Ultra-Early and Short-Term Tranexamic Acid Treatment in Patients With Good- and Poor-Grade Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND AND OBJECTIVES: The results of the ULTRA trial showed that ultra-early and short-term treatment with tranexamic acid (TXA) does not improve clinical outcome after aneurysmal subarachnoid hemorrhage (aSAH). Possibly, the lack of a beneficial effect in all patients with aSAH is masked by antagonistic effects of TXA in certain subgroups. In this post hoc subgroup analysis, we investigated the effect of TXA on clinical outcome in patients with good-grade and poor-grade aSAH. METHODS: The ULTRA trial was a multicenter, prospective, randomized, controlled, open-label trial with blinded outcome assessment. Participants received ultra-early and short-term TXA in addition to usual care or usual care only. This post hoc subgroup analysis included only ULTRA participants with confirmed aSAH and available World Federation of Neurosurgical Societies (WFNS) grade on admission. Patients were categorized into those with good-grade (WFNS 1-3) and poor-grade (WFNS 4-5) aSAH. The primary outcome was clinical outcome assessed by the modified Rankin scale (mRS). Odds ratios (ORs) and adjusted ORs (aORs) with 95% CIs were calculated using ordinal regression analyses. Analyses were performed using the as-treated principle. In all patients with aSAH, no significant effect modification of TXA on clinical outcome was observed for admission WFNS grade (p = 0.10). RESULTS: Of the 812 ULTRA participants, 473 patients had (58%; N = 232 TXA, N = 241 usual care) good-grade and 339 (42%; N = 162 TXA, N = 176 usual care) patients had poor-grade aSAH. In patients with good-grade aSAH, the TXA group had worse clinical outcomes (OR: 0.67, 95% CI 0.48-0.94, aOR 0.68, 95% CI 0.48-0.94) compared with the usual care group. In patients with poor-grade aSAH, clinical outcomes were comparable between treatment groups (OR: 1.04, 95% CI 0.70-1.55, aOR 1.05, 95% CI 0.70-1.56). DISCUSSION: This post hoc subgroup analysis provides another important argument against the use of TXA treatment in patients with aSAH, by showing worse clinical outcomes in patients with good-grade aSAH treated with TXA and no clinical benefit of TXA in patients with poor-grade aSAH, compared with patients treated with usual care. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov (NCT02684812; submission date February 18, 2016, first patient enrollment on July 24, 2013). CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that tranexamic acid, given for <24 hours within the first 24 hours, does not improve the 6-month outcome in good-grade or poor initial-grade aneurysmal SAH.

Adverse drug events caused by three high-risk drug-drug interactions in patients admitted to intensive care units: A multicentre retrospective observational study.

AIMS: Knowledge about adverse drug events caused by drug-drug interactions (DDI-ADEs) is limited. We aimed to provide detailed insights about DDI-ADEs related to three frequent, high-risk potential DDIs (pDDIs) in the critical care setting: pDDIs with international normalized ratio increase (INR+ ) potential, pDDIs with acute kidney injury (AKI) potential, and pDDIs with QTc prolongation potential. METHODS: We extracted routinely collected retrospective data from electronic health records of intensive care units (ICUs) patients (≥18 years), admitted to ten hospitals in the Netherlands between January 2010 and September 2019. We used computerized triggers (e-triggers) to preselect patients with potential DDI-ADEs. Between September 2020 and October 2021, clinical experts conducted a retrospective manual patient chart review on a subset of preselected patients, and assessed causality, severity, preventability, and contribution to ICU length of stay of DDI-ADEs using internationally prevailing standards. RESULTS: In total 85 422 patients with ≥1 pDDI were included. Of these patients, 32 820 (38.4%) have been exposed to one of the three pDDIs. In the exposed group, 1141 (3.5%) patients were preselected using e-triggers. Of 237 patients (21%) assessed, 155 (65.4%) experienced an actual DDI-ADE; 52.9% had severity level of serious or higher, 75.5% were preventable, and 19.3% contributed to a longer ICU length of stay. The positive predictive value was the highest for DDI-INR+ e-trigger (0.76), followed by DDI-AKI e-trigger (0.57). CONCLUSION: The highly preventable nature and severity of DDI-ADEs, calls for action to optimize ICU patient safety. Use of e-triggers proved to be a promising preselection strategy.

