APROCCHSS trial - Hydrocort plus Fludricort in septic shock

Hydrocortisone plus Fludrocortisone for Adults with Septic Shock

• Djillali Annane, et al. 
for the CRICS-TRIGGERSEP Network*

N Engl J Med 2018; 378:809-818

BACKGROUND
Septic shock is characterized by dysregulation of the host response to infection, with circulatory, cellular, and metabolic abnormalities. We hypothesized that therapy with hydrocortisone plus fludrocortisone or with drotrecogin alfa (activated), which can modulate the host response, would improve the clinical outcomes of patients with septic shock.

HYPOTHESIS -  

therapy with hydrocortisone plus fludrocortisone or with drotrecogin alfa (activated), which can modulate the host response, would improve the clinical outcomes of patients with septic shock.

METHODS

•  multicenter, double-blind, randomized trial with a 2-by-2 factorial design, 

• evaluated the effect of hydrocortisone-plus-fludrocortisone therapy, drotrecogin alfa (activated), the combination of the three drugs, or their respective placebos. 

• primary outcome - 90-day all-cause mortality. 

• Secondary outcomes - mortality at intensive care unit (ICU) discharge and hospital discharge and at day 28 and day 180 and the number of days alive and free of vasopressors, mechanical ventilation, or organ failure. 

• After drotrecogin alfa (activated) was withdrawn from the market, the trial continued with a two-group parallel design. The analysis compared patients who received hydrocortisone plus fludrocortisone with those who did not (placebo group).

RESULTS

• 1241 patients included in the trial, the 90-day mortality was 43.0% (264 of 614 patients) in the hydrocortisone-plus-fludrocortisone group and 49.1% (308 of 627 patients) in the placebo group (P=0.03). 

• The relative risk of death in the hydrocortisone-plus-fludrocortisone group was 0.88 (95% confidence interval, 0.78 to 0.99). 

• Mortality was significantly lower in the hydrocortisone-plus-fludrocortisone group than in the placebo group at ICU discharge (35.4% vs. 41.0%, P=0.04), hospital discharge (39.0% vs. 45.3%, P=0.02), and day 180 (46.6% vs. 52.5%, P=0.04) but not at day 28 (33.7% and 38.9%, respectively; P=0.06). 

• The number of vasopressor-free days to day 28 was significantly higher in the hydrocortisone-plus-fludrocortisone group than in the placebo group (17 vs. 15 days, P<0.001), as was the number of organ-failure–free days (14 vs. 12 days, P=0.003). 

• The number of ventilator-free days was similar in the two groups (11 days in the hydrocortisone-plus-fludrocortisone group and 10 in the placebo group, P=0.07). 

• The rate of serious adverse events did not differ significantly between the two groups, but hyperglycemia was more common in hydrocortisone-plus-fludrocortisone group.

CONCLUSIONS

In this trial involving patients with septic shock, 90-day all-cause mortality was lower among those who received hydrocortisone plus fludrocortisone than among those who received placebo.

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SMART trial - Balanced Crystalloids vs Saline

Balanced Crystalloids versus Saline in Critically Ill Adults

• Matthew W. Semler, et al. 
for the SMART Investigators and the Pragmatic Critical Care Research Group

N Engl J Med 2018; 378:829-839

BACKGROUND: 

Both balanced crystalloids and saline are used for intravenous fluid administration in critically ill adults, but it is not known which results in better clinical outcomes.

METHODS

• A pragmatic, cluster-randomized, multiple-crossover trial conducted in five intensive care units at an academic center, 

• assigned 15,802 adults to receive saline (0.9% sodium chloride) or balanced crystalloids (lactated Ringer’s solution or Plasma-Lyte A) according to the randomization of the unit to which they were admitted. 

• The primary outcome was a major adverse kidney event within 30 days — a composite of death from any cause, new renal-replacement therapy, or persistent renal dysfunction (defined as an elevation of the creatinine level to ≥200% of baseline) — all censored at hospital discharge or 30 days, whichever occurred first.

