Early goal-directed nutrition versus standard of care in adult intensive care patients: the single-centre, randomised, outcome assessor-blinded EAT-ICU trial.

PURPOSE: We assessed the effects of early goal-directed nutrition (EGDN) vs. standard nutritional care in adult intensive care unit (ICU) patients. METHODS: We randomised acutely admitted, mechanically ventilated ICU patients expected to stay longer than 3 days in the ICU. In the EGDN group we estimated nutritional requirements by indirect calorimetry and 24-h urinary urea aiming at covering 100% of requirements from the first full trial day using enteral and parenteral nutrition. In the standard of care group we aimed at providing 25 kcal/kg/day by enteral nutrition. If this was not met by day 7, patients were supplemented with parenteral nutrition. The primary outcome was physical component summary (PCS) score of SF-36 at 6 months. We performed multiple imputation for data of the non-responders. RESULTS: We randomised 203 patients and included 199 in the intention-to-treat analyses; baseline variables were reasonably balanced between the two groups. The EGDN group had less negative energy (p < 0.001) and protein (p < 0.001) balances in the ICU as compared to the standard of care group. The PCS score at 6 months did not differ between the two groups (mean difference 0.0, 95% CI -5.9 to 5.8, p = 0.99); neither did mortality, rates of organ failures, serious adverse reactions or infections in the ICU, length of ICU or hospital stay, or days alive without life support at 90 days. CONCLUSIONS: EGDN did not appear to affect physical quality of life at 6 months or other important outcomes as compared to standard nutrition care in acutely admitted, mechanically ventilated, adult ICU patients. Clinicaltrials.gov identifier no. NCT01372176.

Early goal-directed nutrition in ICU patients (EAT-ICU): protocol for a randomised trial.

INTRODUCTION: Extensive weight loss has been docu-mented in intensive care unit (ICU) survivors, primarily as the result of muscle loss, leading to impaired physical function and reduced quality of life. The aim of the EAT-ICU trial is to test the effect of early goal-directed protein-energy nutrition based on measured requirements on short-term clinical outcomes and long-term physical quality of life in ICU patients. METHODS: The EAT-ICU trial is a single-centre, randomised, parallel-group trial with concealed allocation and blinded outcome assessment. A total of 200 consecutive, acutely admitted, mechanically ventilated intensive care patients will be randomised 1:1 to early goal-directed nutrition versus standard of care to show a potential 15% relative risk reduction in the primary outcome measure (physical function) at six months (two-sided significance level α = 0.05; power ß = 80%). Secondary outcomes include energy- and protein balances, metabolic control, new organ failure, use of life support, nosocomial infections, ICU- and hospital length of stay, mortality and cost analyses. CONCLUSION: The optimal nutrition strategy for ICU patients remains unsettled. The EAT-ICU trial will provide important data on the effects of early goal-directed protein-energy nutrition based on measured requirements in these patients. FUNDING: The EAT-ICU trial is funded by Copenhagen University Hospital, Rigshospitalet and Fresenius Kabi A/S and supported by The European Society for Clinical Nutrition and Metabolism (ESPEN). TRIAL REGISTRATION: Clinicaltrials.gov identifier no. NCT01372176.

Nebulised dornase alfa versus placebo or hypertonic saline in adult critically ill patients: a systematic review of randomised clinical trials with meta-analysis and trial sequential analysis.

BACKGROUND: Nebulised dornase alfa is used off-label in critically ill patients. We aimed to assess the benefits and harms of nebulised dornase alfa versus placebo, no prophylaxis, or hypertonic saline on patient-important outcome measures in adult critically ill patients. METHODS: We performed a systematic review with meta-analysis and trial sequential analysis (TSA) using the Cochrane Collaboration methodology. Eligible trials were randomised clinical trials comparing nebulised dornase alfa with placebo, no prophylaxis, or hypertonic saline. The predefined outcome measures were all-cause mortality, duration of mechanical ventilation, length of stay, and adverse events. Two reviewers independently assessed trials for inclusion, data extraction, and risk of bias. Risk ratios (RRs) with 95 % confidence intervals (CIs) were estimated by conventional cumulative meta-analysis, and the robustness of the primary estimate was assessed by TSA. RESULTS: Two trials (n = 63) were included; both were judged to have high risk of bias. There was no statistically significant difference in mortality (random effects model RR (95 % CI) 0.73 (0.09-5.77); P = 0.24; I (2) = 30 %). TSA could not be conducted because less than 1 % of the required information size had been accrued. None of the two trials reported adequate and detailed data on any of the secondary outcome measures. CONCLUSIONS: We found very low quantity and quality of evidence for use of nebulised dornase alfa in adult critically ill patients in this systematic review with meta-analysis. SYSTEMATIC REVIEW REGISTRATION: The International Prospective Register of Systematic Reviews (PROSPERO), no. CRD442015016047.

