ARDS
In a randomized controlled trial of 861 patients with ARDS, mechanical ventilation with a tidal volume of 6 ml/kg and plateau pressure ≤ 30 cmH20, in comparison with tidal volume of 12 ml/kg and plateau pressure ≤ 50cm H20, was associated with a 9% absolute mortality decrease (31% vs 40%, P=0.007; NNT=11) and a 2 day increase in ventilator-free days (12±11 vs. 10±11; P=0.007).
SEPTIC SHOCK
Sprung. Hydrocortisone Therapy for Patients with Septic Shock. N Engl J Med 2008;358:111-124
In a multicentre, double-blind, randomized placebo-controlled trial comparing hydrocortisone (50mg IV 6 hourly, then tapered) with placebo in 499 patients with septic shock, there was no significant difference in 28-day mortality (hydrocortisone group 34.3% vs placebo group 31.5%; P=0.51). Subgroup analyses of 28-day mortality based on response to corticotropin also showed no difference between study groups. Hydrocortisone hastened reversal of shock compared to placebo, however, with more episodes of superinfection, including new sepsis and septic shock.
In a multicenter trial conducted in the tertiary care setting, protocol-based resuscitation of patients in whom septic shock was diagnosed in the emergency department did not improve outcomes.
In a blinded, multicenter, randomized control trial, comparing noradrenaline plus dobutamine with adrenaline in 330 patients with septic shock, aiming to maintain mean arterial pressure at 70 mmHg, there were no significant differences in 28 day mortality (34% vs. 40%, relative risk 0.86, 95% CI 0.65 to 1.14, P=0.31), ICU mortality (47%s vs 75, p=0·69), hospital mortality (52% vs 49%, p=0·51), 90 day mortality (52% vs 50%, p=0·73), time to haemodynamic success (p=0·67), time to vasopressor withdrawal (p=0·09), or rates of serious adverse events.
In a blinded, multicenter, randomized control trial, comparing noradrenaline plus dobutamine with adrenaline in 330 patients with septic shock, aiming to maintain mean arterial pressure at 70 mmHg, there were no significant differences in 28 day mortality (34% vs. 40%, relative risk 0.86, 95% CI 0.65 to 1.14, P=0.31), ICU mortality (47%s vs 75, p=0·69), hospital mortality (52% vs 49%, p=0·51), 90 day mortality (52% vs 50%, p=0·73), time to haemodynamic success (p=0·67), time to vasopressor withdrawal (p=0·09), or rates of serious adverse events.
Compared with conventional insulin therapy, intensive insulin therapy did not improve in-hospital mortality among patients who were treated with hydrocortisone for septic shock. The addition of oral fludrocortisone did not result in a statistically significant improvement in in-hospital mortality
Low-dose vasopressin did not reduce mortality rates as compared with norepinephrine among patients with septic shock who were treated with catecholamine vasopressors.
FLUIDS
In a multicenter, randomized, double-blind trial comparing 0.9% saline or 4% albumin for fluid resuscitation in 6997 critically ill patients in the ICU, there was no difference in mortality (729 v 726, RR 0.99; 95 CI 0.91 to 1.09; P=0.87), new single-organ and multiple-organ failure (P=0.85), mean (SD) numbers of ICU days (6.2±6.2 v 6.5±6.6, P=0.44), hospital days (15.6±9.6 v 15.3±9.6; P=0.30), days of mechanical ventilation (4.3±5.7 v 4.5±6.1; P=0.74), or days of renal-replacement therapy (0.4±2.0 v 0.5±2.3) respectively.
In a blinded randomized controlled trial comparing 6% hydroxyethyl starch 130/0.42 (Voluven) with 0.9% saline for fluid resusciation in 7000 critically ill patients, this colloid therapy was associated with a 21% increased risk of the requirement for renal replacement therapy ( HES RRT requirement 7.0% versus saline 5.8%; relative risk 1.21; 95% CI 1.00 to 1.45; P=0.04 and no mortality benefit (HES mortality 18.0% versus saline mortality 17.0%; relative risk in the HES group, 1.06; 95% CI 0.96 to 1.18; P=0.26). Starch therapy was also associated with increased rates of hepatic failure, rash and pruritus.