RESULTS

• 7942 patients in the balanced-crystalloids group - 1139 (14.3%) had a major adverse kidney event, as compared with 1211 of 7860 patients (15.4%) in the saline group (marginal odds ratio, 0.91; 95% confidence interval [CI], 0.84 to 0.99; conditional odds ratio, 0.90; 95% CI, 0.82 to 0.99; P=0.04).

•  In-hospital mortality at 30 days was 10.3% in the balanced-crystalloids group and 11.1% in the saline group (P=0.06). 

• The incidence of new renal-replacement therapy was 2.5% and 2.9%, respectively (P=0.08), and the incidence of persistent renal dysfunction was 6.4% and 6.6%, respectively (P=0.60).

CONCLUSIONS

Among critically ill adults, the use of balanced crystalloids for intravenous fluid administration resulted in a lower rate of the composite outcome of death from any cause, new renal-replacement therapy, or persistent renal dysfunction than the use of saline. 

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WAKE-UP study : MRI-Guided Thrombolysis for Stroke with Unknown Time of Onset

MRI-Guided Thrombolysis for Stroke with Unknown Time of Onset

• Götz Thomalla, et al. WAKE-UP investigators. 

• BACKGROUND:
  
  - Under current guidelines, intravenous thrombolysis is used to treat acute stroke only if it can be ascertained that the time since the onset of symptoms was less than 4.5 hours. 
  We sought to determine whether patients with stroke with an unknown time of onset and features suggesting recent cerebral infarction on magnetic resonance imaging (MRI) would benefit from thrombolysis with the use of intravenous alteplase.
  
  METHODS
  
  - multicenter trial, 
  - randomly assigned patients who had an unknown time of onset of stroke to receive either intravenous alteplase or placebo. 
  - All the patients had an ischemic lesion that was visible on MRI diffusion-weighted imaging but no parenchymal hyperintensity on fluid-attenuated inversion recovery (FLAIR), which indicated that the stroke had occurred approximately within the previous 4.5 hours. 
  - excluded patients for whom thrombectomy was planned. 
  - The primary end point was favorable outcome, as defined by a score of 0 or 1 on the modified Rankin scale of neurologic disability (which ranges from 0 [no symptoms] to 6 [death]) at 90 days. 
  - A secondary outcome was the likelihood that alteplase would lead to lower ordinal scores on the modified Rankin scale than would placebo (shift analysis).
  
  
  RESULTS
  
  - The trial was stopped early owing to cessation of funding after the enrollment of 503 of an anticipated 800 patients.
  - Of these patients, 254 were randomly assigned to receive alteplase and 249 to receive placebo. 
  - A favorable outcome at 90 days was reported in 131 of 246 patients (53.3%) in the alteplase group and in 102 of 244 patients (41.8%) in the placebo group (adjusted odds ratio, 1.61; 95% confidence interval [CI], 1.09 to 2.36; P=0.02). 
  - The median score on the modified Rankin scale at 90 days was 1 in the alteplase group and 2 in the placebo group (adjusted common odds ratio, 1.62; 95% CI, 1.17 to 2.23; P=0.003). 
  - There were 10 deaths (4.1%) in the alteplase group and 3 (1.2%) in the placebo group (odds ratio, 3.38; 95% CI, 0.92 to 12.52; P=0.07). 
  - The rate of symptomatic intracranial hemorrhage was 2.0% in the alteplase group and 0.4% in the placebo group (odds ratio, 4.95; 95% CI, 0.57 to 42.87; P=0.15).
  
  
  CONCLUSIONS
  
  In patients with acute stroke with an unknown time of onset, intravenous alteplase guided by a mismatch between diffusion-weighted imaging and FLAIR in the region of ischemia resulted in a significantly better functional outcome and numerically more intracranial hemorrhages than placebo at 90 days. 
  
