The local ethics committee approved review of the data, consented and approved the retrospective analysis on prospectively collected data (IRB number 34459, 05/26/2021). The patient informed consent was obtained from all subjects specifying the type of adjuvant parenteral nutrition. Medical history, daily progress notes, diet information, relevant laboratory data, imaging findings, and complications were prospectively updated.
Primary endpoints were to understand the impact of this adjuvant treatment on the clinical outcomes and on RV function after LVAD implant. Differences in echocardiographic parameters as RV Ejection Fraction (RVEF), fractional Area Change (FAC), Tricuspid Annular Plain Systolic Excursion (TAPSE), Global longitudinal Strain (GLS), were recorded before and after KPN. The secondary end-points were identifying effects on urine output volume, liver and kidney laboratory tests, glycemic variability (GV), and the occurrence of adverse events before and after KPN. Additional secondary end-points were clinical outcomes, such as post-operative intensive care unit (ICU) stay, word stay and intra-hospital mortality in LVAD patients with or without adjuvant treatment with KPN.
From February 2012 to April 2021, 192 patients have been implanted with an LVAD (HeartWare 54, Jarvik 62, HMIII 76). Post-implant acute RVF, defined according to International Society Heart and Lung Transplantation (ISHLT) guidelines, occurred in 63 patients (32.8% RVF incidence). Totally, 107 patients, were treated with additional KPN as adjuvant therapy against and or in prevention of acute RVF (KPN-Group). KPN was introduced as additional treatment soon after Hospital admission in 69 patients (38 patients with temporary ECLS and 31 patients with poor RV contractility at echocardiographic parameters) and soon after LVAD implant in 38 patients, as a choice of their first operator. Exclusion criteria for adjuvant treatment were the following: diabetes type 1, hereditary or acquired disorders of triglyceride hydrolysis, severe metabolic acidosis, impaired lipid utilization, or severe coagulopathy, as contraindicated to lipid emulsion therapy (11). The remaining 85 patients, managed without KPN, constituted our control group (No-KPN-Group).
The KPN provided a mixed aminoacid solution (Sintamin10%, Fresenius Kabi, Bad Homburg, Germany) at the dose of 1 g of aminoacid per kilogram of body weight per day and a 20% lipid emulsion (SMOF-lipid 20%, Fresenius-Kabi, Bad Homburg, Germany) at the dose of 1,8 g of lipid per kilogram of body weight per day. The lipid emulsion contained soybean oil, olive oil, medium chain triglycerides (MCTs), fish oil and glycerol (25 g/l). Electrolytes, multivitamin supplement (Cernevit, Baxter SPA, Rome, Italy) and trace elements (Olitrace, B. Braun, Melsungen, Germany) were infused daily in 0,9% sodium chloride solution. Treatment was used as an intravenous infusion until complete oral feeding and then continued orally until purpose was achieved. Therefore it was started while in the ICU and on the ward, and then continued once at home. The treatment would be stopped at any time in case of intolerance of any kind.
In our KPN protocol we did not add glucose because of the small amount of glycerol (12,5 g per day), a gluconeogenic precursor, given with the lipid emulsion. Daily energy infusion, approximately 1300 kilocalories per day, did not meet the theoretical requirements in most subjects. This energy provision was chosen to avoid the infusion of too large amounts of lipids and considering the short period of endovenous nutrition decided to apply.
Biochemical analysis. During the treatment plasma triglycerides, urea, creatinine, ALT (alanine transferase), AST (aspartate transferase) were evaluated according to the scheme in Table I. Blood glucose was measured using ACCU-CHECK Inform II BG monitoring system (Roche Diagnostic, Roche Rotkreuz, Switzerland). Capillary beta-hydroxy-butyrate (BHB) was measured using electrochemical method (FreeStyle Optium H ketone, Abbott Diabetes Care Ltd., Oxon, UK). Urinary KBs were measured by testing strips Siemens Multistics 10 SG (Siemens Healthcare Diagnostics, Deerfield, IL, USA). The assays were conducted according to the manufacturer’s instructions. The glycemic control protocol was performed as previously described (maintaining serum glucose levels 120-180 mg/dL ) (12). Glucose variability (GV) was calculated using standard deviation (SD) of blood glucose measurements.
The echocardiography: exams were performed in blind by the cardiologists, before treatment with KPN, at the 6th day of administration and then every six further days of treatment. The parameters considered to evaluate RV function were fractional area change (FAC %), RV ejection fraction (RVEF %), tricuspid annulus peak systolic velocity (TAPSE) (mm), Global longitudinal strain rate (s-1), pulsed Doppler RV index of myocardial performance (RIMP), tissue Doppler RIMP, tissue Doppler S’ wave (cm/s), color tissue Doppler S wave (cm/s) and dP/dT (mmHg/s). The RVF was defined according to the ISHLT annual INTERMACS reports (13).
RVF medical management and indications for RV support: RV support was indicated in: (i) patients who suffered overt RV failure during or immediately after weaning from cardiopulmonary bypass despite maximal medical management according to the ISHLT guidelines (14) and (ii) patients at high risk of postimplant RV failure like patients on extracorporeal life support (ECLS) prior to LVAD implantation. Indeed, due to the difficulty of RV assessment in these patients, they were considered at high risk and received systematic RV support after LVAD implantation.
Criteria for weaning RV support: Patients were evaluated daily for RV recovery by collecting haemodynamic parameters, routine blood tests and by performing weaning trials during which the RVAD flow was reduced to ∼1.5 l/min for 15 min. RV recovery was defined as a return to the baseline values of the echocardiographic parameters. The following criteria were retained for weaning of RV support: (i) low levels of inotropic support (dobutamine <5 γ kg−1.min−1; epinephrine or norepinephrine <0.05 γ kg−1.min−1); (ii) low lactate levels (<2.1 mmol/L) and (iii) stable mean systemic arterial blood pressure around 70 mmHg, with no RV dilatation at echocardiography and no decrease in LVAD flow during weaning trials. Central venous pressure or other right-sided haemodynamic parameters were not considered (right heart catheterization), since their interpretation in the patients under partial RVAD support is awkward.
Continuous variables are expressed as mean±standard deviation. To analyze trends in observed variables, a linear regression model was estimated using a linear spline transform of time, for evaluating simultaneous trend and change in slope effects of the trajectories over time of each of the variables considered. Significance of trends and change in slope at time of treatment initiation were evaluated using the Akaike Information Criterion for the linear (trend) and non-linear (change in slope at “zero” time in the linear spline). Analyses were performed using the R System (15) and the gMCP and rms (16) Libraries.