In a blinded randomized controlled trial comparing 6% hydroxyethyl starch 130/0.42 (Tetraspan) with Ringers acetate for fluid resuscitation in 804 patients with severe sepsis, at 90 days the use of HES was associated with an 8% absolute increase in mortality (51% v 43%; relative risk: 1.17; 95% CI: 1.01 to 1.36; P=0.03) and a 6% absolute increase in renal replacement therapy (22% v 16%; relative risk: 1.35; 95% CI 1.01 to 1.80; P=0.04)
Maitland. Mortality after Fluid Bolus in African Children with Severe Infection (FEAST Trial). N Engl J Med 2011;364:2483-2495 (Paediatric Study)
Maitland et al performed a stratified (severe hypotension or not), multicenter, randomized control trial, in a resource-limited setting in sub-Saharan Africa, comparing a fluid bolus (20 to 40 ml of 5% albumin or 0.9% saline) with no fluid bolus at admission to hospital in 3,141 children with febrile illness and impaired perfusion, and found fluid bolus therapy was associated with a higher mortality at 48 hours (albumin 10.6%, saline 10.5%, no bolus 7.3%; relative risk bolus therapy versus no bolus 1.45, 95% CI 1.13 to 1.86, P=0.003), and 28 days (12.2%, 12.0% & 8.7%, respectively; RR bolus therapy versus no bolus p=0.004), with similar incidences of pulmonary oedema, increased intracranial pressure (2.6%, 2.2% versus 1.7% P=0.17), and neurological sequela in the three groups (P=0.92).
TRANSFUSION
In a randomized controlled trial comparing a red cell transfusion trigger of 7 g/dL versus 10 g/dl in 838 critically ill resuscitated patient, there was no difference in either total 30 day mortality (18.7% vs 23.3%, P=0.11, respectively) or mortality in those with clinically significant cardiac disease (20.5% vs 22.9%; P=0.69). The restrictive transfusion policy was superior for mortality outcome in patients with APACHE II scores of <20 (8.7% vs 16.1%;P=0.03), in patients < 55 years of age (5.7% vs 13.0%; P=0.02), and during hospitalization (22.2% vs 28.1%;P=0.05).
SEDATION
In a single centre, randomised, controlled trial comparing daily sedation hold with continuous sedation in 128 critically ill mechanically ventilated adults, sedation hold decreased the median durations of mechanical ventilation (4.9 days versus 7.3, p=0.004) and ICU length of stay (6.4 days versus 9.9 days, p = 0.02) as well as the requirement for diagnostic testing for changes in mental status (9% versus 27%, p = 0.02). There were no significant differences in adverse events, including self extubation (intervention group 4% versus control group 7 %, p = 0.88).
GLUCOSE CONTROL
In a multicentre, randomized controlled trial comparing intensive glucose control (81-108 mg/dL / 4.5-6.0 mmol/L) with conventional glucose control (≤180 mg/dL / ≤ 10.0 mmol/L) in 6,104 adult medical and surgical patients, intensive glucose control increased mortality (27.5% vs 24.9%; odds ratio 1.14; 95% CI 1.02 to 1.28; P=0.02). There was no significant difference between medical and surgical patients (odds ratio 1.31 and 1.07 respectively; P=0.10). Severe hypoglycaemic episodes (blood glucose level ≤40mg/dL / 2.2 mmol/L) were more common in the intensive glucose control group (6.8% vs 0.5%; P<0.001). There were no significant differences in the median number of days of mechanical ventilation (P=0.56) or renal-replacement therapy (P=0.39), or days in ICU (P=0.84) or hospital (P=0.86).
KIDNEY INJURY
In a multicentre, randomised, controlled, double-blind study comparing low-dose dopamine (2μg/kg/min) infusion with placebo in 328 patients with at least two SIRS criteria and early renal dysfunction, there were no differences in peak serum creatinine concentration (dopamine 245 vs placebo 249 μmol/L; p=0·93), increase in serum creatinine from baseline to highest value (62 vs 66 μmol/L; p=0·82), patients whose serum creatinine concentration exceeded 300 μmol/L (56 vs 56; p=0·92), requirement for renal replacement therapy (35 vs 40; p=0·55), duration of ICU stay (13 vs 14 days; p=0·67), duration of hospital stay (29 vs 33 days; p=0·29), or mortality (69 deaths versus 66 deaths).
TARGETED TEMPERATURE MANAGEMENT
In a multicenter, randomized, control trial, comparing temperature management at 33°C with 36°C in 939 comatose patients after out-of-hospital cardiac arrest of presumed cardiac cause, there was no difference in mortality at the end of the trial (33°C group 50% vs 36°C group 48%; hazard ratio with 33°C, 1.06; 95% CI 0.89 to 1.28; P = 0.51), 180-day composite of mortality and poor neurological function (54% vs. 52%, respectively; RR 1.02; 95% CI 0.88 to 1.16; P = 0.78), or serious adverse events (93% vs. 90%, respectively; RR 1.03; 95% CI 1.00 to 1.08; P = 0.09).