Tranexamic Acid After Aneurysmal Subarachnoid Hemorrhage: Post-Hoc Analysis of the ULTRA Trial.

BACKGROUND AND OBJECTIVES: The ULTRA-trial showed that ultra-early and short-term tranexamic acid treatment after subarachnoid hemorrhage did not improve clinical outcome at six months. An expected proportion of the included patients had non-aneurysmal subarachnoid hemorrhage In this post-hoc study, we will investigate whether ultra-early and short-term tranexamic acid treatment in patients with aneurysmal subarachnoid hemorrhage improves clinical outcome at six months. METHODS: The ULTRA-trial is a multicenter, prospective, randomized, controlled, open-label trial with blinded outcome assessment, conducted between July 24, 2013 and January 20, 2020. After confirmation of subarachnoid hemorrhage on non-contrast computer tomography, patients were allocated to either ultra-early and short-term tranexamic acid treatment with usual care, or usual care only. In this post-hoc analysis, we included all ULTRA-participants with a confirmed aneurysm on CT angiography and/or digital subtraction angiography. The primary endpoint was clinical outcome at six months, assessed by the modified Rankin Scale, dichotomized into good (0-3) and poor (4-6) outcome. RESULTS: Of the 813 ULTRA-trial patients who had an aneurysmal subarachnoid hemorrhage, 409 (50%) were assigned to the tranexamic acid group and 404 (50%) to the control group. In the intention-to-treat analysis, 233 of 405 (58%) patients in the tranexamic acid group and 238 of 399 (60%) patients in the control group had a good clinical outcome (adjusted odds ratio (aOR) 0·92; 95% confidence interval (C.I.) 0·69 to 1·24). None of the secondary outcomes showed significant differences between the treatment groups: excellent clinical outcome (mRS 0-2) aOR 0.76, 95% C.I. 0.57-1.03, all-cause mortality at 30 days aOR 0.91, 95% C.I. 0.65-1.28), all-cause mortality at six months aOR 1.10 (95% C.I. 0.80-1.52). DISCUSSION: Ultra-early and short-term tranexamic acid treatment did not improve clinical outcome at six months in patients with aneurysmal subarachnoid hemorrhage and therefore, cannot be recommended. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02684812; submission date February 18, 2016, first patient enrollment on July 24th, 2013). CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that tranexamic acid does not improve outcomes in patients presenting with aneurysmal subarachnoid hemorrhage.

Ultra-early tranexamic acid after subarachnoid haemorrhage (ULTRA): a randomised controlled trial.

