High-dose antithrombin III therapy had no effect on 28-day all-cause mortality in adult patients with severe sepsis and septic shock when administered within 6 hours after the onset. High-dose antithrombin III was associated with an increased risk of hemorrhage when administered with heparin. There was some evidence to suggest a treatment benefit of antithrombin III in the subgroup of patients not receiving concomitant heparin.

Signs and symptoms of a withdrawal reaction were observed in several children. The occurrence of withdrawal was statistically related to high doses of midazolam, but it was not possible to determine the influence of morphine. If large doses of midazolam and opioids have been administered, there may be justification for reducing the dose gradually instead of abruptly, or using longer-acting benzodiazepines or opioids on discontinuation of sedation.

BackgroundVasopressin is widely used for vasopressor support in septic shock patients, but experimental evidence suggests that selective V1A agonists are superior. The initial pharmacodynamic effects, pharmacokinetics, and safety of selepressin, a novel V1A-selective vasopressin analogue, was examined in a phase IIa trial in septic shock patients.MethodsThis was a randomized, double-blind, placebo-controlled multicenter trial in 53 patients in early septic shock (aged ≥18 years, fluid resuscitation, requiring vasopressor support) who received selepressin 1.25 ng/kg/minute (n = 10), 2.5 ng/kg/minute (n = 19), 3.75 ng/kg/minute (n = 2), or placebo (n = 21) until shock resolution or a maximum of 7 days. If mean arterial pressure (MAP) ≥65 mmHg was not maintained, open-label norepinephrine was added. Co-primary endpoints were maintenance of MAP >60 mmHg without norepinephrine, norepinephrine dose, and proportion of patients maintaining MAP >60 mmHg with or without norepinephrine over 7 days. Secondary endpoints included cumulative fluid balance, organ dysfunction, pharmacokinetics, and safety.ResultsA higher proportion of the patients receiving 2.5 ng/kg/minute selepressin maintained MAP >60 mmHg without norepinephrine (about 50% and 70% at 12 and 24 h, respectively) vs. 1.25 ng/kg/minute selepressin and placebo (p < 0.01). The 7-day cumulative doses of norepinephrine were 761, 659, and 249 μg/kg (placebo 1.25 ng/kg/minute and 2.5 ng/kg/minute, respectively; 2.5 ng/kg/minute vs. placebo; p < 0.01). Norepinephrine infusion was weaned more rapidly in selepressin 2.5 ng/kg/minute vs. placebo (0.04 vs. 0.18 μg/kg/minute at 24 h, p < 0.001), successfully maintaining target MAP and reducing norepinephrine dose vs. placebo (first 24 h, p < 0.001). Cumulative net fluid balance was lower from day 5 onward in the selepressin 2.5 ng/kg/minute group vs. placebo (p < 0.05). The selepressin 2.5 ng/kg/minute group had a greater proportion of days alive and free of ventilation vs. placebo (p < 0.02). Selepressin (2.5 ng/kg/minute) was well tolerated, with a similar frequency of treatment-emergent adverse events for selepressin 2.5 ng/kg/minute and placebo. Two patients were infused at 3.75 ng/kg/minute, one of whom had the study drug infusion discontinued for possible safety reasons, with subsequent discontinuation of this dose group.ConclusionsIn septic shock patients, selepressin 2.5 ng/kg/minute was able to rapidly replace norepinephrine while maintaining adequate MAP, and it may improve fluid balance and shorten the time of mechanical ventilation.Trial registrationClinicalTrials.gov, NCT01000649. Registered on September 30, 2009.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-017-1798-7) contains supplementary material, which is available to authorized users.

