Dorrilyn Rajbhandari

Hydroxyethyl Starch or Saline for Fluid Resuscitation in Intensive Care

BACKGROUND The safety and efficacy of hydroxyethyl starch (HES) for fluid resuscitation have not been fully evaluated, and adverse effects of HES on survival and renal function have been reported. METHODS We randomly assigned 7000 patients who had been admitted to an intensive care unit (ICU) in a 1:1 ratio to receive either 6% HES with a molecular weight of 130 kD and a molar substitution ratio of 0.4 (130/0.4, Voluven) in 0.9% sodium chloride or 0.9% sodium chloride (saline) for all fluid resuscitation until ICU discharge, death, or 90 days after randomization. The primary outcome was death within 90 days. Secondary outcomes included acute kidney injury and failure and treatment with renal-replacement therapy. RESULTS A total of 597 of 3315 patients (18.0%) in the HES group and 566 of 3336 (17.0%) in the saline group died (relative risk in the HES group, 1.06; 95% confidence interval [CI], 0.96 to 1.18; P=0.26). There was no significant difference in mortality in six predefined subgroups. Renal-replacement therapy was used in 235 of 3352 patients (7.0%) in the HES group and 196 of 3375 (5.8%) in the saline group (relative risk, 1.21; 95% CI, 1.00 to 1.45; P=0.04). In the HES and saline groups, renal injury occurred in 34.6% and 38.0% of patients, respectively (P=0.005), and renal failure occurred in 10.4% and 9.2% of patients, respectively (P=0.12). HES was associated with significantly more adverse events (5.3% vs. 2.8%, P<0.001). CONCLUSIONS In patients in the ICU, there was no significant difference in 90-day mortality between patients resuscitated with 6% HES (130/0.4) or saline. However, more patients who received resuscitation with HES were treated with renal-replacement therapy. (Funded by the National Health and Medical Research Council of Australia and others; CHEST ClinicalTrials.gov number, NCT00935168.).

Multicentre study of delirium in ICU patients using a simple screening tool.

Traditionally, intensive care unit (ICU) delirium was viewed as benign and was under-diagnosed in the absence of ICU-appropriate screening tools. Research suggests that up to half of all ICU patients experiencing delirium will continue to do so after discharge to the ward, and half of those experiencing delirium in the ward will die within 1 year of delirium diagnosis. ICU-specific screening tools are now available. The purpose of this study was to identify the incidence of delirium in ICU and explore its associations to clinical factors and outcomes. A secondary aim was to evaluate the usefulness of the intensive care delirium screening checklist (ICDSC). A total of 185 patients in six ICUs in Australia and New Zealand were screened for delirium using the ICDSC over two 12-hour periods per day for the duration of their ICU admission. Some 84 patients (45%) developed delirium. Development of delirium was associated with increased severity of illness (acute physiology and chronic health evaluation--APACHE II--and sequential organ failure assessment--SOFA), ICU length of stay (LOS), and use of psycho-active drugs. Delirious patients showed no statistically significant difference in ICU and hospital mortality rates, nor prolonged hospital LOS. The ICDSC was found to be user-friendly. The incidence of delirium, observed characteristics and outcomes for patients admitted to Australian and New Zealand ICUs for > 36 hours without any history of altered mental state fell in the mid-range and were generally consistent with previous literature. An ICU-specific delirium assessment, such as the ICDSC, should be included in routine ICU observations to minimise under-diagnosis of this serious phenomenon.

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.

Tryptophan metabolism to kynurenine is a potential novel contributor to hypotension in human sepsis.

Objectives:To determine whether tryptophan metabolism to kynurenine contributes to the direct regulation of vascular tone in human septic shock. Background:Indoleamine 2,3-dioxygenase 1 is an inducible enzyme that converts tryptophan to kynurenine and shares functional similarities with inducible nitric oxide synthase. Recently, kynurenine has been identified as an endothelium-derived relaxing factor produced during inflammation, raising the possibility that this novel pathway may contribute to hypotension in human sepsis. Design:Prospective, matched, single-center, cohort study. Settings:Intensive care unit of a tertiary teaching hospital matched to control subjects from the general medical ward and healthy volunteers. Subjects:Patients (n = 16) with septic shock had indoleamine 2,3-dioxygenase activity assessed as the kynurenine-to-tryptophan ratio, and the severity of hypotension was determined by their inotrope requirements. Healthy and blood pressure-matched nonseptic control subjects were also studied. Interventions:None. Measurements and Main Results:Tissues from septic and control patients were stained for the presence of indoleamine 2,3-dioxygenase 1. Indoleamine 2,3-dioxygenase activity increased up to ninefold in patients with septic shock and was significantly higher than in the two control groups (p < .01). Indoleamine 2,3-dioxygenase activity was strongly correlated with inotrope requirements (p < .001). Indoleamine 2,3-dioxygenase protein was expressed in inflamed cardiac tissue as well as in endothelial cells of resistance vessels in hearts and kidneys from subjects who died from sepsis. Conclusions:Indoleamine 2,3-dioxygenase 1 is expressed in resistance vessels in human sepsis and Indoleamine 2,3-dioxygenase activity correlates with hypotension in human septic shock. Indoleamine 2,3-dioxygenase 1 is thus a potential novel contributor to hypotension in sepsis.