Rocuronium blockade reversal with sugammadex vs. neostigmine: randomized study in Chinese and Caucasian subjects.

BACKGROUND: This study compared efficacy and safety of the selective relaxant binding agent sugammadex (2 mg/kg) with neostigmine (50 µg/kg) for neuromuscular blockade (NMB) reversal in Chinese and Caucasian subjects. METHODS: This was a randomized, active-controlled, multicenter, safety-assessor-blinded study (NCT00825812) in American Society of Anesthesiologists Class 1-3 subjects undergoing surgery with propofol anesthesia. Rocuronium 0.6 mg/kg was administered for endotracheal intubation, with 0.1-0.2 mg/kg maintenance doses given as required. NMB was monitored using TOF-Watch(®) SX. At second twitch reappearance, after last rocuronium dose, subjects received sugammadex 2 mg/kg or neostigmine 50 µg/kg plus atropine 10-20 µg/kg, according to randomization. Primary efficacy variable was time from sugammadex/neostigmine to recovery of the train-of-four (TOF) ratio to 0.9. RESULTS: Overall, 230 Chinese subjects (sugammadex, n = 119, neostigmine, n = 111); and 59 Caucasian subjects (sugammadex, n = 29, neostigmine, n = 30) had evaluable data. Geometric mean (95% CI) time to recovery to TOF ratio 0.9 was 1.6 (1.5-1.7) min with sugammadex vs 9.1 (8.0-10.3) min with neostigmine in Chinese subjects. Corresponding times for Caucasian subjects were 1.4 (1.3-1.5) min and 6.7 (5.5-8.0) min, respectively. Sugammadex 2 mg/kg was generally well tolerated, with no serious adverse events reported. There was no residual NMB or recurrence of NMB. CONCLUSION: Both Chinese and Caucasian subjects recovered from NMB significantly faster after sugammadex 2 mg/kg vs neostigmine 50 µg/kg, with a ~5.7 times (p < 0.0001) faster recovery with sugammadex vs neostigmine in Chinese subjects. Sugammadex was generally well tolerated. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00825812.

[Possible clinical potential in reverting muscular block with sugammadex in anaesthesia and surgery]. / Muligt klinisk potentiale ved revertering af neuromuskulær blokade med sugammadex ved anæstesi og kirurgi.

Neuromuscular blockers (NMBs) provide good conditions for endotracheal intubation and surgery. NMBs have been associated with higher morbidity and mortality, mainly due to post-operative residual neuromuscular block. This may become history with the advent of sugammadex - an antidote to the NMB rocuronium - which within 1-3 minutes neutralizes the effects of rocuronium. High-dose rocuronium is now an alternative to suxamethonium in acute or short procedures and in a situation, where ventilation/intubating cannot be performed, sugammadex can reverse the rocuronium blockade within minutes.

A randomized, dose-response study of sugammadex given for the reversal of deep rocuronium- or vecuronium-induced neuromuscular blockade under sevoflurane anesthesia.

