Recent Negative Trials in Sepsis Contain Some Guidance

SAN DIEGO — Recent trial results have quelled much of the excitement about the promise of interventions designed to reduce the risk of death resulting from sepsis. Yet within the mostly negative results of those studies, there are some findings that help to define appropriate treatment approaches, according to Dr. David A. Schulman, chief of pulmonary and critical care medicine at Emory University Hospital, Atlanta.

The findings of VASST (Vasopressin and Septic Shock Trial) found no difference in 28-day mortality among 778 patients randomized to norepinephrine or to norepinephrine plus vasopressin. Although the difference was not statistically significant, those who had less severe shock and were started on less than 15 mcg/min of norepinephrine had a lower mortality rate with the addition of vasopressin (26.5%), compared with the rate seen in those given norepinephrine alone (35.7%). The result persisted at 90 days (N. Engl. J. Med. 2008;358:877–87).

Thus, vasopressin can be used as a second agent in the hypotensive, septic patient who is on a moderate dose of another pressor, Dr. Schulman said in a presentation at the annual meeting of the Society of Hospital Medicine. Vasopressin, dosed at 0.03 U/min, may be added to norepinephrine with an anticipated effect equivalent to that of norepinephrine alone. Vasopressin should not be titrated, and it should be used only as a second agent. Vasopressin should be used with caution in patients with significant myocardial dysfunction (cardiac index less than 2.1 L/min per m

The recent CORTICUS (Corticosteroid Therapy of Septic Shock) trial concluded that steroids are no better than placebo for reducing mortality, yet the role of steroid therapy in the treatment of septic shock is “more unclear than ever,” Dr. Schulman said. Current data do not provide sufficient evidence that low doses of corticosteroids are harmful in septic patients without relative adrenal insufficiency. The current advisory is to “implement a combination of hydrocortisone and fludrocortisone if a patient remains hypotensive with presumed septic shock for [more than 1 hour] after administration of appropriate fluids and pressors.”

CORTICUS, a randomized controlled trial of 500 septic shock patients, found that 28-day mortality was comparable whether subjects were given placebo or hydrocortisone at 50 mg every 6 hours for 5 days followed by a 6-day taper. Furthermore, the trial discerned no difference in response to steroids among patients with relative adrenal insufficiency. Shock resolved faster in the steroid-treated subjects, but they didn't live any longer than patients who were not given steroids. Also, steroids were associated with an increased risk of hyperglycemia, recurrent sepsis, and recurrent shock (N. Engl. J. Med. 2008;358:111–24).

The findings countered those of the practice-changing study that held that adrenal insufficiency predicted which vasopressor-refractory sepsis patients would respond to steroids (JAMA 2002;288:862–71). In that trial, 300 patients were tested for response to ACTH, and all were treated with glucocorticoid and mineralocorticoid supplementation. At 28 days, survival was higher in those patients who had tested positive for adrenal insufficiency; no benefit was seen in the other patients.

A closer examination of that study indicated that 24% of the patients were given etomidate, which is an adrenal suppressant and is no longer the standard of care. Also, subjects had a higher average dose of pressors at enrollment, an indication that they were sicker than the patients in the CORTICUS trial, and they received fludrocortisone rather than hydrocortisone, Dr. Schulman said.

The results of three trials have called into question the role of drotrecogin alfa (recombinant human activated protein C) in the management of sepsis. Both the RESOLVE (Resolution of Organ Failure in Pediatric Patients With Severe Sepsis) trial in children and the ADDRESS (Administration of Drotrecogin Alfa in Early Severe Sepsis) trial in low-risk patients randomized to recombinant human activated protein C or placebo were stopped early in light of their small chance of benefit and an increased risk of serious bleeding in the ADDRESS trial.

In the third ongoing trial, called PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis), patients with septic shock or severe sepsis were randomized to a continuous infusion of 24 mcg/kg per hour of recombinant human activated protein C for 96 hours. During the course of the trial, however, the protocol was changed to severe sepsis only, the manufacturing process of the product was changed, and the placebo was changed from normal saline to 0.1% albumin. Before the protocol change, no difference was noted in 28-day mortality. After the change, a 0.71 relative risk was noted in the treatment group, Dr. Schulman said.

