Serigne Lo

Intensity of Continuous Renal-Replacement Therapy in Critically Ill Patients

BACKGROUND The optimal intensity of continuous renal-replacement therapy remains unclear. We conducted a multicenter, randomized trial to compare the effect of this therapy, delivered at two different levels of intensity, on 90-day mortality among critically ill patients with acute kidney injury. METHODS We randomly assigned critically ill adults with acute kidney injury to continuous renal-replacement therapy in the form of postdilution continuous venovenous hemodiafiltration with an effluent flow of either 40 ml per kilogram of body weight per hour (higher intensity) or 25 ml per kilogram per hour (lower intensity). The primary outcome measure was death within 90 days after randomization. RESULTS Of the 1508 enrolled patients, 747 were randomly assigned to higher-intensity therapy, and 761 to lower-intensity therapy with continuous venovenous hemodiafiltration. Data on primary outcomes were available for 1464 patients (97.1%): 721 in the higher-intensity group and 743 in the lower-intensity group. The two study groups had similar baseline characteristics and received the study treatment for an average of 6.3 and 5.9 days, respectively (P=0.35). At 90 days after randomization, 322 deaths had occurred in the higher-intensity group and 332 deaths in the lower-intensity group, for a mortality of 44.7% in each group (odds ratio, 1.00; 95% confidence interval [CI], 0.81 to 1.23; P=0.99). At 90 days, 6.8% of survivors in the higher-intensity group (27 of 399), as compared with 4.4% of survivors in the lower-intensity group (18 of 411), were still receiving renal-replacement therapy (odds ratio, 1.59; 95% CI, 0.86 to 2.92; P=0.14). Hypophosphatemia was more common in the higher-intensity group than in the lower-intensity group (65% vs. 54%, P<0.001). CONCLUSIONS In critically ill patients with acute kidney injury, treatment with higher-intensity continuous renal-replacement therapy did not reduce mortality at 90 days. (ClinicalTrials.gov number, NCT00221013.)

Fluid resuscitation with 6% hydroxyethyl starch (130/0.4) in acutely ill patients: an updated systematic review and meta-analysis

BACKGROUND Recent research suggests that 6% hydroxyethyl starch (HES) 130/0.4 is one of the most frequently used resuscitation fluids worldwide. The retraction of studies evaluating its use necessitates a reevaluation of available evidence regarding its safety and efficacy. METHODS We performed a systematic review and meta-analysis of unretracted randomized controlled trials comparing the effects of 6% HES 130/0.4 with other colloid or crystalloid solutions on mortality, acute kidney injury/failure, and bleeding in acutely ill or perioperative patients. A sensitivity analysis including the data from retracted studies was also conducted. RESULTS Overall, 36 studies reporting 2149 participants met the inclusion criteria, of which 11 (n = 541) have been retracted. Of the remaining 25 studies, there was a high risk of bias in 17 studies; 19 studies (n = 1246) were conducted in perioperative patients and 6 (n = 362) in critically ill patients. Sixteen studies reported mortality: 104 deaths in 1184 participants. The relative risk of death was 0.95 (95% confidence interval 0.64-1.42, I(2) = 0%, P = 0.73); including the retracted studies added a further 14 deaths and the relative risk was 0.92 (95% confidence interval 0.63-1.34, I(2) = 0%, P = 0.95). The data reporting acute kidney injury, red blood cell transfusion, and bleeding were of insufficient quantity and quality and not amenable to meta-analysis. CONCLUSIONS Published studies are of poor quality and report too few events to reliably estimate the benefits or risks of administering 6% HES 130/0.4. This same conclusion is reached with or without the retracted studies. Given the widespread use of 6% HES 130/0.4, high-quality trials reporting a large number of events are urgently required.

