):2182–8.CrossRefPubMedGoogle Scholar

Copyright information

© The Author(s). 2019

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors and Affiliations

  1. 1.Department of Anesthesiology, Pharmacology and Intensive CareUniversity Hospital of GenevaGenevaSwitzerland
  2. 2.Faculty of MedicineUniversity of GenevaGenevaSwitzerland
  3. 3.Division of Cardiovascular SurgeryUniversity Hospital of GenevaGenevaSwitzerland
  4. 4.Department of Anesthesiology, Pharmacology and Intensive CareUniversity Hospital Geneva & Faculty of MedicineGenevaSwitzerland

Personalised recommendations