  
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SAFE study - Albumin vs Saline for fluid resuscitation in ICU

A Comparison of Albumin and Saline for Fluid Resuscitation in the Intensive Care Unit

• The SAFE Study Investigators
*

N Engl J Med 2004; 350:2247-2256

BACKGROUND

It remains uncertain whether the choice of resuscitation fluid for patients in intensive care units (ICUs) affects survival. We conducted a multicenter, randomized, double-blind trial to compare the effect of fluid resuscitation with albumin or saline on mortality in a heterogeneous population of patients in the ICU.


METHODS

We randomly assigned patients who had been admitted to the ICU to receive either 4 percent albumin or normal saline for intravascular-fluid resuscitation during the next 28 days. The primary outcome measure was death from any cause during the 28-day period after randomization.


RESULTS

Of the 6997 patients who underwent randomization, 3497 were assigned to receive albumin and 3500 to receive saline; the two groups had similar baseline characteristics. There were 726 deaths in the albumin group, as compared with 729 deaths in the saline group (relative risk of death, 0.99; 95 percent confidence interval, 0.91 to 1.09; P=0.87). The proportion of patients with new single-organ and multiple-organ failure was similar in the two groups (P=0.85). There were no significant differences between the groups in the mean (±SD) numbers of days spent in the ICU (6.5±6.6 in the albumin group and 6.2±6.2 in the saline group, P=0.44), days spent in the hospital (15.3±9.6 and 15.6±9.6, respectively; P=0.30), days of mechanical ventilation (4.5±6.1 and 4.3±5.7, respectively; P=0.74), or days of renal-replacement therapy (0.5±2.3 and 0.4±2.0, respectively; P=0.41).


CONCLUSIONS

In patients in the ICU, use of either 4 percent albumin or normal saline for fluid resuscitation results in similar outcomes at 28 days.


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ARDS Network - Low tidal volume vs Traditional tidal volume

Ventilation with Lower Tidal Volumes as Compared with Traditional Tidal Volumes for Acute Lung Injury and the Acute Respiratory Distress Syndrome

• The Acute Respiratory Distress Syndrome Network
*

N Engl J Med 2000; 342:1301-1308

BACKGROUND-

Traditional approaches to mechanical ventilation use tidal volumes of 10 to 15 ml per kilogram of body weight and may cause stretch-induced lung injury in patients with acute lung injury and the acute respiratory distress syndrome. We therefore conducted a trial to determine whether ventilation with lower tidal volumes would improve the clinical outcomes in these patients.


METHODS

Patients with acute lung injury and the acute respiratory distress syndrome were enrolled in a multicenter, randomized trial. The trial compared traditional ventilation treatment, which involved an initial tidal volume of 12 ml per kilogram of predicted body weight and an airway pressure measured after a 0.5-second pause at the end of inspiration (plateau pressure) of 50 cm of water or less, with ventilation with a lower tidal volume, which involved an initial tidal volume of 6 ml per kilogram of predicted body weight and a plateau pressure of 30 cm of water or less. The first primary outcome was death before a patient was discharged home and was breathing without assistance. The second primary outcome was the number of days without ventilator use from day 1 to day 28.


RESULTS

The trial was stopped after the enrollment of 861 patients because mortality was lower in the group treated with lower tidal volumes than in the group treated with traditional tidal volumes (31.0 percent vs. 39.8 percent, P=0.007), and the number of days without ventilator use during the first 28 days after randomization was greater in this group (mean [±SD], 12±11 vs. 10±11; P=0.007). The mean tidal volumes on days 1 to 3 were 6.2±0.8 and 11.8±0.8 ml per kilogram of predicted body weight (P<0.001), respectively, and the mean plateau pressures were 25±6 and 33±8 cm of water (P<0.001), respectively.


CONCLUSIONS

In patients with acute lung injury and the acute respiratory distress syndrome, mechanical ventilation with a lower tidal volume than is traditionally used results in decreased mortality and increases the number of days without ventilator use.