DIGESTIVE TRACT DECONTAMINATION
In an unblinded, single center, randomized control trial comparing selective digestive tract decontamination (oral and enteral polymyxin E, tobramycin, and amphotericin B combined with an initial 4-day course of intravenous cefotaxime) with standard treatment in 934 critically ill patients, SDD was associated with reductions in ICU mortality (15% versus 23%, P=0.002), hospital mortality (24% versus 31%, P=0.02) and colonization with resistant gram-negative bacteria (16% versus 26%, P=0.001), with equal colonization of vancomycin resistant enterococcus (1% versus 1% p=1.0) and absence of methicillin resistant staphylococcus aureus colonization.
In an ICU population in which the mortality rate associated with standard care was 27.5% at day 28, the rate was reduced by an estimated 3.5 percentage points with SDD and by 2.9 percentage points with SOD.
PA Catheters
In a multicenter, randomized control trial comparing critical care management with a pulmonary artery catheter to management without a pulmonary artery catheter in 1,014 general ICU patients, there was no difference in hospital mortality (68% versus 66%, hazard ratio 1.09, 95% CI 0.94 to 1.27, P=0.39) or complications, with the incidence of non-fatal complications secondary to pulmonary artery catheterization being 9.5%.
In a multicenter, randomized control trial, comparing ongoing conventional mechanical ventilation in a non-ECMO centre with transfer to an ECMO centre for respiratory support with either conventional mechanical ventilation or ECMO in 180 patients with severe hypoxic respiratory failure, ECMO centre management, where only 75% of the transferred patients actually received ECMO, was associated with increased 6-month survival (63% vs. 47%, relative risk 0.69, 95% CI 0.05 to 0.97, P=0.03) and a gain of 0·03 quality-adjusted life-years at 6-months, with a lifetime model predicting the cost per QALY of ECMO to be £19 252 (95% CI 7622—59 200) at a discount rate of 3·5%
In a blinded, multicenter, randomized, control trial, comparing activated protein C (24 µg/kg/hr for 96 hours) with a placebo, in 1,697 adults with septic shock, there were no significant differences in mortality at 28 (26.4% vs. 24.2%, relative risk with APC 1.09, 95% CI 0.92 to 1.28 P=0.31) or 90 days (34.1% versus 32.7%, relative risk with APC 1.04, 95% CI 0.90 to 1.19, P=0.56), including those with initially low levels of APC (28 day mortality 28.7% vs. 30.8%, RR 0.93, 95% CI 0.74 to 1.17; p=0.54), or difference in serious bleeding (APC 10 patients versus placebo 8 patients, P=0.81).
In a blinded, international, multicenter, randomized control trial, largely in resource limited healthcare systems, comparing administration of tranexamic acid (TXA) within 8 hours of traumatic injury (1g over 10 min, then infusion of 1g over 8 hours) with placebo in 20,211 adult patients, with or at risk of significant haemorrhage (SBP <90 mmHg or HR >110 bpm, or both), TXA was associated with reduced mortality (14.5% versus 16.0%; relative risk 0.91, 95% CI 0.85 to 0.97; p=0.0035), including reduced bleeding-related mortality (4.9% versus 5.7%; RR 0.85, 95% CI 0.76 to 0.96; p=0.0077), despite no difference in requirement for blood transfusions (50.4% vs. 51.3%) or vascular-occlusive events. In a subsequent post hoc analysis, the bleeding-related mortality reduction with TXA was time dependent, and actually reversed with late administration after 3 hours of injury (TXA 4.4% vs. placebo 3.1%, p=0.004).
Targeting a mean arterial pressure of 80 to 85 mm Hg, as compared with 65 to 70 mm Hg, in patients with septic shock undergoing resuscitation did not result in significant differences in mortality at either 28 or 90 days.
Casaer. Early versus Late Parenteral Nutrition in Critically Ill Adults. NEJM 2011;365:506-517
In a multicenter, randomized trial comparing early parenteral nutrition (within 48 hours of ICU admission) with late parenteral nutrition (within day 8 of ICU admission) to supplement inadequate enteral nutrition, in 4,640 critically ill patients, late parenteral nutrition was associated with multiple improvements, including shorter durations of ICU (3 days vs. 4 days;p=0.02) and hospital (14 vs. 16 days, p=0.004) stay, fewer ICU infections (22.8% vs. 26.2%, P=0.008), lower incidence of cholestasis (P<0.001), reduced requirement for ventilation for > 2 days (36.3% vs. 40.2%, P=0.006), less duration of renal-replacement therapy (7 vs. 10 days, P=0.008) and mean reduction in health care costs of £910 (P=0.04).