SAN DIEGO — Recent trial results have quelled much of the excitement about the promise of interventions designed to reduce the risk of death resulting from sepsis. Yet within the mostly negative results of those studies, there are some findings that help to define appropriate treatment approaches, according to Dr. David A. Schulman, chief of pulmonary and critical care medicine at Emory University Hospital, Atlanta.

The findings of VASST (Vasopressin and Septic Shock Trial) found no difference in 28-day mortality among 778 patients randomized to norepinephrine or to norepinephrine plus vasopressin. Although the difference was not statistically significant, those who had less severe shock and were started on less than 15 mcg/min of norepinephrine had a lower mortality rate with the addition of vasopressin (26.5%), compared with the rate seen in those given norepinephrine alone (35.7%). The result persisted at 90 days (N. Engl. J. Med. 2008;358:877–87).

Thus, vasopressin can be used as a second agent in the hypotensive, septic patient who is on a moderate dose of another pressor, Dr. Schulman said in a presentation at the annual meeting of the Society of Hospital Medicine. Vasopressin, dosed at 0.03 U/min, may be added to norepinephrine with an anticipated effect equivalent to that of norepinephrine alone. Vasopressin should not be titrated, and it should be used only as a second agent. Vasopressin should be used with caution in patients with significant myocardial dysfunction (cardiac index less than 2.1 L/min per m

The recent CORTICUS (Corticosteroid Therapy of Septic Shock) trial concluded that steroids are no better than placebo for reducing mortality, yet the role of steroid therapy in the treatment of septic shock is “more unclear than ever,” Dr. Schulman said. Current data do not provide sufficient evidence that low doses of corticosteroids are harmful in septic patients without relative adrenal insufficiency. The current advisory is to “implement a combination of hydrocortisone and fludrocortisone if a patient remains hypotensive with presumed septic shock for [more than 1 hour] after administration of appropriate fluids and pressors.”

CORTICUS, a randomized controlled trial of 500 septic shock patients, found that 28-day mortality was comparable whether subjects were given placebo or hydrocortisone at 50 mg every 6 hours for 5 days followed by a 6-day taper. Furthermore, the trial discerned no difference in response to steroids among patients with relative adrenal insufficiency. Shock resolved faster in the steroid-treated subjects, but they didn't live any longer than patients who were not given steroids. Also, steroids were associated with an increased risk of hyperglycemia, recurrent sepsis, and recurrent shock (N. Engl. J. Med. 2008;358:111–24).

The findings countered those of the practice-changing study that held that adrenal insufficiency predicted which vasopressor-refractory sepsis patients would respond to steroids (JAMA 2002;288:862–71). In that trial, 300 patients were tested for response to ACTH, and all were treated with glucocorticoid and mineralocorticoid supplementation. At 28 days, survival was higher in those patients who had tested positive for adrenal insufficiency; no benefit was seen in the other patients.

A closer examination of that study indicated that 24% of the patients were given etomidate, which is an adrenal suppressant and is no longer the standard of care. Also, subjects had a higher average dose of pressors at enrollment, an indication that they were sicker than the patients in the CORTICUS trial, and they received fludrocortisone rather than hydrocortisone, Dr. Schulman said.

The results of three trials have called into question the role of drotrecogin alfa (recombinant human activated protein C) in the management of sepsis. Both the RESOLVE (Resolution of Organ Failure in Pediatric Patients With Severe Sepsis) trial in children and the ADDRESS (Administration of Drotrecogin Alfa in Early Severe Sepsis) trial in low-risk patients randomized to recombinant human activated protein C or placebo were stopped early in light of their small chance of benefit and an increased risk of serious bleeding in the ADDRESS trial.

In the third ongoing trial, called PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis), patients with septic shock or severe sepsis were randomized to a continuous infusion of 24 mcg/kg per hour of recombinant human activated protein C for 96 hours. During the course of the trial, however, the protocol was changed to severe sepsis only, the manufacturing process of the product was changed, and the placebo was changed from normal saline to 0.1% albumin. Before the protocol change, no difference was noted in 28-day mortality. After the change, a 0.71 relative risk was noted in the treatment group, Dr. Schulman said.

