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Update in intensive care medicine: Studies that challenged our practice in the last 5 years

Cleveland Clinic Journal of Medicine. 2011 October;78(10):665-674 | 10.3949/ccjm.78a.10188
October 1, 2011|Cleveland Clinic Journal of Medicine
Enrique Diaz-Guzman, MD;Juan Sanchez, MD;Alejandro C. Arroliga, MD, FCCP
Author and Disclosure Information

Enrique Diaz-Guzman, MD
Assistant Professor of Medicine, Chief, Pulmonary Section, Lexington Veterans Affairs Medical Center, Division of Pulmonary & Critical Care Medicine, University of Kentucky, Lexington

Juan Sanchez, MD
Assistant Professor of Medicine, Division of Pulmonary & Critical Care Medicine, Scott & White Health Center, and Texas A&M College of Medicine, Temple, TX

Alejandro C. Arroliga, MD, FCCP
Chairman and Professor, Dr. A. Ford Wolf and Brooksie Nell Boyd Wolf Centennial Chair of Medicine, Department of Internal Medicine, Scott & White Health Center, and Texas A&M Health Science Center College of Medicine, Temple, TX

Address: Enrique Diaz-Guzman, MD, University of Kentucky, L543 Kentucky Clinic, 740 S. Limestone Street, Lexington, KY 40536-0284; e-mail enriquedgz@uky.edu

ABSTRACTDuring the last 5 years, new randomized trials in critically ill patients have challenged a number of traditional treatment strategies in intensive care. The authors review eight studies that helped change their medical practices.

KEY POINTS

  • In patients with acute respiratory distress syndrome (ARDS), fluid restriction is associated with better outcomes. A pulmonary arterial catheter is not indicated in the routine management of ARDS. Corticosteroid use can result in improved oxygenation but may be associated with worse outcomes if treatment is started late, ie, more than 14 days after the onset of the disease.
  • Intensive insulin therapy is associated with hypoglycemia and may be associated with complications in medical patients.
  • In patients with septic shock, corticosteroid therapy is associated with faster shock reversal, but its effects on mortality rates remain controversial. Vasopressin improves hemodynamic variables but is not associated with a lower mortality rate.
  • Daily interruption of sedation and early awakening of mechanically ventilated patients result in better outcomes.
  • Compared with norepinephrine, dopamine is associated with more cardiac adverse events in patients with shock.

CORTICOSTEROID USE IN ARDS

Key points

  • In selected patients with ARDS, the prolonged use of corticosteroids may result in better oxygenation and a shorter duration of mechanical ventilation.
  • Late use of corticosteroids in patients with ARDS (> 14 days after diagnosis) is not indicated and may increase the risk of death.
  • The role of corticosteroids in early ARDS (< 7 days after diagnosis) remains controversial.

Background

Systemic corticosteroid therapy was commonly used in ARDS patients in the 1970s and 1980s. However, a single-center study published in the late 1980s showed that a corticosteroid in high doses (methylprednisolone 30 mg/kg) resulted in more complications and was not associated with a lower mortality rate.4 On the other hand, a small study that included only patients with persistent ARDS (defined as ARDS lasting for more than 7 days) subsequently showed that oxygenation was significantly better and that fewer patients died while in the hospital with the use of methylprednisolone 2 mg/kg for 32 days.5

In view of these divergent findings, the ARDS Network decided to perform a study to help understand the role of corticosteroids in ARDS.

The Late Steroid Rescue Study (LaSRS)

STEINBERG KP, HUDSON LD, GOODMAN RB, ET AL; NATIONAL HEART, LUNG, AND BLOOD INSTITUTE ACUTE RESPIRATORY DISTRESS SYNDROME (ARDS) CLINICAL TRIALS NETWORK. EFFICACY AND SAFETY OF CORTICOSTEROIDS FOR PERSISTENT ACUTE RESPIRATORY DISTRESS SYNDROME. N ENGL J MED 2006; 354:1671–1684.

The Late Steroid Rescue Study (LaSRS),6 a double-blind, multicenter trial, randomly assigned 180 patients with persistent ARDS (defined as ongoing disease 7–28 days after its onset) to receive methylprednisolone or placebo for 21 days.

Methylprednisolone was given in an initial dose of 2 mg/kg of predicted body weight followed by a dose of 0.5 mg/kg every 6 hours for 14 days and then a dose of 0.5 mg/kg every 12 hours for 7 days, and then it was tapered over 2 to 4 days and discontinued. It could be discontinued if 21 days of treatment were completed or if the patient was able to breathe without assistance.

The primary end point was the mortality rate at 60 days. Secondary end points included the number of ventilator-free days, organ-failure-free days, and complications and the levels of biomarkers of inflammation.