BACKGROUND: Sugammadex is the first of a new class of selective muscle relaxant binding drugs developed for the rapid and complete reversal of neuromuscular blockade induced by rocuronium and vecuronium. Many studies have demonstrated a dose-response relationship with sugammadex for reversal of neuromuscular blockade in patients induced and maintained under propofol anesthesia. However, sevoflurane anesthesia, unlike propofol, can prolong the effect of neuromuscular blocking drugs (NMBDs) such as rocuronium and vecuronium. METHODS: We designed this randomized, open-label, dose-response trial to explore the dose-response relationship of sugammadex for the reversal of deep neuromuscular blockade induced by rocuronium or vecuronium under propofol-induced and sevoflurane-maintained anesthesia. As a secondary objective, the safety variables of sugammadex were evaluated. After anesthesia induction with propofol, 102 patients aged > or = 20 and < 65 yr were randomized to receive a single bolus dose of rocuronium 0.9 mg/kg (n = 50) or vecuronium 0.1 mg/kg (n = 52), followed by maintenance doses (rocuronium 0.1-0.2 mg/kg or vecuronium 0.02-0.03 mg/kg) as needed. Neuromuscular blockade was monitored using acceleromyography. After the last dose of NMBD, at 1-2 posttetanic counts, a single bolus dose of sugammadex 0.5, 1.0, 2.0, 4.0, or 8.0 mg/kg was administered. The primary efficacy variable was time from start of sugammadex administration to recovery of the T(4)/T(1) ratio to 0.9. RESULTS: The per-protocol population consisted of 48 patients in the rocuronium group and 47 in the vecuronium group. A dose-response effect was demonstrated for decreased mean time to recovery of the T(4)/T(1) ratio to 0.9 with increasing sugammadex dose in both NMBD groups (per-protocol population): rocuronium group, 79.8 (SD 33.0) min (sugammadex 0.5 mg/kg) to 1.7 (0.7) min (4.0 mg/kg) and 1.1 (0.3) min (8.0 mg/kg subgroup); vecuronium group, 68.4 (31.9) min (0.5 mg/kg) to 3.3 (3.5) min (4.0 mg/kg), and 1.7 (0.8) min (8.0 mg/kg subgroup). Neuromuscular monitoring showed recurrent neuromuscular blockade in 5 patients, all in the rocuronium group (2 given sugammadex 0.5 mg/kg and 3 given 1.0 mg/kg), but there were no clinical events attributable to recurrent or residual neuromuscular blockade. CONCLUSION: Sugammadex at doses of > or = 4 mg/kg provides rapid reversal of deep rocuronium- and vecuronium-induced neuromuscular blockade under sevoflurane maintenance anesthesia.

Should dosing of rocuronium in obese patients be based on ideal or corrected body weight?

BACKGROUND: Pharmacokinetic studies in obese patients suggest that dosing of rocuronium should be based on ideal body weight (IBW). This may, however, result in a prolonged onset time or compromised conditions for tracheal intubation. In this study, we compared onset time, conditions for tracheal intubation, and duration of action in obese patients when the intubation dose of rocuronium was based on three different weight corrections. METHODS: Fifty-one obese patients, with a median (range) body mass index of 44 (34-72) kg/m2, scheduled for laparoscopic gastric banding or gastric bypass under propofol-remifentanil anesthesia were randomized into three groups. The patients received rocuronium (0.6 mg/kg) based on IBW (IBW group, n = 17), IBW plus 20% of excess weight (corrected body weight [CBW]20% group, n = 17), or IBW plus 40% of excess weight (CBW40% group, n = 17). Propofol was administered as a bolus of 200 mg and an infusion at 5 mg x kg(-1) x h(-1) and remifentanil was administered at 1.0 microg x kg(-1) x min(-1), both according to CBW40%. Neuromuscular function was monitored with train-of-four nerve stimulation and acceleromyography. The primary end point was duration of action, defined as time to reappearance of the fourth twitch in train-of-four. RESULTS: The median (range) duration of action was 32 (18-49), 38 (25-66), and 42 (24-66) min in the IBW, CBW20%, and CBW40% groups, respectively (P = 0.001 for comparison of the IBW and CBW40% group). There were no significant differences in onset time (85 vs 84 vs 80 s) or in intubation conditions 90 s after administration of rocuronium. CONCLUSIONS: In obese patients undergoing gastric banding or gastric bypass, rocuronium dosed according to IBW provided a shorter duration of action without a significantly prolonged onset time or compromised conditions for tracheal intubation.

Is the performance of acceleromyography improved with preload and normalization? A comparison with mechanomyography.