SAN DIEGO — Recent trial results have quelled much of the excitement about the promise of interventions designed to reduce the risk of death resulting from sepsis. Yet within the mostly negative results of those studies, there are some findings that help to define appropriate treatment approaches, according to Dr. David A. Schulman, chief of pulmonary and critical care medicine at Emory University Hospital, Atlanta.

The findings of VASST (Vasopressin and Septic Shock Trial) found no difference in 28-day mortality among 778 patients randomized to norepinephrine or to norepinephrine plus vasopressin. Although the difference was not statistically significant, those who had less severe shock and were started on less than 15 mcg/min of norepinephrine had a lower mortality rate with the addition of vasopressin (26.5%), compared with the rate seen in those given norepinephrine alone (35.7%). The result persisted at 90 days (N. Engl. J. Med. 2008;358:877–87).

Thus, vasopressin can be used as a second agent in the hypotensive, septic patient who is on a moderate dose of another pressor, Dr. Schulman said in a presentation at the annual meeting of the Society of Hospital Medicine. Vasopressin, dosed at 0.03 U/min, may be added to norepinephrine with an anticipated effect equivalent to that of norepinephrine alone. Vasopressin should not be titrated, and it should be used only as a second agent. Vasopressin should be used with caution in patients with significant myocardial dysfunction (cardiac index less than 2.1 L/min per m

The recent CORTICUS (Corticosteroid Therapy of Septic Shock) trial concluded that steroids are no better than placebo for reducing mortality, yet the role of steroid therapy in the treatment of septic shock is “more unclear than ever,” Dr. Schulman said. Current data do not provide sufficient evidence that low doses of corticosteroids are harmful in septic patients without relative adrenal insufficiency. The current advisory is to “implement a combination of hydrocortisone and fludrocortisone if a patient remains hypotensive with presumed septic shock for [more than 1 hour] after administration of appropriate fluids and pressors.”

CORTICUS, a randomized controlled trial of 500 septic shock patients, found that 28-day mortality was comparable whether subjects were given placebo or hydrocortisone at 50 mg every 6 hours for 5 days followed by a 6-day taper. Furthermore, the trial discerned no difference in response to steroids among patients with relative adrenal insufficiency. Shock resolved faster in the steroid-treated subjects, but they didn't live any longer than patients who were not given steroids. Also, steroids were associated with an increased risk of hyperglycemia, recurrent sepsis, and recurrent shock (N. Engl. J. Med. 2008;358:111–24).

The findings countered those of the practice-changing study that held that adrenal insufficiency predicted which vasopressor-refractory sepsis patients would respond to steroids (JAMA 2002;288:862–71). In that trial, 300 patients were tested for response to ACTH, and all were treated with glucocorticoid and mineralocorticoid supplementation. At 28 days, survival was higher in those patients who had tested positive for adrenal insufficiency; no benefit was seen in the other patients.

A closer examination of that study indicated that 24% of the patients were given etomidate, which is an adrenal suppressant and is no longer the standard of care. Also, subjects had a higher average dose of pressors at enrollment, an indication that they were sicker than the patients in the CORTICUS trial, and they received fludrocortisone rather than hydrocortisone, Dr. Schulman said.

The results of three trials have called into question the role of drotrecogin alfa (recombinant human activated protein C) in the management of sepsis. Both the RESOLVE (Resolution of Organ Failure in Pediatric Patients With Severe Sepsis) trial in children and the ADDRESS (Administration of Drotrecogin Alfa in Early Severe Sepsis) trial in low-risk patients randomized to recombinant human activated protein C or placebo were stopped early in light of their small chance of benefit and an increased risk of serious bleeding in the ADDRESS trial.

In the third ongoing trial, called PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis), patients with septic shock or severe sepsis were randomized to a continuous infusion of 24 mcg/kg per hour of recombinant human activated protein C for 96 hours. During the course of the trial, however, the protocol was changed to severe sepsis only, the manufacturing process of the product was changed, and the placebo was changed from normal saline to 0.1% albumin. Before the protocol change, no difference was noted in 28-day mortality. After the change, a 0.71 relative risk was noted in the treatment group, Dr. Schulman said.