Adjunctive Glucocorticoid Therapy in Patients with Septic Shock

BACKGROUND Whether hydrocortisone reduces mortality among patients with septic shock is unclear. METHODS We randomly assigned patients with septic shock who were undergoing mechanical ventilation to receive hydrocortisone (at a dose of 200 mg per day) or placebo for 7 days or until death or discharge from the intensive care unit (ICU), whichever came first. The primary outcome was death from any cause at 90 days. RESULTS From March 2013 through April 2017, a total of 3800 patients underwent randomization. Status with respect to the primary outcome was ascertained in 3658 patients (1832 of whom had been assigned to the hydrocortisone group and 1826 to the placebo group). At 90 days, 511 patients (27.9%) in the hydrocortisone group and 526 (28.8%) in the placebo group had died (odds ratio, 0.95; 95% confidence interval [CI], 0.82 to 1.10; P=0.50). The effect of the trial regimen was similar in six prespecified subgroups. Patients who had been assigned to receive hydrocortisone had faster resolution of shock than those assigned to the placebo group (median duration, 3 days [interquartile range, 2 to 5] vs. 4 days [interquartile range, 2 to 9]; hazard ratio, 1.32; 95% CI, 1.23 to 1.41; P<0.001). Patients in the hydrocortisone group had a shorter duration of the initial episode of mechanical ventilation than those in the placebo group (median, 6 days [interquartile range, 3 to 18] vs. 7 days [interquartile range, 3 to 24]; hazard ratio, 1.13; 95% CI, 1.05 to 1.22; P<0.001), but taking into account episodes of recurrence of ventilation, there were no significant differences in the number of days alive and free from mechanical ventilation. Fewer patients in the hydrocortisone group than in the placebo group received a blood transfusion (37.0% vs. 41.7%; odds ratio, 0.82; 95% CI, 0.72 to 0.94; P=0.004). There were no significant between‐group differences with respect to mortality at 28 days, the rate of recurrence of shock, the number of days alive and out of the ICU, the number of days alive and out of the hospital, the recurrence of mechanical ventilation, the rate of renal‐replacement therapy, and the incidence of new‐onset bacteremia or fungemia. CONCLUSIONS Among patients with septic shock undergoing mechanical ventilation, a continuous infusion of hydrocortisone did not result in lower 90‐day mortality than placebo. (Funded by the National Health and Medical Research Council of Australia and others; ADRENAL ClinicalTrials.gov number, NCT01448109.)

Traditional landmark versus ultrasound guided tracheal puncture during percutaneous dilatational tracheostomy in adult intensive care patients: a randomised controlled trial

IntroductionLong-term ventilated intensive care patients frequently require tracheostomy. Although overall risks are low, serious immediate and late complications still arise. Real-time ultrasound guidance has been proposed to decrease complications and improve the accuracy of the tracheal puncture. We aimed to compare the procedural safety and efficacy of real-time ultrasound guidance with the traditional landmark approach during percutaneous dilatational tracheostomy (PDT).MethodsA total of 50 patients undergoing PDT for clinical indications were randomly assigned, after obtaining informed consent, to have the tracheal puncture procedure carried out using either traditional anatomical landmarks or real-time ultrasound guidance. Puncture position was recorded via bronchoscopy. Blinded assessors determined in a standardised fashion the deviation of the puncture off midline and whether appropriate longitudinal position between the first and fourth tracheal rings was achieved. Procedural safety and efficacy data, including complications and number of puncture attempts required, were collected.ResultsIn total, 47 data sets were evaluable. Real-time ultrasound guidance resulted in significantly more accurate tracheal puncture. Mean deviation from midline was 15 ± 3° versus 35 ± 5° (P = 0.001). The proportion of appropriate punctures, defined a priori as 0 ± 30° from midline, was significantly higher: 20 (87%) of 23 versus 12 (50%) of 24 (RR = 1.74; 95% CI = 1.13 to 2.67; P = 0.006). First-pass success rate was 20 (87%) of 23 in the ultrasound group and 14 (58%) of 24 in the landmark group (RR = 1.49; 95% CI = 1.03 to 2.17; P = 0.028). The observed decrease in procedural complications was not statistically significant: 5 (22%) of 23 in the ultrasound group versus 9 (37%) of 24 in the landmark group (RR = 0.58; 95% CI = 0.23 to 1.47; P = 0.24).ConclusionsUltrasound guidance significantly improved the rate of first-pass puncture and puncture accuracy. Fewer procedural complications were observed; however, this did not reach statistical significance. These results support wider general use of real-time ultrasound guidance as an additional tool to improve PDT.Trial registrationAustralian New Zealand Clinical Trials Registry ID: ACTRN12611000237987 (registered 4 March 2011)

Method to introduce mannitol powder to intubated patients to improve sputum clearance.