No reduction in mortality rates with steroids

The mortality rates did not differ significantly in the corticosteroid group vs the placebo group at 60 days:

  • 29.2% with methylprednisolone (95% confidence interval [CI] 20.8–39.4)
  • 28.6% with placebo (95% CI 20.3–38.6, P = 1.0).

Mortality rates at 180 days were also similar between the groups:

  • 31.5% with methylprednisolone (95% CI 22.8–41.7)
  • 31.9% with placebo (95% CI 23.2–42.0, P = 1.0).

In patients randomized between 7 and 13 days after the onset of ARDS, the mortality rates were lower in the methylprednisolone group than in the placebo group but the differences were not statistically significant. The mortality rate in this subgroup was 27% vs 36% (P = .26) at 60 days and was 27% vs 39% (P = .14) at 180 days.

However, in patients randomized more than 14 days after the onset of ARDS, the mortality rate was significantly higher in the methylprednisolone group than in the placebo group at 60 days (35% vs 8%, P = .02) and at 180 days (44% vs 12%, P = .01).

Some benefit in secondary outcomes

At day 28, methylprednisolone was associated with:

  • More ventilator-free days (11.2 ± 9.4 vs 6.8 ± 8.5, P < .001)
  • More shock-free days (20.7 ± 8.9 vs 17.9 ± 10.2, P = .04)
  • More ICU-free days (8.9 ± 8.2 vs 6.7 ± 7.8, P = .02).

Similarly, pulmonary physiologic indices were better with methylprednisolone, specifically:

  • The ratio of Pao2 to the fraction of inspired oxygen at days 3, 4, and 14 (P < .05)
  • Plateau pressure at days 4, 5, and 7 (P < .05)
  • Static compliance at days 7 and 14 (P < .05).

In terms of side effects, methylprednisolone was associated with more events associated with myopathy or neuropathy (9 vs 0, P = .001), but there were no differences in the number of serious infections or in glycemic control.

Comments

Although other recent studies suggested that corticosteroid use may be associated with a reduction in mortality rates,7–9 LaSRS did not confirm this effect. Although the doses and length of therapy were similar in these studies, LaSRS was much larger and included patients from the ARDS Network.

Nevertheless, LaSRS was criticized because of strict exclusion criteria and poor enrollment (only 5% of eligible patients were included). Additionally, it was conducted over a period of time when some ICU practices varied significantly (eg, low vs high tidal volume ventilation, tight vs loose glucose control).

The role of corticosteroids in early ARDS (< 7 days after diagnosis) remains controversial at best. Table 1 summarizes recent studies that evaluated the use of corticosteroids in patients with ARDS.

INTERRUPTING SEDATION DURING MECHANICAL VENTILATION

Key points

  • Daily awakening of mechanically ventilated patients is safe.
  • Daily interruption of sedation in mechanically ventilated patients is associated with a shorter length of mechanical ventilation.

Background

Sedatives are a central component of critical care. Continuous infusions of narcotics, benzodiazepines, and anesthetic agents are frequently used to promote comfort in patients receiving mechanical ventilation.

Despite its widespread use in the ICU, there is little evidence that such sedation improves outcomes. Observational and randomized trials10–12 have shown that patients who receive continuous infusions of sedatives need to be on mechanical ventilation longer than those who receive intermittent dosing. Additionally, an earlier randomized controlled trial13 showed that daily interruption of sedative drug infusions decreased the duration of mechanical ventilation by almost 50% and resulted in a reduction in the length of stay in the ICU.

Despite these findings, many ICU physicians remain skeptical of the value of daily interruption of sedative medications and question the safety of this practice.

The Awakening and Breathing Controlled (ABC) trial

GIRARD TD, KRESS JP, FUCHS BD, ET AL. 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; 371:126–134.

The Awakening and Breathing Controlled (ABC) trial14 was a multicenter, randomized controlled trial that included 336 patients who required at least 12 consecutive hours of mechanical ventilation. All patients had to be receiving patient-targeted sedation.

Those in the intervention group (n = 168) had their sedation interrupted every day, followed by a clinical assessment to determine whether they could be allowed to try breathing spontaneously. The control group (n = 168) also received a clinical assessment for a trial of spontaneous breathing, while their sedation was continued as usual.

In patients in the intervention group who failed the screening for a spontaneous breathing trial, the sedatives were resumed at half the previous dose. Criteria for failure on the spontaneous breathing trial included any of the following: anxiety, agitation, respiratory rate more than 35 breaths per minute for 5 minutes or longer, cardiac arrhythmia, oxygen saturation less than 88% for 5 minutes or longer, or two or more signs of respiratory distress, tachycardia, bradycardia, paradoxical breathing, accessory muscle use, diaphoresis, or marked dyspnea.

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