BACKGROUND: In patients with aneurysmal subarachnoid haemorrhage, short-term antifibrinolytic therapy with tranexamic acid has been shown to reduce the risk of rebleeding. However, whether this treatment improves clinical outcome is unclear. We investigated whether ultra-early, short-term treatment with tranexamic acid improves clinical outcome at 6 months. METHODS: In this multicentre prospective, randomised, controlled, open-label trial with masked outcome assessment, adult patients with spontaneous CT-proven subarachnoid haemorrhage in eight treatment centres and 16 referring hospitals in the Netherlands were randomly assigned to treatment with tranexamic acid in addition to care as usual (tranexamic acid group) or care as usual only (control group). Tranexamic acid was started immediately after diagnosis in the presenting hospital (1 g bolus, followed by continuous infusion of 1 g every 8 h, terminated immediately before aneurysm treatment, or 24 h after start of the medication, whichever came first). The primary endpoint was clinical outcome at 6 months, assessed by the modified Rankin Scale, dichotomised into a good (0-3) or poor (4-6) clinical outcome. Both primary and safety analyses were according to intention to treat. This trial is registered at ClinicalTrials.gov, NCT02684812. FINDINGS: Between July 24, 2013, and July 29, 2019, we enrolled 955 patients; 480 patients were randomly assigned to tranexamic acid and 475 patients to the control group. In the intention-to-treat analysis, good clinical outcome was observed in 287 (60%) of 475 patients in the tranexamic acid group, and 300 (64%) of 470 patients in the control group (treatment centre adjusted odds ratio 0·86, 95% CI 0·66-1·12). Rebleeding after randomisation and before aneurysm treatment occurred in 49 (10%) patients in the tranexamic acid and in 66 (14%) patients in the control group (odds ratio 0·71, 95% CI 0·48-1·04). Other serious adverse events were comparable between groups. INTERPRETATION: In patients with CT-proven subarachnoid haemorrhage, presumably caused by a ruptured aneurysm, ultra-early, short-term tranexamic acid treatment did not improve clinical outcome at 6 months, as measured by the modified Rankin Scale. FUNDING: Fonds NutsOhra.

A novel approach to resolve severe mediastinal and subcutaneous emphysema occurring in Pneumocystis jirovecii pneumonia using vacuum-assisted closure therapy.

A 50-year-old human immunodeficiency virus positive patient who was diagnosed with Pneumocystis jirovecii pneumonia developed severe subcutaneous and mediastinal emphysema, which was progressive despite low pressure mechanical ventilation. Infraclavicular skin incisions and vacuum-assisted closure therapy were used to resolve the emphysema. The subcutaneous emphysema decreased significantly, and after 1 week the vacuum-assisted closure therapy was ended successfully. This technique has previously been described in several case reports, where it is a promising treatment in severe subcutaneous emphysema, but it is not yet widely used. This case report supports the further use of vacuum-assisted closure therapy in subcutaneous emphysema. Successful treatment of severe mediastinal and subcutaneous emphysema in Pneumocystis jirovecii pneumonia can be achieved by vacuum-assisted closure therapy on infraclavicular skin incisions.

Very high intact-protein formula successfully provides protein intake according to nutritional recommendations in overweight critically ill patients: a double-blind randomized trial.

BACKGROUND: Optimal energy and protein provision through enteral nutrition is essential for critically ill patients. However, in clinical practice, the intake achieved is often far below the recommended targets. Because no polymeric formula with sufficient protein content is available, adequate protein intake can be achieved only by supplemental amino acids or semi-elemental formula administration. In the present study, we investigated whether protein intake can be increased with a new, very high intact-protein formula (VHPF) for enteral feeding. METHODS: In this randomized, controlled, double-blind, multicenter trial, 44 overweight (body mass index ≥ 25 kg/m2) intensive care unit patients received either a VHPF (8 g/100 kcal) or a commercially available standard high protein formula (SHPF) (5 g/100 kcal). Protein and energy intake, gastrointestinal tolerance (gastric residual volume, vomiting, diarrhea, and constipation), adverse events, and serious adverse events were recorded. Total serum amino acid levels were measured at baseline and day 5. RESULTS: The primary outcome, protein intake at day 5, was 1.49 g/kg body weight (95% CI 1.21-1.78) and 0.76 g/kg body weight (95% CI 0.49-1.03, P < 0.001) for VHPF and SHPF, respectively. Daily protein intake was statistically significantly higher in the VHPF group compared with the SHPF group from day 2 to day 10. Protein intake in the VHPF group as a percentage of target (1.5 g/kg ideal body weight) was 74.7% (IQR 53.2-87.6%) and 111.6% (IQR 51.7-130.7%) during days 1-3 and days 4-10, respectively. Serum amino acid concentrations were higher at day 5 in the VHPF group than in the SHPF group (P = 0.031). No differences were found in energy intake, measures of gastrointestinal tolerance, and safety. CONCLUSIONS: Enteral feeding with VHPF (8 g/100 kcal) resulted in higher protein intake and plasma amino acid concentrations than an isocaloric SHPF (5 g/100 kcal), without an increase in energy intake. This VHPF facilitates feeding according to nutritional guidelines and is suitable as a first-line nutritional treatment for critically ill overweight patients. TRIAL REGISTRATION: Netherlands Trial Register, NTR5643 . Registered on 2 February 2016.