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ADRENAL trial - Adjunctive Glucocorticoid Therapy in Patients with Septic Shock

Adjunctive Glucocorticoid Therapy in Patients with Septic Shock

B.  Venkatesh,  S.  Finfer, et al.

N Engl J Med 2018; 378:797-808

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:
Hi 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 renalreplacement  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.)

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Colistin vs Colistin plus meropenem in MDR GNB

Colistin alone versus colistin plus meropenem for treatment of severe infections caused by carbapenem-resistant Gram-negative bacteria: an open-label, randomised controlled trial.

Mical Paul, George L Daikos, et al.

The Lancet Volume 18, No. 4, p391–400, April 2018

Background: 

Colistin–carbapenem combinations are synergistic in vitro against carbapenem-resistant Gram-negative bacteria. We aimed to test whether combination therapy improves clinical outcomes for adults with infections caused by carbapenem-resistant or carbapenemase-producing Gram-negative bacteria.

Methods: 

A randomised controlled superiority trial was done in six hospitals in Israel, Greece, and Italy. We included adults with bacteraemia, ventilator-associated pneumonia, hospital-acquired pneumonia, or urosepsis caused by carbapenem-non-susceptible Gram-negative bacteria. Patients were randomly assigned (1:1) centrally, by computer- generated permuted blocks strati ed by centre, to intravenous colistin (9-million unit loading dose, followed by 4·5 million units twice per day) or colistin with meropenem (2-g prolonged infusion three times per day). 

The trial was open-label, with blinded outcome assessment. Treatment success was defined as survival, haemodynamic stability, improved or stable Sequential Organ Failure Assessment score, stable or improved ratio of partial pressure of arterial oxygen to fraction of expired oxygen for patients with pneumonia, and microbiological cure for patients with bacteraemia. The primary outcome was clinical failure, defined as not meeting all success criteria by intention- to-treat analysis, at 14 days after randomisation. This trial is registered at ClinicalTrials.gov, number NCT01732250, and is closed to accrual.

Findings: 

Between Oct 1, 2013, and Dec 31, 2016, we randomly assigned 406 patients to the two treatment groups. Most patients had pneumonia or bacteraemia (355/406, 87%), and most infections were caused by Acinetobacter baumannii (312/406, 77%). 

No significant difference between colistin monotherapy (156/198, 79%) and combination therapy (152/208, 73%) was observed for clinical failure at 14 days after randomisation (risk difference –5·7%, 95% CI –13·9 to 2·4; risk ratio [RR] 0·93, 95% CI 0·83–1·03). 

Results were similar among patients with A baumannii infections (RR 0·97, 95% CI 0·87–1·09). Combination therapy increased the incidence of diarrhoea (56 [27%] vs 32 [16%] patients) and decreased the incidence of mild renal failure (37 [30%] of 124 vs 25 [20%] of 125 patients at risk of or with kidney injury).

Interpretation: 

Combination therapy was not superior to monotherapy. The addition of meropenem to colistin did not improve clinical failure in severe A baumannii infections. The trial was unpowered to specifically address other bacteria.

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TICH-2 : Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage

Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage (TICH-2): an international randomised, placebo-controlled, phase 3 superiority trial

Nikola Sprigg, Katie Flaherty, et al.

The Lancet, Published Online May 16, 2018.

Abstract:

Background: 

Tranexamic acid can prevent death due to bleeding after trauma and post-partum haemorrhage. We aimed to assess whether tranexamic acid reduces haematoma expansion and improves outcome in adults with stroke due to intracerebral haemorrhage. 

Methods:

We did an international, randomised placebo-controlled trial in adults with intracerebral haemorrhage from acute stroke units at 124 hospital sites in 12 countries. Participants were randomly assigned (1:1) to receive 1 g intravenous tranexamic acid bolus followed by an 8 h infusion of 1 g tranexamic acid or a matching placebo, within 8 h of symptom onset. Randomisation was done centrally in real time via a secure website, with stratification by country and minimisation on key prognostic factors. Treatment allocation was concealed from patients, outcome assessors, and all other health-care workers involved in the trial. 