Doig et al performed a multicenter, randomized trial comparing standard care with early parenteral nutrition in 1,372 critically ill patients with relative contraindications to enteral nutrition remaining in ICU for > 2 days, and found no difference in 60 day mortality (standard care 22.8% vs. early PN 21.5%; risk difference −1.26%; 95% CI −6.6 to 4.1; P = 0.60). Early parenteral nutrition patients required fewer days of mechanical ventilation (7.73 versus 7.26, risk difference −0.47; 95% CI −0.82 to −0.11; P = 0.01), less muscle wasting based on subjective global assessment (0.43 versus 0.27; mean difference −0.16; 95% CI −0.28 to −0.038; P = 0.01) and less fat loss (0.44 versus 0.31; mean difference −0.13; 95% CI −0.25 to −0.01; P = 0.04). Day-60 quality of life (RAND-36 General Health Status) was statistically higher in the early PN group, which was not clinically meaningful. (45.5 versus 49.8; mean difference 4.3; 95% CI 0.95 to 7.58; P = 0.01).
Mechanical ventilation with conventional tidal volumes is associated with sustained cytokine production, as measured in plasma. Our data suggest that mechanical ventilation with conventional tidal volumes contributes to the development of lung injury in patients without ALI at the onset of mechanical ventilation
Girard. Efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (Awakening and Breathing Controlled trial): a randomised controlled trial). Lancet 2008;371(9607):126-134
In a multicentre, randomised controlled trial comparing paired daily sedation hold plus daily spontaneous breathing trial (intervention) versus uninterrupted sedation plus a daily spontaneous breathing trial (control) in 336 sedated, mechanically ventilated patients, the intervention was associated with more days breathing without assistance (14·7 vs 11·6 days; 95% CI 0·7 to 5·6; p=0·02), earlier discharge from both intensive care (median time in ICU 9·1 days vs 12·9 days; p=0·01) and the hospital (median time in the hospital 14·9 days vs 19·2 days; p=0·04), and reduced one-year mortality (HR 0·68; 95% CI 0·50 to 0·92; p=0·01; NNT 7.4, 95% CI 4·2 to 35·5). More patients in the intervention group self-extubated, but with similar rates for both reintubation after self-extubation and total reintubation.
For patients with severe traumatic brain injury, care focused on maintaining monitored intracranial pressure at 20 mm Hg or less was not shown to be superior to care based on imaging and clinical examination.
In patients with severe sepsis, albumin replacement in addition to crystalloids, as compared with crystalloids alone, did not improve the rate of survival at 28 and 90 days.
Intensive renal support in critically ill patients with acute kidney injury did not decrease mortality, improve recovery of kidney function, or reduce the rate of nonrenal organ failure as compared with less-intensive therapy involving a defined dose of intermittent hemodialysis three times per week and continuous renal-replacement therapy at 20 ml per kilogram per hour.
In a single centre, randomized controlled trial comparing semirecumbent with supine body position in 86 mechanically ventilated medical patients, the semirecumbent group had a lower frequency of suspected noscomial pneumonia (8% vs 34%; 95% CI for difference 10·0 to 42.0; P=0·003) and microbiologically confirmed pneumonia (5% vs 23%; 95% CI 4.2 to 31.8; p=0·018). Supine body position (odds ratio 6.8; 95% CI 1.7 – 26.7; P=0·006) and enteral nutrition (odds ration 5.7; 95% CI 1.5 – 22.8; P=0·013) were independent risk factors for nosocomial pneumonia.
For mechanically ventilated adults managed with protocolized sedation, the addition of daily sedation interruption did not reduce the duration of mechanical ventilation or ICU stay
In a multicentre, double-blind, randomized controlled trial comparing 48 hours of cisatracurium besylate with placebo in 340 patients with early severe ARDS, neuromuscular blockade was associated with a trend for reduced crude 90-day mortality {31.6% (95% CI 25.2 – 38.8) vs 40.7% (95% CI 33.5 – 48.4)} (P=0.08). After adjustment for baseline PaO2:FiO2, plateau pressure and Simplified Acute Physiology II scores, neuromuscular blockade reduced the adjusted hazard ratio for death at 90 days (HR 0.68, 95% CI 0.48 to 0.98; P=0.04). There was no difference in the rate of ICU-acquired paresis.
Among patients with septic shock who were treated to normalize central venous and mean arterial pressure, additional management to normalize lactate clearance compared with management to normalize ScvO2 did not result in significantly different in-hospital mortality.
