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Mon 21 Apr 2008 04:00 AM

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Making sense of septic shock

Septic shock accounts for many of the deaths in medical and surgical critical care.

Timing is everything when it comes to patient survival.

Recognition of septic shock has been increasing, thanks to developments in the understanding of its pathophysiology, new treatment modalities, and revised international treatment guidelines with the stated aim of lowering the mortality rate.

But more attention is needed, say some critical care doctors, because when it comes to patient survival, timing is everything.

Septic shock accounts for many of the deaths in medical and surgical critical care. Worldwide, sepsis is increasingly common and treatment consumes a large amount of healthcare resources.

Septic shock accounts for many of the deaths in medical and surgical critical care.

And in an editorial in the Feb. 28 issue of the New England Journal of Medicine, Dr. Joseph Parrillo, Chief of the Department of Medicine at Cooper University Hospital in Camden, N.J., and Professor of Medicine at Robert Wood Johnson Medical School, calls septic shock, "one of the most challenging problems in critical care."

But despite its prevalence and severity, septic shock isn't nearly as well recognized as other emergencies, including trauma, heart attack, and cardiogenic shock, Parrillo told Healthcare Middle East, adding that often clinicians don't treat it with the same sense of "urgency" as other emergencies.

Unfortunately, this delay can have tragic consequences. In this In Practice, Parrillo explains why early intervention is so important, and discusses the latest thinking on antibiotic therapy, steroids, and glucose control.

Sepsis is a complex medical condition that begins with an infection and results in an exaggerated immune response. The inflammatory response ultimately leads to organ damage and eventually multiple organ failure.

Early goal-directed therapy

Research suggests that early intervention is critical to patients' survival, Parrillo says. "When someone comes to the emergency room with septic shock, they need to be treated immediately and aggressively."

He emphasizes the importance of an approach called early goal-directed therapy, which involves treating low blood pressure with aggressive fluid resuscitation and maintaining it with vasopressors. Beginning antibiotic therapy within the first hour is important as well.

Initiating such therapies as close as possible to the onset of septic shock is invaluable, says Parrillo, noting that several studies confirm the relationship between timing and mortality.

For example, a randomized controlled trial published in the Nov. 8 2001 issue of the New England Journal of Medicine, showed that giving early cardiovascular support (using a defined protocol of fluids, vasopressors, dobutamine, and blood transfusions) reduced mortality from more than 45 percent to around 30 percent.

Another large observational study, published in 2006 in Critical Care Medicine, showed that giving patients with septic shock antibiotics within the first hour of onset resulted in a 20% mortality rate, whereas giving that treatment six hours later nearly tripled that mortality rate.

These studies point to what Parrillo calls a "golden hour" for applying therapy to patients with septic shock. This thinking is reflected in updated international guidelines published in the January issue of the journal Critical Care Medicine.

The guidelines strongly recommend that fluid resuscitation begin immediately in patients with hypotension (no change from the 2004 guideline), and therapy with broad-spectrum antibiotics begin within the first hour of recognizing severe sepsis and septic shock (a more strongly worded recommendation than the previous guideline contained).

Vasopressors

The current "Surviving Sepsis" guidelines not only recommend vasopressors to treat hypotension in patients with septic shock but recommend particular agents, norepinephrine or dopamine. Over the years, some investigators have looked at the value of substituting vasopressin for norepinephrine.

But the authors of a recent randomized controlled trial of 779 patients (the VASST Trial), published in the Feb. 28, 2008 New England Journal of Medicine, found that substituting vasopressin for norepinephrine did not reduce mortality rates, and concluded that there is no value in such substitution.

Parrillo agrees with this conclusion. Although this study found that adding vasopressin to norepinephrine therapy in patients with septic shock appears to be safe, he says, "there is no advantage to using vasopressin instead of norepinephrine." But he emphasizes that the timing of vasopressor therapy is more decisive than is the choice of vasopressor agent.

Steroids

Steroids represent one of the most controversial areas in septic shock therapy. For the past three decades, investigators have been looking at the role of corticosteroids in treating septic shock.

When the body is stressed, the adrenal glands make corticosteroids to help maintain blood pressure and other homeostatic mechanisms. Studies done 30 years ago suggested that a large dose would be helpful in septic shock.

