Restriction of Intravenous Fluid in ICU Patients with Septic Shock.

BACKGROUND: Intravenous fluids are recommended for the treatment of patients who are in septic shock, but higher fluid volumes have been associated with harm in patients who are in the intensive care unit (ICU). METHODS: In this international, randomized trial, we assigned patients with septic shock in the ICU who had received at least 1 liter of intravenous fluid to receive restricted intravenous fluid or standard intravenous fluid therapy; patients were included if the onset of shock had been within 12 hours before screening. The primary outcome was death from any cause within 90 days after randomization. RESULTS: We enrolled 1554 patients; 770 were assigned to the restrictive-fluid group and 784 to the standard-fluid group. Primary outcome data were available for 1545 patients (99.4%). In the ICU, the restrictive-fluid group received a median of 1798 ml of intravenous fluid (interquartile range, 500 to 4366); the standard-fluid group received a median of 3811 ml (interquartile range, 1861 to 6762). At 90 days, death had occurred in 323 of 764 patients (42.3%) in the restrictive-fluid group, as compared with 329 of 781 patients (42.1%) in the standard-fluid group (adjusted absolute difference, 0.1 percentage points; 95% confidence interval [CI], -4.7 to 4.9; P = 0.96). In the ICU, serious adverse events occurred at least once in 221 of 751 patients (29.4%) in the restrictive-fluid group and in 238 of 772 patients (30.8%) in the standard-fluid group (adjusted absolute difference, -1.7 percentage points; 99% CI, -7.7 to 4.3). At 90 days after randomization, the numbers of days alive without life support and days alive and out of the hospital were similar in the two groups. CONCLUSIONS: Among adult patients with septic shock in the ICU, intravenous fluid restriction did not result in fewer deaths at 90 days than standard intravenous fluid therapy. (Funded by the Novo Nordisk Foundation and others; CLASSIC ClinicalTrials.gov number, NCT03668236.).

Multimodal analgesia with gabapentin, ketamine and dexamethasone in combination with paracetamol and ketorolac after hip arthroplasty: a preliminary study.

BACKGROUND AND OBJECTIVE: It has been hypothesized that combinations of analgesics with different mechanisms of action may reduce or even prevent postoperative pain. We, therefore, investigated the analgesic effect of gabapentin, dexamethasone and low-dose ketamine in combination with paracetamol and ketorolac as compared with paracetamol and ketorolac alone after hip arthroplasty. METHODS: In this double-blind study, 42 patients were randomly assigned to either a combination group [gabapentin 1200 mg+dexamethasone 8 mg+ketamine (0.15 mg kg(-1))+paracetamol 1 g+ketorolac 15 mg] or a control group (placebo+paracetamol 1 g+ketorolac 15 mg). The medication was given preoperatively except for ketorolac, which was given at the end of surgery. Postoperative pain treatment was paracetamol 1 gx3; ketorolac 15 mgx3; and patient-controlled intravenous morphine. Morphine consumption, pain intensity at rest and during mobilization, nausea and vomiting, sedation, dizziness, hallucination and consumption of ondansetron were recorded 2, 4 and 24 h after operation. A P value of less than 0.05 was considered statistically significant. RESULTS: Morphine consumption was not significantly different between groups (P=0.085). Overall pain scores were improved in the combination group as compared with the control group both at rest (P=0.042) and during mobilization (P=0.027). In the combination group, individual pain score above 30 mm on a 100 mm visual analogue scale was almost eliminated. The incidence of side effects did not differ between the groups. CONCLUSION: Preoperative gabapentin, dexamethasone and ketamine combined with paracetamol and ketorolac reduced overall pain scores in patients after hip arthroplasty as compared with paracetamol and ketorolac alone. Morphine consumption was not reduced.

Transport of cisplatin by the copper efflux transporter ATP7B.

ATP7B is a P-type ATPase that mediates the efflux of copper. Recent studies have demonstrated that ATP7B regulates the cellular efflux of cisplatin (DDP) and controls sensitivity to the cytotoxic effects of this drug. To determine whether DDP is a substrate for ATP7B, DDP transport was assayed in vesicles isolated from Sf9 cells infected with a baculovirus that expressed either the wild-type ATP7B or a mutant ATP7B that was unable to transport copper as a result of conversion of the transmembrane metal binding CPC motif to CPA. Only the wild-type ATP7B-expressing vesicles exhibited copper-dependent ATPase activity, copper-induced acyl-phosphate formation, and ATP-dependent transport of copper. The amount of DDP that became bound was higher for vesicles expressing either type of ATP7B than for those not expressing either form of ATP7B, but only the vesicles expressing wild-type ATP7B mediated ATP-dependent accumulation of the drug. At pH 4.6, the vesicles expressing the wild-type ATP7B exhibited ATP-dependent accumulation of DDP with an apparent K(m) of 1.2 +/- 0.5 (S.E.M.) muM and V(max) of 0.03 +/- 0.002 (S.E.M.) nmol/mg of protein/min. DDP also induced the acyl-phosphorylation of ATP7B but at a much slower rate than copper. Copper and DDP each inhibited the ATP-dependent transport of the other. These results establish that DDP is a substrate for ATP7B but is transported at a much slower rate than copper.