BACKGROUND Poor sputum clearance is a common problem encountered in intubated patients, which may cause airway obstruction, hypoxaemia, and increased risk of lower respiratory tract infection. This may result in longer intensive care unit (ICU) stay or even death. Dry powder mannitol has been shown to improve sputum clearance, and thus we developed a system to deliver it to intubated patients. METHODS This delivery system consists of a standard adult manual ventilation bag, a one-way duck-billed valve, and a dry powder inhaler (Osmohaler™) contained within a delivery chamber to allow positive pressure ventilation, which in turn, is connected in series to an endotracheal or tracheostomy tube. The aerosol is delivered by compressing the ventilation bag in a reproducible manner to generate positive pressure airflow to disperse the powder into the tracheal tube. We tested the powder output and characteristics of the powder in vitro from two endotracheal tubes (7.0 and 8.5 mm in diameter, 300 mm in length), and two tracheostomy tubes (7.0 mm in diameter and 95 mm in length; 90 mm in diameter and 115 mm in length). RESULTS AND CONCLUSIONS Approximately 50 to 60% of the loaded dose of dry powder mannitol is delivered to the distal end of the tracheal tubes for both 4 × 40-mg and 4 × 80-mg capsules. The fine particle fraction (particles smaller than 5 μm) ranges from 20 to 31% of the loaded dose. Powder was emptied from each 40- and 80-mg capsule within 5 ± 1 puffs and 6 ± 1 puffs, respectively. This delivery system has been shown to consistently deliver a very high dose of powder with a favourable fine particle fraction to the distal end of a number of tracheal tubes. This has the potential for a number of clinical therapeutic applications in critically ill patients.

Rates and determinants of informed consent: A case study of an international thromboprophylaxis trial

BACKGROUND Successful completion of randomized trials depends upon efficiently and ethically screening patients and obtaining informed consent. Awareness of modifiable barriers to obtaining consent may inform ongoing and future trials. OBJECTIVE The objective of this study is to describe and examine determinants of consent rates in an international heparin thromboprophylaxis trial (Prophylaxis for ThromboEmbolism in Critical Care Trial, clinicaltrials.gov NCT00182143). DESIGN Throughout the 4-year trial, research personnel approached eligible critically ill patients or their substitute decision makers for informed consent. Whether consent was obtained or declined was documented daily. SETTING The trial was conducted in 67 centers in 6 countries. MEASUREMENTS AND MAIN RESULTS A total of 3764 patients were randomized. The overall consent rate was 82.2% (range, 50%-100%) across participating centers. Consent was obtained from substitute decision makers and patients in 90.1% and 9.9% of cases, respectively. Five factors were independently associated with consent rates. Research coordinators with more experience achieved higher consent rates (odds ratio [OR], 3.43; 95% confidence interval, 2.42-4.86; P < .001 for those with >10 years of experience). Consent rates were higher in smaller intensive care units with less than 15 beds compared with intensive care units with 15 to 20 beds, 21 to 25 beds, and greater than 25 beds (all ORs, <0.5; P < .001) and were higher in centers with more than 1 full-time research staff (OR, 1.95; 95% confidence interval, 1.28-2.99; P < .001). Consent rates were lower in centers affiliated with the Canadian Critical Care Trials Group or the Australian and New Zealand Intensive Care Society Clinical Trials Group compared with other centers (OR, 0.57; 95% confidence interval, 0.42-0.77; P < .001). Finally, consent rates were highest during the pilot trial, lowest during the initiation of the full trial, and increased over years of recruitment (P < .001). CONCLUSIONS Characteristics of study centers, research infrastructure, and experience were important factors associated with successfully procuring informed consent to participate in this thromboprophylaxis trial.

Is kynurenine a novel and important vasodilator in human septic shock

The enzyme indoleamine 2,3-dioxygenase (IDO) convertsthe amino acid tryptophan (Trp) to kynurenine (Kyn).IDO, which shares many functional similarities withiNOS [1], is also induced in sepsis [2]. Here, we investi-gated whether IDO plays a role in human septic shock andmouse endotoxemia akin to iNOS.