BACKGROUND: Many studies have indicated that acceleromyography and mechanomyography cannot be used interchangeably. To improve the agreement between the two methods, it has been suggested to use a preload and to refer all train-of-four (TOF) ratios to the control TOF (normalization) when using acceleromyography. The first purpose of this study was to test whether a preload applied to acceleromyography would increase the precision and the agreement with mechanomyography. The second purpose was to evaluate whether normalization would improve the agreement with mechanomyography. METHODS: Sixty patients were randomized to acceleromyography with or without a preload (Hand Adapter; Organon, Oss, the Netherlands). On the contralateral arm, mechanomyography was used. Anesthesia was induced with propofol and an opioid, and neuromuscular block with 0.6 mg/kg rocuronium. The precision and the bias and limits of agreement (with or without normalization) between the methods were evaluated using TOF stimulation. RESULTS: Preload improved the precision of acceleromyography by 21%, but it also increased the mean control TOF ratio from 1.07 to 1.13. Normalization of the acceleromyographic TOF ratios diminished the bias to mechanomyography during recovery (e.g., from 0.15 to 0.05 at TOF 0.90); when the mechanomyographic TOF values were normalized as well, the bias was eliminated. However, normalization did not exclude wide individual differences between acceleromyography and mechanomyography (+/- 0.10-0.20 at TOF 0.90). CONCLUSION: Preload increases the precision of acceleromyography, and normalization of the TOF ratios decreases bias in relation to mechanomyography. When both acceleromyography and mechanomyography are normalized, there is no significant bias between the two methods.

Reversal of profound, high-dose rocuronium-induced neuromuscular blockade by sugammadex at two different time points: an international, multicenter, randomized, dose-finding, safety assessor-blinded, phase II trial.

BACKGROUND: Sugammadex (Org 25969), a novel, selective relaxant binding agent, was specifically designed to rapidly reverse rocuronium-induced neuromuscular blockade. The efficacy and safety of sugammadex for the reversal of profound, high-dose rocuronium-induced neuromuscular blockade was evaluated. METHODS: A total of 176 adult patients were randomly assigned to receive sugammadex (2, 4, 8, 12, or 16 mg/kg) or placebo at 3 or 15 min after high-dose rocuronium (1.0 or 1.2 mg/kg) during propofol anesthesia. The primary endpoint was time to recovery of the train-of-four ratio to 0.9. Neuromuscular monitoring was performed using acceleromyography. RESULTS: Sugammadex administered 3 or 15 min after injection of 1 mg/kg rocuronium decreased the median recovery time of the train-of-four ratio to 0.9 in a dose-dependent manner from 111.1 min and 91.0 min (placebo) to 1.6 min and 0.9 min (16 mg/kg sugammadex), respectively. After 1.2 mg/kg rocuronium, sugammadex decreased time to recovery of train-of-four from 124.3 min (3-min group) and 94.2 min (15-min group) to 1.3 min and 1.9 min with 16 mg/kg sugammadex, respectively. There was no clinical evidence of reoccurrence of neuromuscular blockade or residual neuromuscular blockade. Exploratory analysis revealed that prolongation of the corrected QT interval considered as possibly related to sugammadex occurred in one patient. Another two patients developed markedly abnormal arterial blood pressure after sugammadex that lasted approximately 15 min. CONCLUSION: Sugammadex provides a rapid and dose-dependent reversal of profound neuromuscular blockade induced by high-dose rocuronium (1.0 or 1.2 mg/kg) in adult surgical patients.

Acceleromyography for use in scientific and clinical practice: a systematic review of the evidence.

This systematic review describes the evidence on the use of acceleromyography for perioperative neuromuscular monitoring in clinical practice and research. The review documents that although acceleromyography is widely used in research, it cannot be used interchangeably with mechanomyography and electromyography for construction of dose-response curves or for recording different pharmacodynamic variables after injection of a neuromuscular blocking agent. Some studies indicate that it may be beneficial to use a preload to increase the precision of acceleromyography, and to "normalize" the train-of-four ratio to decrease the bias in relation to mechanomyography and electromyography. However, currently the evidence is insufficient to support the routine clinical use of preload and "normalization." In contrast, there is good evidence that acceleromyography improves detection of postoperative residual paralysis. A train-of-four ratio of 1.0 predicts with a high predictive value recovery of pulmonary and upper airway function from neuromuscular blockade.