Efficacy and safety of procalcitonin guidance in reducing the duration of antibiotic treatment in critically ill patients: a randomised, controlled, open-label trial.

BACKGROUND: In critically ill patients, antibiotic therapy is of great importance but long duration of treatment is associated with the development of antimicrobial resistance. Procalcitonin is a marker used to guide antibacterial therapy and reduce its duration, but data about safety of this reduction are scarce. We assessed the efficacy and safety of procalcitonin-guided antibiotic treatment in patients in intensive care units (ICUs) in a health-care system with a comparatively low use of antibiotics. METHODS: We did a prospective, multicentre, randomised, controlled, open-label intervention trial in 15 hospitals in the Netherlands. Critically ill patients aged at least 18 years, admitted to the ICU, and who received their first dose of antibiotics no longer than 24 h before inclusion in the study for an assumed or proven infection were eligible to participate. Patients who received antibiotics for presumed infection were randomly assigned (1:1), using a computer-generated list, and stratified (according to treatment centre, whether infection was acquired before or during ICU stay, and dependent on severity of infection [ie, sepsis, severe sepsis, or septic shock]) to receive either procalcitonin-guided or standard-of-care antibiotic discontinuation. Both patients and investigators were aware of group assignment. In the procalcitonin-guided group, a non-binding advice to discontinue antibiotics was provided if procalcitonin concentration had decreased by 80% or more of its peak value or to 0·5 µg/L or lower. In the standard-of-care group, patients were treated according to local antibiotic protocols. Primary endpoints were antibiotic daily defined doses and duration of antibiotic treatment. All analyses were done by intention to treat. Mortality analyses were completed for all patients (intention to treat) and for patients in whom antibiotics were stopped while being on the ICU (per-protocol analysis). Safety endpoints were reinstitution of antibiotics and recurrent inflammation measured by C-reactive protein concentrations and they were measured in the population adhering to the stopping rules (per-protocol analysis). The study is registered with ClinicalTrials.gov, number NCT01139489, and was completed in August, 2014. FINDINGS: Between Sept 18, 2009, and July 1, 2013, 1575 of the 4507 patients assessed for eligibility were randomly assigned to the procalcitonin-guided group (761) or to standard-of-care (785). In 538 patients (71%) in the procalcitonin-guided group antibiotics were discontinued in the ICU. Median consumption of antibiotics was 7·5 daily defined doses (IQR 4·0-12·7) in the procalcitonin-guided group versus 9·3 daily defined doses (5·0-16·6) in the standard-of-care group (between-group absolute difference 2·69, 95% CI 1·26-4·12, p<0·0001). Median duration of treatment was 5 days (3-9) in the procalcitonin-guided group and 7 days (4-11) in the standard-of-care group (between-group absolute difference 1·22, 0·65-1·78, p<0·0001). Mortality at 28 days was 149 (20%) of 761 patients in the procalcitonin-guided group and 196 (25%) of 785 patients in the standard-of-care group (between-group absolute difference 5·4%, 95% CI 1·2-9·5, p=0·0122) according to the intention-to-treat analysis, and 107 (20%) of 538 patients in the procalcitonin-guided group versus 121 (27%) of 457 patients in the standard-of-care group (between-group absolute difference 6·6%, 1·3-11·9, p=0·0154) in the per-protocol analysis. 1-year mortality in the per-protocol analysis was 191 (36%) of 538 patients in the procalcitonin-guided and 196 (43%) of 457 patients in the standard-of-care groups (between-group absolute difference 7·4, 1·3-13·8, p=0·0188). INTERPRETATION: Procalcitonin guidance stimulates reduction of duration of treatment and daily defined doses in critically ill patients with a presumed bacterial infection. This reduction was associated with a significant decrease in mortality. Procalcitonin concentrations might help physicians in deciding whether or not the presumed infection is truly bacterial, leading to more adequate diagnosis and treatment, the cornerstones of antibiotic stewardship. FUNDING: Thermo Fisher Scientific.