A Randomized Controlled Trial of Regional Citrate Versus Regional Heparin Anticoagulation for Continuous Renal Replacement Therapy in Critically Ill Adults

Objective:To determine whether regional anticoagulation of continuous renal replacement therapy circuits using citrate and calcium prolongs circuit life and/or affects circulating cytokine levels compared with regional anticoagulation using heparin and protamine. Design:Multicenter, parallel group randomized controlled trial. Setting:Seven ICUs in Australia and New Zealand. Patients:Critically ill adults requiring continuous renal replacement therapy. Interventions:Patients were randomized to receive one of two methods of regional circuit anticoagulation: citrate and calcium or heparin and protamine. Measurements and Main Results:The primary outcome was functional circuit life measured in hours, assessed using repeated events survival analysis. In addition, we measured changes in interleukin-6, interleukin-8, and interleukin-10 blood levels. We randomized 212 subjects who were treated with 857 continuous renal replacement therapy circuits (median 2 circuits per patient [interquartile range, 1–6], 390 in citrate group vs 467 in heparin group). The groups were well matched for baseline characteristics. Patients receiving regional continuous renal replacement therapy anticoagulation with heparin and protamine were more likely to experience circuit clotting than those receiving citrate and calcium (hazard ratio, 2.03 [1.36–3.03]; p < 0.0005; 857 circuits). The median lifespan of the first study circuit in each patient was 39.2 hours (95% CI, 32.1–48.0 hr) in the citrate and calcium group versus 22.8 hours (95% CI, 13.3–34.0 hr) in the heparin and protamine group (log rank p = 0.0037, 204 circuits). Circuit anticoagulation with citrate and calcium had similar effects on cytokine levels compared with heparin and protamine anticoagulation. There were more adverse events in the group assigned to heparin and protamine anticoagulation (11 vs 2; p = 0.011). Conclusions:Regional citrate and calcium anticoagulation prolongs continuous renal replacement therapy circuit life compared with regional heparin and protamine anticoagulation, does not affect cytokine levels, and is associated with fewer adverse events.

Sleep-Deprived Young Drivers and the Risk for Crash: The DRIVE Prospective Cohort Study

IMPORTANCE Short sleep duration is common in adolescents and young adults, and short sleep duration is a risk factor for motor vehicle crash. OBJECTIVE To assess the association between hours of sleep and the risk for motor vehicle crash, including the time of day of crash and types of crash (single, multiple vehicle, run off road, and intersection). DESIGN Prospective cohort study. SETTING New South Wales, Australia. PARTICIPANTS Questionnaire responses were obtained from 20,822 newly licensed drivers aged 17 to 24 years. Participants held a first-stage provisional license between June 2003 and December 2004 prospectively linked to licensing and police-reported crash data, with an average of 2 years of follow-up. Analyses were conducted on a subsample of 19,327 participants for which there was full information. EXPOSURE Sleeping 6 or fewer hours per night. MAIN OUTCOMES AND MEASURES The main outcome variable was police-reported crash. Multivariable Poisson regression models were used to investigate the role of sleep duration on the risk for crash. RESULTS On average, those who reported sleeping 6 or fewer hours per night had an increased risk for crash compared with those who reported sleeping more than 6 hours (relative risk [RR], 1.21; 95% CI, 1.04-1.41). Less weekend sleep was significantly associated with an increased risk for run-off-road crashes (RR, 1.55; 95% CI, 1.21-2.00). Crashes for individuals who had less sleep per night (on average and on weekends) were significantly more likely to occur between 8 pm and 6 am (RR, 1.86; 95% CI, 1.11-3.13, for midnight to 5:59 am and RR, 1.66; 95% CI, 1.15-2.39, for 8:00 pm to 11:59 pm). CONCLUSIONS AND RELEVANCE Less sleep per night significantly increased the risk for crash for young drivers. Less sleep on weekend nights increased the risk for run-off-road crashes and crashes occurring in the late-night hours. This provides rationale for governments and health care providers to address sleep-related crashes among young drivers.

Comparison of radiation exposure of trauma patients from diagnostic radiology procedures before and after the introduction of a panscan protocol.