The primary outcome was functional status at day 90, measured by shift in the modified Rankin Scale, using ordinal logistic regression with adjustment for stratification and minimisation criteria. All analyses were done on an intention-to-treat basis. This trial is registered with the ISRCTN registry, number ISRCTN93732214. 

Findings:

We recruited 2325 participants between March 1, 2013, and Sept 30, 2017. 1161 patients received tranexamic acid and 1164 received placebo; the treatment groups were well balanced at baseline. 

The primary outcome was assessed for 2307 (99%) participants. The primary outcome, functional status at day 90, did not differ significantly between the groups (adjusted odds ratio [aOR] 0·88, 95% CI 0·76–1·03, p=0·11). 

Although there were fewer deaths by day 7 in the tranexamic acid group (101 [9%] deaths in the tranexamic acid group vs 123 [11%] deaths in the placebo group; aOR 0·73, 0·53–0·99, p=0·0406), there was no difference in case fatality at 90 days (250 [22%] vs 249 [21%]; adjusted hazard ratio 0·92, 95% CI 0·77–1·10, p=0·37). 

Fewer patients had serious adverse events after tranexamic acid than after placebo by days 2 (379 [33%] patients vs 417 [36%] patients), 7 (456 [39%] vs 497 [43%]), and 90 (521 [45%] vs 556 [48%]). 

Interpretation:

Functional status 90 days after intracerebral haemorrhage did not differ significantly between patients who received tranexamic acid and those who received placebo, despite a reduction in early deaths and serious adverse events. Larger randomised trials are needed to confirm or refute a clinically significant treatment effect.

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ICU-ROX - results of the pilot phase

Intensive care unit randomised trial comparing two approaches to oxygen therapy (ICU-ROX): results of the pilot phase.

Young PJ, Mackle DM, et al.; The ICU-ROX pilot investigators; The Australian and New Zealand Intensive Care Society Clinical Trials Group.

Crit Care Resusc. 2017 Dec;19(4):344-354.

Abstract:

OBJECTIVE:

The objective of the intensive care unit randomised trial comparing two approaches to oxygen therapy (ICU-ROX) pilot phase, which included the first 100 patients of an overall sample of 1000, was to examine feasibility.

DESIGN:

Investigator-initiated, prospective, parallel-group, pilot randomised controlled trial.

SETTING:

Six medical-surgical intensive care units (ICUs) in Australia and New Zealand, with participants recruited from September 2015 through June 2016.

PARTICIPANTS:

100 patients ≥ 18 years of age who required invasive mechanical ventilation in the ICU and were expected to be receiving it beyond the next calendar day at the time of randomisation.

INTERVENTIONS:

Conservative oxygen therapy or standard care.

MAIN OUTCOME MEASURES:

Eligibility, recruitment rate, and separation in oxygen exposure (fraction of inspired oxygen [FiO2] and oxygen saturation measured by pulse oximetry [SpO2Z]).

RESULTS:

94 of 99 participants (94.9%) were confirmed by study monitors to fulfil the study eligibility criteria. 3.6 patients per site per month were enrolled (95% confidence interval [CI], 2.5-4.7). Patients allocated to conservative oxygen therapy spent significantly more time on an FiO2 of 0.21 in the ICU; median, 31.5 hours (interquartile range [IQR], 7-63.5) for conservative oxygen therapy patients v 0 hours for standard oxygen therapy patients (IQR, 0-10; midpoint difference, 21.5 hours; 95% CI, 9-34; P < 0.0001). Patients allocated to conservative oxygen therapy spent less time in the ICU with an SpO2Z of ≥ 97% than patients allocated to standard oxygen therapy; median, 18.5 hours (IQR, 5-46) for conservative oxygen therapy patients v 32 hours for standard oxygen therapy (IQR, 17-80; midpoint difference, 13.5 hours; 95% CI, 2-25; P = 0.02).

CONCLUSIONS:

Our findings confirm the feasibility of completing the ICU-ROX trial without the need for substantive changes to the study protocol for the remaining 900 trial participants.

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