In mechanically ventilated patients with mildly elevated gastric residual volumes and already receiving nasogastric nutrition, early nasojejunal nutrition did not increase energy delivery and did not appear to reduce the frequency of pneumonia. The rate of minor gastrointestinal hemorrhage was increased. Routine placement of a nasojejunal tube in such patients is not recommended.
Early provision of glutamine or antioxidants did not improve clinical outcomes, and glutamine was associated with an increase in mortality among critically ill patients with multiorgan failure
The addition of nighttime intensivist staffing to a low-intensity daytime staffing model was associated with reduced mortality. However, a reduction in mortality was not seen in ICUs with high-intensity daytime staffing.
The use of enoxaparin plus elastic stockings with graduated compression, as compared with elastic stockings with graduated compression alone, was not associated with a reduction in the rate of death from any cause among hospitalized, acutely ill medical patients.
Kumar. Initiation of inappropriate antimicrobial therapy results in a fivefold reduction of survival in human septic shock. Chest 2009; 136(5):1237-1248.
Inappropriate initial antimicrobial therapy for septic shock occurs in about 20% of patients and is associated with a fivefold reduction in survival. Efforts to increase the frequency of the appropriateness of initial antimicrobial therapy must be central to efforts to reduce the mortality of patients with septic shock.
Effective antimicrobial administration within the first hour of documented hypotension was associated with increased survival to hospital discharge in adult patients with septic shock. Despite a progressive increase in mortality rate with increasing delays, only 50% of septic shock patients received effective antimicrobial therapy within 6 hrs of documented hypotension.
Chastre. Comparison of 8 vs 15 days of antibiotic therapy for ventilator-associated pneumonia in adults: a randomized trial. JAMA 2003; 290: 2588- 2598
Among patients who had received appropriate initial empirical therapy, with the possible exception of those developing nonfermenting gram-negative bacillus infections, comparable clinical effectiveness against VAP was obtained with the 8- and 15-day treatment regimens. The 8-day group had less antibiotic use
In a multicentre, blinded, randomised, controlled trial comparing therapeutic hypothermia (33°C, achieved within 2 hours of ROSC and maintained for 12 hours) with normothermia in 77 comatose survivors of out-of-hospital VF cardiac arrest, hypothermia improved survival with a good outcome (49% versus 26%, p=0.046; odds ratio 5.25, 95% CI 1.47 to 18.76, p = 0.011). Hypothermia was associated with a lower cardiac index, higher systemic vascular resistance, hyperglycemia, with no difference in the frequency of adverse events.
In a multicentre, blinded, randomized, controlled trial comparing therapeutic hypothermia (32°C to 34°C for 24 hours) with normothermia in 273 comatose survivors of out-of-hospital VF/VT, hypothermia improved favourable neurological outcomes (55% vs 39%; RR 1.40, 95% CI 1.08 to 1.81) and 6 month mortality (41% vs 55%; RR 0.74, 95% CI 0.58 to 0.95). The complication rate did not differ significantly between the two groups.
Intensive insulin therapy to maintain blood glucose at or below 110 mg per deciliter reduces morbidity and mortality among critically ill patients in the surgical intensive care unit.
In routine ICU practice, universal decolonization was more effective than targeted decolonization or screening and isolation in reducing rates of MRSA clinical isolates and bloodstream infection from any pathogen.
Among patients with cardiac arrest requiring vasopressors, combined vasopressin-epinephrine and methylprednisolone during CPR and stress-dose hydrocortisone in postresuscitation shock, compared with epinephrine/saline placebo, resulted in improved survival to hospital discharge with favorable neurological status.
Stelfox. Intensive Care Unit Bed Availability and Outcomes for Hospitalized Patients With Sudden Clinical Deterioration. Arch Intern Med 2012;epublished ahead of print1
Mier. Early versus late necrosectomy in severe necrotzing pancreatitis. Am J Surg 1997;173:71–5
Martin. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med 2003, 348:1546-1554..
Ranieri. Drotrecogin Alfa (Activated) in Adults with Septic Shock ( PROWESS-SHOCK Study). N Engl J Med 2012;366:2055-206
Girotra. Trends in Survival after In-Hospital Cardiac Arrest. N Engl J Med 2012;367:1912-192
Van den Berghe. Intensive Insulin Therapy in Critically Ill Patients. N Engl J Med 2001;345:1359-67
Van den Berghe. Intensive Insulin Therapy in the Medical ICU. N Engl J Med 2006;354:449-61.
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