Practice of strict glycemic control in critically ill patients.

Blood glucose control aiming at normoglycemia, frequently referred to as "strict glycemic control", decreases mortality and morbidity of critically ill patients. We searched the medical literature for export opinions, surveys, and clinical reports on blood glucose control in intensive care medicine. While strict glycemic control has been recommended standard of care for critically ill patients, the risk of severe hypoglycemia with strict glycemic control is frequently mentioned by experts. Some rationalize this risk, though others strongly point out the high incidence of hypoglycemia to be (one) reason not to perform strict glycemic control. Implementation of strict glycemic control is far from complete in intensive care units across the world. Frequently local guidelines accept higher blood glucose levels than those with strict glycemic control. Only a minority of retrieved manuscripts are on blood glucose regimens with the lower targets as with strict glycemic control. Hypoglycemia certainly is encountered with blood glucose control, in particular with strict glycemic control. Reports show intensive care-nurses can adequately and safely perform strict glycemic control. Implementation of strict glycemic control is far from complete, at least in part because of the feared risks of hypoglycemia. The preference for hyperglycemia over intermittent hypoglycemia is irrational, however, because there is causal evidence of harm for the former but only associative evidence of harm for the latter. For several reasons it is wise to have strict glycemic control being a nurse-based strategy.

Fatal anaphylactoid reaction following ioversol administration.

We report a fatal intravenous ioversol administration in a 60-year old male patient. Although the introduction of new low-osmolar non-ionogenic contrast media with a more favourable efficacy-toxicity balance has diminished the side-effects significantly, everyone involved in radiodiagnostic procedures should be aware of the potential life-threatening effects. Especially patients with risk factors for side-effects should be monitored carefully.

Clinical outcome of immunonutrition in a heterogeneous intensive care population.

OBJECTIVE: To study the effect of a high-protein enteral formula enriched with arginine, glutamine, and antioxidants and containing omega3 fatty acids and a mixture of fibers, on the clinical outcome of a heterogeneous intensive care (ICU) population. DESIGN AND SETTING: A randomized, prospective, double blind, controlled, two-center clinical trial in two intensive care units in The Netherlands. PATIENTS AND PARTICIPANTS: A total of 597 adult ICU patients expected to require enteral tube feeding for more than 2 days were randomized to receive immunonutrition or an isocaloric control formula. INTERVENTIONS: Patients received either the immunonutrition or the control feed. MEASUREMENTS AND RESULTS: Intention-to-treat and per-protocol analyses showed no statistically significant difference in clinical outcome parameters between the two groups. Results of the intention-to-treat analysis in control vs. immunonutrition were: median ICU length of stay in days, 8.0 (IQR 5.0-16.0) vs. 7.0 (4.0-14.0); median hospital length of stay in days, 20.0 (IQR 10.0-34.0) vs. 20.0 (10.0-35.0); median days of ventilation, 6.0 (IQR 3.0-12.0) vs. 6.0 (IQR 3.0-12.0); ICU mortality, 26.8% vs. 28.2%; in-hospital mortality, 36.4% vs. 38.5%; infectious complications, 41.7% vs. 43.0%. CONCLUSIONS: The results of this largest randomized, controlled trial found that in the general ICU population immunonutrition has no beneficial effect on clinical outcome parameters. These results are consistent with the literature that is currently available.