The study was designed to isolate the pure temperature effects on left ventricular function and electromechanical relations. The study protocol for global left ventricular function data has previously been reported in detail (25). Patients without evident cardiac dysfunction, scheduled for elective ascending aortic surgery were included. To minimize the occurrence of myocardial function heterogeneity and change in left ventricular loading conditions, exclusion criteria were ejection fraction <55%, previous myocardial infarction, atrial fibrillation or planned aortic valve surgery. Written informed consents for collecting and publishing data, were obtained for all patients and the study was approved by the Regional Committee for Medical and Health research Ethics, South-East Norway (2013/565 B).
Anaesthesia, technical instrumentation, and surgical procedures
The patients were pre-medicated with diazepam (5-10 mg). Anaesthesia was induced by intravenous (iv.) fentanyl (3.5-7.5 mg/kg), midazolam (0.05-0.15 mg/kg), thiopental (2.5-7.0 mg/kg) and cisatracurium (0.15 mg/kg) and maintained with sevoflurane-inhalation (1.0-2.5%) and repeated doses of iv. fentanyl (1-2 mg/kg). The patients were monitored according to the department’s standardized protocol during aortic surgery. Three-lead electrocardiogram (ECG) was obtained by surface leads. Blood pressure was registered from an arterial line in the radial artery. Central venous catheter (Arrow International Inc., Reading. PA, USA), and pulmonary artery catheter (Swan-Ganz CCO; Edwards Lifesciences Corporation, Irvine, CA, USA) were inserted. After induction of anaesthesia, the patients underwent the initial surgery with sternotomy and pericardiotomy, before atrial pacemaker leads (Medtronic streamline, Medtronic Inc., Mn, USA)) were sutured on the right atrium. The patients were cannulated and connected to cardiopulmonary bypass (CPB), (Stöckert S5, Sarin Group Deutschland GmbH, Munich, Germany). During CPB, ventilation was discontinued, and sedation was provided with propofol infusion (3.5 mg/kg/h). All patients received thiopental (1g) and methylprednisolone (2g) prior to graft procedure. When suturing distal anastomosis the patients were cooled to deep hypothermia (28 °C). 18/20 patients underwent brief circulatory arrest in this phase. Ice cold cardioplegia was infused in all patients before suturing of the proximal anastomosis. After completed aortic repair and cardiac reperfusion, the patients were rewarmed and weaned off CPB.
Study protocol
All measurements were made while the patients were on cardiopulmonary bypass (CPB) with open thorax, to achieve optimal comparable conditions. The measurements were made at three time points (Fig.1): T1 at 36 °C defined as baseline, T2 at 32 °C prior to graft surgery defined as moderate hypothermia, and T3 at rewarming to 36 °C after aortic repair and cardiac reperfusion. As the core temperature dropped <37 °C during surgical preparations, 36 °C was chosen as baseline temperature to avoid excessive time spent on rewarming to normothermia and also in accordance with the targeted temperature management recommendations in the current resuscitation guidelines. All recordings were made at spontaneous HR, and at atrial paced HR 90 beats per minute (bpm) to compensate for individual HR variability, and to adjust for the recognized hypothermia-induced bradycardia, both which could influence electrical and mechanical systolic duration. Two patients had spontaneous HR ≥90 bpm and where not paced at T1. One patient got atrial fibrillation at 32 °C whereof measurements at T2 were not included.
The surgical setting with CPB enabled standardization with accurate control of body temperature by a heat-exchanger connected to the CPB, and loading conditions. To obtain comparable and near-to-normal cardiac working conditions, CPB flow was carefully reduced to 20% of the estimated maximum flow, and loading conditions were made comparable by clamping venous drainage adjusted to mean arterial pressure (MAP) >50 mmHg and central venous pressure (CVP) ± 10% of baseline value. All measurements were performed during stable phase, with no change in anaesthesia or hemodynamic support. Surgical manipulation was paused during the measurements and between T1 and T2. Low dose norepinephrine (0.01 mg/kg/min) was used in two patients during T1 and T2, and low dose nitroprusside infusion (0.25-0.5 mg/kg/min) was continued in five patients at T3. These exceptions were controlled for and had no influence on statistical significance, thus data from all the 20 patients included are presented.