But over the past five or six years, there has been a growing consensus that it is preferable to give patients a smaller, physiologic dose (around 300 mg/day) instead.
According to a trial published in the August 21, 2002 Journal of the American Medical Association, low doses of hydrocortisone and fludrocortisone significantly lowered the risk of death in patients with septic shock and relative adrenal deficiency without increasing adverse events.

However, a subsequent study (the CORTICUS Trial) published in the New England Journal of Medicine on January 20 compared hydrocortisone to placebo use in septic shock and did not show any improvement in patients who received hydrocortisone.

This is the trial on which the Surviving Sepsis guidelines base their low-level (level 2) recommendation to use hydrocortisone in someone who is in septic shock. Parrillo disagrees with the level of this recommendation.

Despite its prevalence and severity, septic shock isn’t nearly as well recognized as other emergencies.

Based on the quality of the 2002 study as compared to the relatively poorly conducted CORTICUS trial, and his experience treating thousands of patients with septic shock, he says, he gives a physiologic dose of hydrocortisone for 4-5 days to patients with septic shock who are not responding or poorly responsive to fluids and norepinephrine.

He adds that a soon-to-be published consensus statement written by investigators involved in both trials reaches the same conclusion. It will appear within the next few months in the journal Critical Care Medicine, which Parrillo edits.

Glycemic control

The Surviving Sepsis guidelines provide a strong recommendation for glycemic control using an insulin drip protocol. But the recommendation for the specific target (150 mg/dl) is weak, reflecting controversy surrounding the appropriate target since the publication of the 2004 guidelines.

Glycemic control in critically ill patients made headlines in 2001 with the publication of a study in the Nov. 8 New England Journal of Medicine showing improved survival and reduced nosocomial complications in surgical patients treated with intensive glycemic control (at or below 110 mg/dl) compared with more normal glucose control.

But subsequent studies have suggested that the benefit of tight glycemic control results from maintaining normal blood glucose rather than administering insulin.

Other studies have questioned the efficacy of tight glycemic control and the resulting hypoglycemia associated with aggressive insulin administration. Two studies, the Volume Substitution and Insulin Therapy in Severe Sepsis study and the Glucontrol study, were stopped early due to lack of efficacy and safety concerns.

Finally, a study published in the New England Journal of Medicine in 2006 showed less impressive results from intensive insulin therapy in medical (compared to surgical) ICU patients.

The bottom line? At Cooper University Hospital "we aim for a blood glucose level between 100 and 150 mg/dl," says Parrillo. "And we have not seen excess hypoglycemia."

Activated protein C

Much has been made of previous Surviving Sepsis Campaign recommendations concerning recombinant human activated protein C, a drug manufactured by the pharmaceutical company that sponsors the guidelines.

In an editorial in the October, 2006 New England Journal of Medicine, senior investigators at the National Institutes of Health pointed to these guidelines as evidence that such clusters of recommendations are vulnerable to manipulation by the companies that fund them.

The guideline recommendations were based on a large randomized controlled trial (PROWESS) published in 2001 which showed a significant overall survival benefit at 28 days for the sickest patients given activated protein C. Based on this trial, the US Food and Drug Administration did approve the drug's use in severe sepsis with a high risk of death (eg. APACHE scores of >25).

However, due to questions about the methodology and other problems with the trial, the US Food and Drug Administration voted to require that further trials be conducted to clarify the drug's role in other less sick populations of patients.

Subsequent randomized controlled studies (the ADDRESS study and the RESOLVE study) were terminated early because they were deemed unlikely to show a significant decrease in mortality and confirmed an increased risk of serious bleeding. These studies showed that activated protein C should not be used in less sick patients or in children.

In light of these findings, the 2008 Surviving Sepsis guidelines were revised, and the recommendation for activated protein c was made weaker. The guidelines now note that patients with severe sepsis and low risk of death should not receive the drug. Some people feel that even this recommendation is biased by drug company ties.

But Parrillo, who has no ties to Eli Lilly, says he recommends using activated protein c in the sickest patients (Apache II score of 25 or greater, particularly those patients with septic shock or acute respiratory distress syndrome), but that the drug should not be used in less sick adults, adults who have had recent surgery, adults at increased risk of bleeding, or children.

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