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Disease and treatment

Researchers investigate how best to treat sepsis

In 2012, Danish researchers revolutionized the treatment of sepsis. Now they have begun another major clinical trial to investigate whether the way people with sepsis are most frequently treated is optimal.

For many years, intensive care units in Denmark and around the world have treated people with sepsis using antibiotics and large volumes of intravenous fluids.

The rationale for intravenous fluid therapy is that people with sepsis often appear to be dehydrated and have impaired blood flow, and using high fluid volumes may counteract this. The problem is that no large clinical trial has ever investigated whether intravenous fluid therapy is effective and what the optimal amount of fluid should be.

Researchers from Rigshospitalet in Copenhagen now aim to fill this gap in medical knowledge through a major international clinical trial.

“For many years, we have applied intravenous fluid therapy to people with sepsis even though no good evidence indicates that it actually works. In addition, the pharmaceutical companies have little interest in this because fluid solutions are not very profitable, so little research has been carried out on its effectiveness. This type of research requires public funding, foundation grants and philanthropic donations, which we have now received to conduct this major clinical trial to examine whether our practice over many years is optimal,” explains the leader of the research initiative, Anders Perner, Chair, Centre for Research in Intensive Care and Professor, Department of Intensive Care, Rigshospitalet.

Anders Perner and colleagues recently summarized their latest research on treating people with sepsis and established the terms of reference for their future research in an article in Intensive Care Medicine.

Millions of people die from sepsis each year

Sepsis may be a somewhat neglected subject, but it is actually the third most frequent cause of death globally. Millions of people die annually from virulent infections. Fatal septic shock can result when these infections get out of control.

The most common causes of sepsis are respiratory tract infections, urinary tract infections and gastrointestinal infections that spread from a single organ to the rest of the body. Infections resulting from the use of catheters or permanent infusion lines are another source of sepsis.

Things can happen very rapidly when an infection initially spreads in the body. The person’s condition seriously worsens within a few hours. In severe cases, this often results in dangerously low blood pressure or septic shock, with the body shutting down completely.

“Without rapid interventions, nearly everyone who develops septic shock dies. The standard treatment today is antibiotics and large volumes of intravenous fluids. However, this may not be the optimal treatment despite being recommended by healthcare systems in both the United States and Europe,” says Anders Perner.

Ten countries and 50 intensive care units participating

The clinical trial that began on 1 December 2018 will include 1500 participants with septic shock from 10 countries and 50 intensive care units. Half will get the standard treatment of antibiotics and about 15 litres of intravenous fluid during their stay in the intensive care unit. The other half will get antibiotics and about 7 litres of intravenous fluid.

The researchers will then monitor the participants for 12 months to assess how the treatments influence patient outcome. Anders Perner thinks that the treatment groups may differ significantly, with those receiving less intravenous fluid surviving longer and achieving better mental and physical well-being.

“I and other doctors have had doubts about whether giving people with sepsis high volumes of fluid really is optimal, and we will now elucidate this. I think that our results may contribute to changing future clinical practice,” says Anders Perner.

Danish research changed international clinical practice in 2012

Anders Perner’s explicit optimism is based on many years of experience. The Danish professor is one of the world’s leading researchers on intravenous fluid therapy for sepsis and his research led to sweeping changes in existing practices in 2012.

Until 2012, clinicians used two types of fluid for people with sepsis. However, Anders Perner performed a clinical trial comparing their effect and found that the more expensive fluid, hydroxyethyl starch, actually increased mortality compared with ordinary saline solution.

The results changed practices worldwide. In Denmark, this has saved 700–800 lives and an estimated DKK 50 million in healthcare costs. Globally, this has meant hundreds of thousands of lives saved and billions in cost savings.

“The study showed the potential for the clinical trial we are doing now. We currently use a type of treatment for very ill people without really knowing whether this is the right treatment for them. After this study, we will know how to optimally treat people with sepsis,” explains Anders Perner.

The clinical trial is expected to be completed in 2021.

Focus on fluid therapy and nutritional support” has been published in Intensive Care Medicine. In 2017, the Novo Nordisk Foundation awarded a grant to Anders Perner for the project Effects of Restricting Intravenous Fluids on Patient-important Outcome Measures in Patients with Septic Shock – the Conservative vs. Liberal Approach to Fluid Therapy of Septic Shock in Intensive Care (CLASSIC) Trial.

Anders Perner
Professor
Anders Perner is a senior staff specialist in Intensive Care, Rigshospitalet and professor in intensive care at Copenhagen University Hospital. He chairs the Scandinavian Critical Care Trials Group and the strategic research programme ‘New resuscitation strategies in patients with severe sepsis’. This ongoing program will randomize 2000 patients with severe sepsis in three RCTs of resuscitation in 30 ICUs in all the Nordic countries. The first RCT, the 6S trial has been published and the second, the TRISS trial, has been finalized and the third, the CLASSIC trial, is protocolized.