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MHRA withdraws starches

Created: 2/8/2013
Updated: 5/8/2013
 
At the end of June 2013, the use of starch drips to treat critically ill patients and those undergoing surgery was suspended in the UK by the Medicines and Healthcare products Regulatory Agency (MHRA), because their benefits no longer outweigh the risk of using them.

These drips had been used in a range of clinical settings for the treatment and prevention of low blood volume (hypovolaemia) and a steep drop in blood pressure (hypovolaemic shock), as well as for maintenance of adequate circulation during surgical procedures.

The risks and benefits of starch drips were the subject of an EU-wide review following the publication of studies which suggested an increased risk of renal injury and death in patients treated with these products. The decision followed a recommendation by the European Medicines Agency (EMA) and a review of the evidence by the MHRA’s independent expert group – the Commission on Human Medicines (CHM) – which found that the benefits of their use no longer outweighed the risks.

Two of the trials that influenced this decision were 6S (Scandinavian Starch for Severe Sepsis/Septic Shock) and CHEST (Crystalloid versus Hydroxyethyl Starch Trial), both published in 2012.

 

The 6S study


6S, published in the New England Journal of Medicine, studied the usage of hydroxyethyl starch (HES) 130/0.4 in patients with severe sepsis. Current recommendations from the Surviving Sepsis Guidelines recommend the use of either colloids or crystalloids [1]. When choosing a colloid, some clinicians choose a gelatin, such as Volplex or Isoplex (which has a balanced ionic composition), whereas others choose a starch. Evidence that traditional starches may have increased the incidence of acute kidney failure in patients with severe sepsis led to a shift towards the use of the newer starches (HES 130/0.4)[2, 3]. In order to evaluate the effects of HES 130/0.4 in severe sepsis, the 6S Trial compared HES with Ringer’s acetate on the composite primary outcomes of death or end-stage kidney failure.

This was a multicentre, parallel group, blinded trial. A total of 798 patients with severe sepsis requiring fluid resuscitation in the ICU were randomised either to HES 130/0.4 or Ringer’s acetate. The primary outcomes were measured at 90 days after randomisation. The results are summarised in the table below [4].


   Death Renal replacement therapy  
 HES 130/0.4  51%  22%
 Ringer’s acetate  43%  16%
 p Value  0.03  0.04


The 6S trial concluded that patients with severe sepsis who were assigned to the HES 130/0.4 arm of the study:

“.... had an increased risk of death at day 90 and were more likely to require renal-replacement therapy, as compared with those receiving Ringer’s acetate”.

 

The CHEST study


The publication of the CHEST results, also published in the New England Journal of Medicine, generated much interest, especially following on from the results of the 6S trial earlier the same year. The CHEST study aimed to establish whether the most commonly used colloid, HES 130/0.4, is safe and effective in critically ill patients, via a large-scale, randomised, controlled trial.

A total of 6,742 patients admitted to ICU who required fluid resuscitation over and above that required for maintenance or replacement were randomised to receive either HES 130/0.4 in 0.9% saline (Voluven) or 0.9% saline [5]. Excluded were: 

  • Patients who had received more than 1000 ml of HES before screening
  • Patients with impending or current dialysis-dependent renal failure
  • Patients with evidence of intracranial haemorrhage on cranial computed tomography.


The primary outcome measure was all-cause mortality 90 days after randomisation. Secondary outcomes (measured within the 90-day follow-up period) included: 

  • The incidence of acute kidney injury
  • The use of renal-replacement therapy
  • New organ failures for cardiovascular, respiratory, coagulation and liver dysfunction 
  • Duration of mechanical ventilation and renal-replacement therapy
  • Cause-specific mortality.
The results are summarised in the table below.


   Renal outcomes  New organ failure
  Death  RRT   RIFLE-R  RIFLE-I  RIFLE-F  Respiratory  CV Coagulation   Hepatic
 HES 130/0.4 in 0.9% saline  18%  7%  54%  34.6%  10.4%  26.2%  36.5%  4.8%  1.9%
 0.9% saline  17%  5.8%  57.3%  38%  9.2%  25%  39.9%  4.0%  1.2%
 p Value  0.26  0.04  0.007  0.005  0.12  0.39  0.03  0.13  0.03
 Relative risk  1.06  1.21  0.94  0.91  1.12  1.05  0.91  1.20  1.56
CV = cardiovascular; RRT = renal-replacement therapy


The authors of CHEST concluded that there was no significant difference in the primary endpoint of mortality at 90 days. However, the use of HES resulted in a 21% relative increase in the number of patients requiring renal replacement therapy. HES was also associated with an increase in new hepatic failure and an increased number of adverse events, including pruritus and rash.

The overall conclusion was that the trial did not show any clinical benefit for using HES 130/0.4 for resuscitation in the intensive care unit.

 

 

Which colloid to use?

The withdrawal of starches from the market raises the clinical question of what to use instead. One possibility would be to use a crystalloid, as highlighted in the 6S and CHEST studies. However, there may be situations where an alternative colloid is required. There are few alternative colloids available, although gelatins are key alternative colloids that are widely used in the UK.

The starches that were used the most were ones that were balanced (suspended in a balanced electrolyte solution) rather than unbalanced (suspended in sodium chloride). It may therefore be more logical to switch to a balanced gelatin. Indeed, recently published evidence (click here) indicates that there is a benefit to the patient if the fluid used is balanced rather than saline based.

 

References

[1] Dellinger RP et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Intensive Care Med 2008; 34:17-60
[2] Schortgen F et al. Effects of hydroxyethylstarch and gelatin on renal function in severe sepsis: a multicentre randomised study. Lancet 2001; 357: 911-6
[3] Brunkhorst FM et al. Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med 2008; 358: 125-39
[4] Perner et al. Hydroxyethyl starch 130/0.42 versus Ringer's acetate in severe sepsis. N Engl J Med 2012; 367: 124-34
[5] Crystalloid versus Hydroxyethyl Starch Trial (CHEST) Management Committee. The Crystalloid versus Hydroxyethyl Starch Trial: protocol for a multi-centre randomised controlled trial of fluid resuscitation with 6% hydroxyethyl starch (130/0.4) compared to 0.9% sodium chloride (saline) in intensive care patients on mortality. Intensive Care Med 2011; 37(5): 816-23


ArticleDate:20130802
SiteSection: Article
 
   
    
                                            
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