Objectives: To compare the proportion of patients exposed to a radiation dose in excess of 20 mSv, and to document missed injuries before and after the introduction of a panscan protocol for blunt trauma.

Activity and safety of radiotherapy with anti-PD-1 drug therapy in patients with metastatic melanoma

ABSTRACT The anti-PD-1 antibodies nivolumab and pembrolizumab are active in metastatic melanoma; however, there is limited data on combining anti-PD-1 antibody and radiotherapy (RT). We sought to review clinical outcomes of patients receiving RT and anti-PD-1 therapy. All patients receiving anti-PD-1 antibody and RT for metastatic melanoma were identified. RT and systemic treatment, clinical outcome, and toxicity data were collected. Fifty-three patients were included; 35 patients received extracranial RT and/or intracranial stereotactic radiosurgery (SRS) and 21 received whole brain radiotherapy (WBRT) (three of whom also received SRS/extracranial RT). Patients treated with extracranial RT or SRS received treatment either sequentially (RT then anti-PD-1, n = 11), concurrently (n = 16), or concurrent “salvage” treatment to lesions progressing on anti-PD-1 therapy (n = 15). There was no excessive anti-PD-1 or RT toxicity observed in patients receiving extracranial RT. Of six patients receiving SRS, one patient developed grade 3 radiation necrosis. In 21 patients receiving WBRT, one patient developed Stevens–Johnson syndrome, one patient developed acute neurocognitive decline, and one patient developed significant cerebral edema in the setting of disease. Response in irradiated extracranial/intracranial SRS lesions was 44% for sequential treatment and 64% for concurrent treatment (p=0.448). Likewise there was no significant difference between sequential or concurrent treatment in lesional response of non-irradiated lesions. For progressing lesions subsequently irradiated, response rate was 45%. RT and anti-PD-1 antibodies can be safely combined, with no detectable excess toxicity in extracranial sites. WBRT and anti-PD-1 therapy is well tolerated, although there are rare toxicities and the role of either anti-PD-1 or WBRT in the etiology of these is uncertain.

Effect of a computer-guided, quality improvement program for cardiovascular disease risk management in primary health care: the treatment of cardiovascular risk using electronic decision support cluster-randomized trial

Background— Despite effective treatments to reduce cardiovascular disease risk, their translation into practice is limited. Methods and Results— Using a parallel arm cluster-randomized controlled trial in 60 Australian primary healthcare centers, we tested whether a multifaceted quality improvement intervention comprising computerized decision support, audit/feedback tools, and staff training improved (1) guideline-indicated risk factor measurements and (2) guideline-indicated medications for those at high cardiovascular disease risk. Centers had to use a compatible software system, and eligible patients were regular attendees (Aboriginal and Torres Strait Islander people aged ≥35 years and others aged ≥45 years). Patient-level analyses were conducted using generalized estimating equations to account for clustering. Median follow-up for 38 725 patients (mean age, 61.0 years; 42% men) was 17.5 months. Mean monthly staff support was <1 hour/site. For the coprimary outcomes, the intervention was associated with improved overall risk factor measurements (62.8% versus 53.4% risk ratio; 1.25; 95% confidence interval, 1.04–1.50; P=0.02), but there was no significant differences in recommended prescriptions for the high-risk cohort (n=10 308; 56.8% versus 51.2%; P=0.12). There were significant treatment escalations (new prescriptions or increased numbers of medicines) for antiplatelet (4.3% versus 2.7%; P=0.01), and BP lowering (18.2% versus 11.0%; P=0.02) but not lipid-lowering medications. Conclusions— In Australian primary healthcare settings, a computer-guided quality improvement intervention, requiring minimal support, improved cardiovascular disease risk measurement but did not increase prescription rates in the high-risk group. Computerized quality improvement tools offer an important, albeit partial, solution to improving primary healthcare system capacity for cardiovascular disease risk management. Clinical Trial Registration— URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=336630. Australian New Zealand Clinical Trials Registry No. 12611000478910.