Transoesophageal echocardiographic recordings
A Vivid E95 scanner (GE Vingmed Ultrasound, Horten, Norway) was used for echocardiographic 2D and Pulsed Wave- (PW) Doppler recordings with a 5 MHz transesophageal echocardiographic probe (6VT-D, GE Vingmed Ultrasound, Horten, Norway). The recordings were obtained from mid-esophageal two- and four-chamber and long axis views, and transgastric short axis view at mid-papillary level. All recordings were analysed offline by designated software (EchoPac version 203, GE Healthcare, Horten, Norway). Measurements were made from three consecutive heart cycles and averaged. Four isolated measurements from segment 2 were for-shortened at T2 in three different patients at spontaneous heart rate; hence these measurements were excluded from the calculation of mechanical dispersion. Data were de-identified, and the investigator was blinded to patient ID and situation.
Calculations of the electrical events
The standardized electrocardiogram (ECG) lead II, was used for electrical measurements and was synchronized with the echocardiographic scanner (Fig.2). Electrical systole was represented by QT interval and measured from ECG onset-QRS to end of T-wave (Te), and this was also HR corrected (QTc) (26). The manual tangent method was used to determine Te, defined by the intersection of the isoelectric line with the tangent to the steepest downslope of the T-wave (27). Dispersion of repolarization was measured from the ECG T-wave as inter-individual variation in duration of the T-peak to T-end interval (TpTe). T-peak (Tp) was defined as the first maximum positive or negative deflection of the T-wave from the isoelectric line (28).
Calculation of mechanical events
Aortic- and mitral valvar opening and closing were registered from echocardiographic recordings (Fig.2). Ejection time (ET) was measured from aortic valve opening (AVO) to aortic valve closing (AVC). Isovolumic contraction time (IVCT) and isovolumic relaxation time (IVRT) were measured from mitral valve closing (MVC) to AVO and AVC to mitral valve opening (MVO) respectively. Diastolic filling time was measured from MVO to MVC. Mechanical systole was defined by the interval from onset of QRS to AVC (QAVC). Electromechanical window was calculated as the difference between mechanical and electrical systole measured in the same beat (QAVC – QT).
Regional strain and mechanical dispersion
Speckle tracking echocardiography was used to obtain longitudinal strain in four-chamber, two-chamber and long axis views (29, 30) from 2D recordings with frame rate 52 ± 11 ms. Endocardial border was traced manually, and segments were adjusted to the myocardial thickness. Global longitudinal strain was derived from 18 segments and the peak systolic strain values were measured. Time to peak strain was defined from QRS-onset in ECG to peak longitudinal strain in each segment, (Fig.2). Mechanical dispersion was calculated as standard deviation of time to peak strain in the 18 segments model (9).
Global cardiac function
HR, MAP and CVP were obtained from the patients monitor (Siemens SC8000 patient monitor, Siemens Healthcare Erlangen, Germany). Cardiac output was measured from the pulmonary artery catheter by thermodilution with infusion of 10 mL 4 °C NaCl 9 mg/ml (Vigilance II, Edwards Lifesciences Corporation, Irvine, CA, USA), and cardiac index and stroke volume index were calculated. Fractional shortening was calculated from echocardiographic measured end-diastolic and end-systolic dimensions from short axis view, and systolic mitral ring peak velocity (s’) from mitral ring tissue PW-Doppler registrations.
Statistical analyses
Sample size calculation was performed based on previous experimental results, to provide 80 % statistical power to identify ≥20 % change in left ventricular function with a two-sided alpha level of 0.05. Statistical analyses were calculated in SPSSv.26 software (SPSS, Inc., Chicago, IL, USA). Data are presented as mean ± standard deviation. One-way analysis of variance (ANOVA) for repeated measures was used to determine whether there were any statistical significant differences between the three sets of scores and comparisonsbetween time points T2 and T1, and T3 and T1, were performed by paired Student’s t test. P value <0.05 was considered statistically significant, and post-hoc Bonferroni correction was done with alpha level 0.025.