Continuous versus intermittent neuromuscular blockade in patients during targeted temperature management after resuscitation from cardiac arrest-A randomized, double blinded, double dummy, clinical trial.

AIM OF THE STUDY: Current guidelines recommend targeted temperature management to improve neurological outcome after cardiac arrest. Evidence regarding an ideal sedative/analgesic regimen including skeletal muscle paralysis is limited. METHODS: Patients were randomized to either a continuous administration of rocuronium (continuous-NMB-group) or to a continuous administration of saline supplemented by rocuronium bolus administration if demanded (bolus-NMB-group). The primary outcome was the number of shivering episodes. Secondary outcomes included survival and neurological status one year after cardiac arrest, time to awakening, length of stay as well as required cumulative dose of rocuronium, midazolam and fentanyl. RESULTS: Sixty-three patients (32 continuous-NMB-group; 31 bolus-NMB-group) were enrolled. Differences in baseline characteristics were not significant. Shivering episodes were detected in 94% of the patients in the bolus-NMB-group compared to 25% of the patients receiving continuous rocuronium infusion (p<0.01). The continuous-NMB-group received significant lower doses of midazolam (4.3±0.8mg/kg vs. 5.1±0.9mg/kg, p<0.01) and fentanyl (62±14µg/kg vs. 71±7µg/kg, p<0.01), but higher cumulative doses of rocuronium (7.8±1.8mg/kg vs. 2.3±1.6mg/kg, p<0.01). Earlier awakening (2 [IQR 2;3] vs. 4 [IQR 2;7.5] days, p=0.04) and decreased length of stay at the ICU (6 [IQR 3;5.9] vs. 10 [IQR 5;15] days, p=0.03) were observed in the continuous-NMB-group. There were no significant differences in survival and quality of life 12 months after cardiac arrest. CONCLUSIONS: Continuous neuromuscular blockade during the first day after resuscitation reduced shivering, midazolam and fentanyl requirement, time to awakening and discharge from intensive care unit. There were no differences in overall survival, cooling rate and time to target temperature.

Skeletal, cardiac and tongue muscle pathology, defective retinal transmission, and neuronal migration defects in the Large(myd) mouse defines a natural model for glycosylation-deficient muscle - eye - brain disorders.

We have recently shown that a deletion in the Large gene, encoding a putative glycosyltransferase, is the molecular defect underlying the myodystrophy (previously myd; now Large(myd)) mouse. Here we show that the muscular dystrophy phenotype is not confined to skeletal muscle, but is also present in the heart and tongue. Immunohistochemistry indicates disruption of the dystrophin-associated glycoprotein complex (DGC) in skeletal and cardiac muscle. Quantitative western blotting shows a general increase in the expression of DGC proteins and of dysferlin and caveolin-3 in mutant skeletal muscle. In contrast, the expression of DGC proteins is reduced in cardiac muscle. Overlay assays show loss of laminin binding by alpha-dystroglycan in Large(myd) skeletal and cardiac muscle and in brain. We also show that the phenotype of Large(myd) mice is not restricted to muscular dystrophy, but also includes ophthalmic and central nervous system (CNS) defects. Electroretinograms of homozygous mutant mice show gross abnormalities of b-wave characteristics, indicative of a complex defect in retinal transmission. The laminar architecture of the cortices of the cerebrum and the cerebellum is disturbed, indicating defective neuronal migration. Thus, the phenotype of the Large(myd) mouse shows similarities to the heterogeneous group of human muscle eye brain diseases characterized by severe congenital muscular dystrophy, eye abnormalities and CNS neuronal migration defects. These diseases include Fukuyama-type muscular dystrophy and muscle-eye-brain disease, both of which are also due to mutations in predicted glycosylation enzymes. Therefore, the Large(myd) mouse represents an important animal model for studying the function of glycosylation in muscle, brain and retina.