This manuscript was written according to CONSORT statement. The study was approved by an independent Ethics Committee (Fundació Unio Catalana Hospitals) on 27 January 2015 (CEIC 15/03). All patients signed an informed consent to participate. The study was conducted according to the Declaration of Helsinki and all local legal and regulatory requirements. Trial registration: NCT02479321 (24/06/2015)
2.1. Study design
Single-centre, non-randomised, hospital-based intervention study with a historical control group (CG) and 12-month follow-up after hospital discharge.
2.2. Inclusion / Exclusion criteria
Patients over 64 years with hip fracture within an Enhanced Recovery Pathway (ERP) who underwent surgical treatment were included.
Exclusion criteria were: patients with pathological fractures, traffic-related fractures, refractures, patients with known contraindication or limitations to advanced hemodynamic monitoring with ClearSight® system and EV1000 platform (Edwards Lifesciences, Irvine, USA) (Saugel et al. 2015): patients with Raynaud disease, with aortic valve prosthesis, proximal aortic aneurysm, known intra-cardiac shunts; moderate to severe mitral or aortic regurgitation; moderate to severe aortic or mitral stenosis, patients with poor quality arterial waveform signal (see below), patients with significant preoperative psychomotor agitation.
2.3. Conduct of the study
2.3.1. Perioperative management common to both groups.
Both groups were treated during the perioperative period in a multidisciplinary Enhanced Recovery Pathway (ERP) unit created in 2010 exclusively dedicated to patients undergoing hip fracture repair (Reguant et al. 2019). (A detailed description of this unit is in Additional file 1).
Intraoperative period
All subjects received standard of care with a 3-lead electrocardiogram, pulse oximetry, and two peripheral intravenous lines. Patients in both groups received standard measures to maintain oxygen saturation by pulse oximetry >94% and heart rate (HR) <100 beats/min. Anaesthetic technique was at the discretion of the anesthetist.
Post-Anaesthetic Care Unit (PACU)
After surgery, patients were treated in the PACU. The attendant physician determined discharge from this unit according to the local protocol.
2.3.2. Study arms
Control group
Data from patients who underwent surgery for hip fracture between October 2010 and November 2011 with follow-up to December 2012 were used for the CG (Reguant et al. 2019).
Haemodynamic management was at the discretion of the attending anesthetist, using fluid therapy with crystalloids (normal saline, lactated Ringer or IsofundinÒ), colloids (VoluvenÒ, Gelaspan Ò), and/or cardiovascular drugs (in bolus - ephedrine – or continuous infusion – noradrenaline, dobutamine).
Non-invasive, intermittent arterial pressure measurement was obtained at least every 5 minutes using a cuff (Dahtex Ohmeda-GE S/5 Aespire Ò).
Intervention group
Data from patients who underwent surgery for hip fracture between June 2015 and February 2018 with follow-up to March 2019 were used as the IG.
Pre- and intraoperative non-invasive hemodynamic monitoring was conducted using ClearSight® monitor (Edwards Lifesciences, Irvine, USA). This monitoring system is based on the volume clamp method to continuously measure arterial pressure and the Physiocal method that periodically recalibrates the system (Saugel et al. 2015). Baseline haemodynamic measurements were taken when the Physiocal value exceeded 30 (Wesseling, K H; de Wit, B; Van der Hoeven, A;Van Goudoever 1995). If a Physiocal value over 30 was not obtained after 7 minutes´ monitoring, the patient was excluded due to a poor quality arterial waveform signal (Wesseling, K H; de Wit, B; Van der Hoeven, A;Van Goudoever 1995).
Haemodynamic optimisation was performed according to the following GDHT protocol.
GDHT protocol (Figure 2):
Three groups of cardiac index (CI) goals were formed according to age and prior functional capacity (METS) (Montenij et al. 2014). Additional file 2.
Fluids were given based on a protocolized haemodynamic algorithm to achieve and maintain an adequate Indexed Stroke Volume (SVI) using crystalloids (0.9% Saline, Lactated Ringer or Isofundin Ò) or colloids (if preoperative glomerular filtration rate was above 60 mL/min using MDRD equation (Ishihara 2014)- Voluven Ò, Gelaspan Ò). Choice of fluid type was based on anaesthesiologist criteria.
Vasopressor was administered to maintain systolic arterial pressure above 90 mmHg (in bolus - ephedrine, phenylephrine – or continuous infusion – noradrenaline). Continuous infusion of dobutamine was added to achieve individualized cardiac index goal.
Phase 1: Preoperative resuscitation
On arrival in the surgical area, patients received a fluid bolus (FB) of 250 ml for 5 minutes. If SVI increased by 10% or more (FirstFluid Bolus Responder), the fluid bolus was repeated (Cecconi et al. 2011). Fluid boluses of 250 ml were repeated until the SV failed to increase by 10%.