SummaryFigdor et al.' demonstrated in 1957 that a series of structurally related pregnanes, without notable endocrine action, were anaesthetically active when administered to mice. The most active of these pregnanes was pregnanolone (3a-hydroxy-5/l-pregnane-20-one), which is a naturally occurring metabolite of progesterone, first isolated from urine of pregnant women in 1937.' The anaesthetic effect of pregnanolone has been demonstrated in several animal speciesZ3 but its lack of water solubility prevented its development in clinical practice. Pregnanolone is now prepared in a stable emulsion which may prove to be suitable for clinical use. It is solubilised in soya bean oil and emulsified in a similar way to diazepam in the form of Diazemuls.A wide species variation in toxicity and tolerance of pregnanolone emulsion was observed in preclinical studies. Administration of a single bolus injection of 40 mg/kg did not cause any (or only marginal) mortality in the mouse and the rat. No organ toxicity was noted after repeated daily intravenous injections in several species: rat 16 mglkg for 4 days and 7 mg/kg for 28 days; dog 12 mg/kg for 4 days and 3 mg/kg for 28 days; monkey 28 mg/kg for 14 days and 21 mg/kg for 28 days. Hepatic lesions restricted to the biliary system, manifested as morphological changes and increased serum enzymes, occurred after daily administration of 40-64 mg/kg for 4 days and after 14 mg/kg for 28 days in the rat. In the dog the threshold dose for hepatobiliary changes at repeated doses was about 7 mg/kg. The liver damage was clearly related to the dose, but also to the duration of the treatment, and was reversible at least in its initial state (toxicological report, not published). The anaesthetic and anticonvulsive properties of pregnanolone in animals are encouraging and very similar to those of Althesin.-This study reports the findings of a preliminary and limited clinical investigation with pregnanolone emulsion in male volunteers.

Background: Sepsis and complications to sepsis are major causes of mortality in critically ill patients. Rapid treatment of sepsis is of crucial importance for survival of patients. The infectious status of the critically ill patient is often difficult to assess because symptoms cannot be expressed and signs may present atypically. The established biological markers of inflammation (leucocytes, Creactive protein) may often be influenced by other parameters than infection, and may be unacceptably slowly released after progression of an infection. At the same time, lack of a relevant antimicrobial therapy in an early course of infection may be fatal for the patient. Specific and rapid markers of bacterial infection have been sought for use in these patients.

Summary In a double‐blind controlled study. epidural buprenorphine 0.3 mg was compared with 4 mg of epidural morphine for postoperative pain relief the first 24 hours after major orthopaedic surgery. The degree of analgesia was equal and sarisfactory in both groups. Duration of action was 620 minutes with buprenorphine and 580 minutes with morphine, which was not significantly deferent. The only serious side effects were recorded in the morphine group, with two patients complaining of pruritus and give of urinary retention. In conclusion, epidural buprenorphine did not offer any advantages in preference to morphine for postoperative pain relief following orthopaedic surgery.

Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background Biphasic allergic reactions—recurrence of allergy symptoms after a symptom-free period—are reported to occur in 1 to 23% of allergic reactions. Patients admitted to an intensive care unit after anaphylaxis potentially have more severe reactions and a higher risk of biphasic allergic reactions. The purpose of this study was to examine incidence, triggers, symptoms, and treatment of biphasic allergic reactions, in patients admitted to an intensive care unit. Methods Records of patients admitted to intensive care units with anaphylaxis from 2011 to 2014 were reviewed. Only patients with a reaction fulfilling internationally accepted criteria for anaphylaxis were included. Potential biphasic allergic reactions, defined as renewed allergy symptoms 1 to 72 h after initial symptoms had resolved, without further exposure to the trigger, were identified. Results A total of 83 cases of anaphylaxis were identified, and the most frequent triggers were medications (58 of 83 [70%]). Skin symptoms occurred in 69 (83%) cases, and circulatory and respiratory symptoms in 48 (58%) and 45 (54%) cases, respectively. In total, 82 (99%), 80 (96%), and 66 (80%) were treated with antihistamines, corticosteroids, and epinephrine, respectively. Only 10 patients presented with one or more relevant symptoms after the initial allergic reaction. Of these, three were possible, and one was a probable biphasic allergic reaction, giving a total incidence of 4 of 83 (4.8% [95% CI, 1.6 to 12.5]) or 1 of 83 (1.2% [95% CI, 0.1 to 7.46]), respectively. All cases were mild, presenting with skin symptoms only, occurring on average 14 h after initial reactions. Conclusions The authors observed a low incidence of biphasic reactions in patients admitted to an intensive care unit after anaphylaxis, at a rate equivalent to that reported in other patient groups.

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