The Bidirectional Relationship Between Pain Intensity and Sleep Disturbance/Quality in Patients with Low Back Pain

Objectives:This study investigated the bidirectional relationship between the intensity of low back pain (LBP) and sleep disturbance. Further, the study aimed to determine whether any relationship is dependent on pain duration, symptoms of depression and anxiety, and the method of sleep assessment (subjective vs. objective). Materials and Methods:Eighty patients with LBP completed a sleep diary. A subgroup of 50 patients additionally wore an electronic device (Armband) to measure sleep for 7 consecutive days. Pain intensity was assessed twice daily using a sleep diary. Depression and anxiety symptoms were assessed at baseline using the Depression Anxiety Stress Scale questionnaire. Generalized estimating equations (GEE) with an exchangeable correlation structure were used to examine the relationship between day-time pain intensity and sleep. Results:The GEE analysis showed that a night of poor sleep quality, difficulty falling sleep (assessed by the sleep diary), waking after sleep onset, and low sleep efficiency (assessed by the sleep diary and Armband) were followed by a day with higher pain intensity. Further, a day with higher pain intensity was associated with a decrease in the subsequent night’s sleep quality, an increase in sleep latency (assessed by the sleep diary), waking after sleep onset (assessed by both measures), and low sleep efficiency (assessed by the Armband). Discussion:The findings demonstrate that there is a bidirectional relationship between sleep and pain intensity in patients with LBP. The relationship is independent of pain duration and baseline symptoms of depression and anxiety and somewhat dependent on the method of sleep measurement (sleep diary or Armband). Future research is needed to determine whether targeting sleep improvement in patients with LBP contributes to pain reduction.

Circulating tumour DNA predicts response to anti-PD1 antibodies in metastatic melanoma

Background Programmed death 1 (PD1) inhibitors are now a foundation of medical management of metastatic melanoma. This study sought to determine whether circulating tumour DNA (ctDNA) provides useful early response and prognostic information. Patients and methods We evaluated the relationship between pre-treatment and early on treatment ctDNA and outcome in melanoma patients treated with PD1 inhibitors alone or in combination with ipilimumab. Results ctDNA was detected in 40/76 patients (53%) at baseline, and correlated with stage, LDH levels, disease volume and ECOG performance. RECIST response was 72% (26/36) in group A (undetectable ctDNA at baseline), 77% (17/22) in group B (elevated ctDNA at baseline but undetectable within 12 weeks of therapy) and 6% (1/18) in group C (elevated ctDNA at baseline and remained elevated during treatment). The median PFS was not reached in groups A and B and was 2.7 months for group C [hazard ratio (HR) 0.09; P < 0.001 for group A versus C, and 0.16; P < 0.001 for group B versus C]. The median OS was not reached for groups A and B and was 9.2 months for group C (HR 0.02; P < 0.001 for group A versus C and 0.14; P < 0.001 for group B versus C). The poor outcome measures associated with group C remained significant in multivariate analysis adjusted for LDH, performance status, tumour stage and disease volume. The predictive value for ctDNA for response was confirmed in a separate validation cohort (n = 29, P < 0.01). Conclusion Longitudinal assessment of ctDNA in metastatic melanoma patients receiving treatment with PD1 inhibitors is an accurate predictor of tumour response, PFS and OS. Patients who had a persistently elevated ctDNA on therapy had a poor prognosis, and this may guide combination and sequencing of subsequent therapies.

Poor Sleep Quality Is Strongly Associated With Subsequent Pain Intensity in Patients With Acute Low Back Pain

Recent research suggests that sleep quality and pain intensity are intimately linked. Although sleep problems are common in patients with low back pain, the effect of sleep quality on the levels of pain intensity is currently unknown. The aim of this study was to investigate the effect of sleep quality on subsequent pain intensity in patients with recent‐onset low back pain.