Once preoperative resuscitation was completed, prophylactic antibiotic was infused (Additional file 1). This fluid contribution covered the estimated insensible losses during surgery (Jacob et al. 2007).
Phase 2: Post-induction optimisation
Post-induction optimisation began 15 minutes after the surgical incision, if the haemodynamic stabilisation was achieved (SAP and heart rate variation < 10% for 3 minutes); meanwhile, the haemodynamic priority was the maintenance of arterial pressure above goal set (Tassoudis et al. 2011).
Haemodynamic optimisation consisted of a 100 ml fluid bolus administered for less than 3 minutes (Guinot et al. 2015; Mallat et al. 2015; Marik 2015; Muller et al. 2011). If SVI rose >10%, the 100 ml fluid bolus was repeated. The trigger SVI during surgery was calculated by subtracting 10% from the SVI obtained from the last positive 100 ml fluid bolus (Muñoz et al. 2016).
Phase 3: Maintenance during surgery
If any of SAP over 90 mmHg and SVI superior to trigger SVI were not achieved, SVI was analysed. If it was lower than the trigger SVI, a 100 ml fluid bolus was administered.
If SVI was higher than trigger SVI, CI determined our decision. If its value was under goal level, dobutamine was added. When CI was above goal level, a vasopressor was chosen.
After each therapy, we re-evaluated the achievement of SAP and SVI goals.
2.4. Measurements and data handling
2.4.1. Procedure
Intraoperative haemodynamic parameters (arterial pressure, heart rate, SpO2 in CG and also CI and SVI in IG) were registered at 15-minute intervals. Haemodynamic instability, between intervals was registered as an event in the next record. Fluids and cardiovascular drugs used from the patient's arrival in the surgical area to their admission to the PACU were collected. In both groups, the evaluation of intraoperative complications, was based on the intraoperative anesthesia charts, whereas the postoperative complications were documented in the clinical course and hospital discharge report.
Post-discharge follow-up consisted of a structured telephone interview at 1, 3, 6 and 12 months after surgery. When the information could not directly be obtained from the patients (including deceased patients), the interview was done with next of kin or carer.
2.4.2. Assessment of outcomes.
Primary outcome measures
The primary combined outcome was the percentage of patients who developed perioperative complications:
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Intraoperatively: haemodynamic instability, defined as one measurement of SAP < 90 mmHg in the CG and for at least one minute in the IG, or the presence of sustained cardiac arrhythmias.
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Postoperatively: postoperative complications as explained in Supplementary Appendix C
Secondary outcome measures
Total intraoperative volume and type of administered fluids, doses of cardiovascular drugs used, perioperative packed red blood cell transfusion, length of hospital stay, readmission within 30 days of surgery, and survival within 12 months after surgery.
2.5. Statistical analysis
2.5.1. Sample size
The rate of intraoperative haemodynamic instability described with standard of care was 37.5% (Reguant et al. 2019). We planned a relative risk reduction of 30% in IG.
To achieve a power of 80% using a bilateral χ2-square test for two independent samples with a level of significance of 0.05, 538 patients had to be included (269 patients in each group). With a potential dropout of 5%, 568 patients were included.
The percentage of patients who developed one or more postoperative complications in CG was 45.2%. A meta-analysis by Grocott and colleagues suggested a RR reduction of 0.68 for complications in patients undergoing major surgery (Grocott et al. 2013). A sample size of 568 patients, 284 in each group, would have 80% power to detect a reduction of at least 22% in the number of IG patients presenting one or more postoperative complications, using a bilateral χ2-square test for two independent samples.
2.5.2. Statistical analysis
Categorical variables were presented as absolute values and relative frequencies. Continuous variables are summarised as means and standard deviation for normal distribution and by the median and interquartile range (IQR) (25th to 75th percentiles) for non-normal distributions.
In the bivariate analysis, we used the Student’s t-test or the non-parametric Mann-Whitney U test for continuous variables. We used the χ2-square test for categorical variables, and Fisher’s exact test or bilateral exact p-values in contingency tables when the expected frequencies were less than five.
One-year survival Kaplan–Meier curves were constructed, and the log-rank test was used to compare them. Crude and adjusted hazard ratios (HR) and confidence intervals (CI 95%) were calculated using Cox proportional regression models. The proportionality of hazards was verified by examining Schoenfeld residual plots.
Outcomes were analysed on an intention-to-treat basis. The level of statistical significance was two-sided 5% (p < 0.05). The IBM SPSS Statistics v.26 (IBM Corporation®, Armonk, New York) and Stata v.14 (StataCorp LP®, College Station, Texas) programs were used for statistical analysis.