Materials and methods
This is a single centre, unblinded, randomized controlled trial approved by the Ethics Committee of the University Hospital “Santa Maria della Misericordia”
of Udine (n° 2016-O-015-ASUIUD) and registered at ClinicalTrials.gov (NCT02697929) prior to patient enrollment. This manuscript adheres to the applicable
CONSORT guidelines and the study protocol conformed to the ethical guidelines of the
Declaration of Helsinki.
After ClinicalTrial.gov registration, we evaluated consecutive LTx performed at Academic Hospital “S. Maria
della Misericordia”, Udine, Italy. When written informed consent was obtained before
LTx starting, patients were randomly allocated to the sugammadex or neostigmine group
using an online computer-generated table.
All clinical data were collected in an Excel spreadsheet (Microsoft Excel for Mac,
Version 14.0.0, Microsoft Corporation, USA).
Inclusion criteria were as follows:
- Age > 18 years;
- Neuromuscular transmission data acquired with TOF-Watch SX Monitor Software® (Organon, Dublin, Ireland. Version 1.2) from anaesthesia induction until extubation;
Exclusion criteria were as follows:
- American Society of Anesthesiologists (ASA) status > 3;
- Neuromuscular disease;
- Other than rocuronium bromide used;
- Body mass index (BMI) < 18 kg/m2 or > 40 kg/m2;
- Pre-operative impaired renal function, defined as an estimated glomerular filtration rate < 30 ml/min/1.73 m2;
- Inner body temperature < 35 °C or thenar temperature < 32 °C at reversal administration;
- Haemodynamic instability defined as norepinephrine dosage > 0.1 mcg.kg-1.min-1 and/or dobutamine >3 mcg.kg-1.min-1 and/or epinephrine > 0.1 mcg.kg-1.min-1 at the time of reversal administration and/or mean arterial pressure <60 mmHg and/or HR>100 bpm;
- Acidosis defined as an arterial pH<7.30 at the time of reversal administration;
- Incorrect dosage of reversal (50 mcg/kg for neostigmine and 2 mg/kg for sugammadex);
Pre-operative data included sex, age, weight, body mass index (BMI), liver disease,
model for end stage liver disease (MELD), liver function, and renal function.
Intra-operative collected data included duration of surgery, intra-operative blood
losses, packet red cells (PRC), fresh frozen plasma (FFP) and salvage blood transfused,
platelets (PLT) use, fibrinogen administration, net fluid balance, cold ischaemia
time (CIT), warm ischaemia time (WIT), total dose of rocuronium administered and total
millilitres of crystalloids and colloids infused. Cardiac output, cardiac index and
central temperature (values obtained from pulmonary artery catheter) with thenar temperature
at the time of reversal administration were recorded. Adverse events reported in the
anaesthesia sheet were recorded.
Anaesthesia was induced with propofol (1-1.5 mg/kg) and fentanyl (3-5 mcg/kg) or alfentanil
(7-15 mcg/kg) after facial mask denitrogenation with FIO2=0.8. NMBA (rocuronium 0.6 mg.kg based on lean body weight) was administered at anaesthesia induction only after TOF
Watch SX® calibration (Organon, Dublin, Ireland).
Maintenance of anaesthesia was provided by sevoflurane (ET% targeted to keep the bispectral
index in the 40-60 range) and continuous infusion of remifentanil (0.05-0.3 mcg.kg-1.min-1), while neuromuscular block was maintained with rocuronium bromide (Esmeron® 50 mg/5 mL, MSD Italia S.r.l., Roma) intravenous continuous infusion (0.3-0.6 mg.kg-1.h-1) to keep T1<10%.
Haemodynamic monitoring with pulmonary artery catheter (CCOmbo catheter 777HF8; Edwards
Lifescience, Irvine, California, USA) was targeted to optimize indexed oxygen delivery
(DOI2>600 ml.min-1.m2) for the first 6 hours postoperatively.
All LTx were performed with the same surgical equipe dedicated to solid organ transplant
surgery.
As per our routine practice for NMT monitoring with TOF-Watch, two electrodes were
placed over the left ulnar nerve at the wrist and the acceleration transducer was
put on the thumb, together with a hand adapter that immobilized the other fingers.
Data was collected into a dedicated computer using the TOF-Watch SX Monitor Software® which registered the response to ulnar nerve stimulation every 15 s. After anaesthesia
induction, but before rocuronium administration, the TOF-Watch SX was calibrated.
Afterward, the rocuronium bolus for tracheal intubation was given, and continuous
infusion was started.
At the end of surgery reversal agents - sugammadex 2 mg/kg based on actual body weight
(Bridion® 100 mg/mL, MSD Rome, Italy) or neostigmine 50 mcg/kg based on adjusted body weight
plus 10 mcg/kg of atropine (Intrastigmina®, 0.5 mg/mL, Lusofarmaco S.p.a., Rozzano, Italy) were administered, according to randomization,
after the appearance of three consecutiveT2 twitches (the so called moderate neuromuscular block) detected by TOF Watch SX®.
Recovery time was defined as the time interval from the administration of the reversal
agent to the achievement of 3 consecutive measurements of TOFR≥ 0.9.
Our secondary objective was to analyse the main possible correlations between factors
that may have influenced recovery time of sugammadex and neostigmine: BMI, MELD, pre-operative
and postoperative liver and renal function, surgical procedure length, blood loss,
intraoperative fluid balance, cold and warm ischaemia time, total amount of NMB delivered,
millilitres of crystalloid and colloid infused, CO and CI when reversal was given.
Statistical Analysis
Illman and colleagues found a mean difference of 11.6 minutes between sugammadex and
neostigmine, administered when two twitches were detectable, to reach a TOFR>90%.26 Considering a 1:1 treatment ratio and an expected 5-minute reduction in the sugammadex
group, with an alpha level of 0.05 and a power (1-ß) of 90%, the calculated sample
size was 16 subjects for each group. Taking into consideration a dropout of 20%, and
to increase the statistical significance, we decided to enroll at least 20 subjects
per group.
Descriptive statistics (mean and standard deviation for quantitative variables, and
absolute and relative frequencies for qualitative variables) were calculated for each
group. To test for a difference of recovery times between the two groups with respect
to the primary objective, we implemented a two-sided unpaired t test as well as an F-test to compare variances and to control for whether the t test assumptions were met. The same test was applied to all remaining data.The alpha level of statistical significance for all applied tests was 0.05. No imputation
of missing data was used for the analysis. Finally, to detect possible relationships
between the recovery times of the two drugs with other variables, we performed both
the Spearman rank and the Pearson correlation tests as their difference, or lack thereof,
could provide additional information.
GraphPad Prism version 6.01 (GraphPad Software, California, USA) was used for the
final statistical analysis.