View Full Version : Hypertonic Saline trial stopped for Trauma Patients

04-15-2009, 15:56
New Analysis of Halted Trial of Hypertonic Saline for Patients in Traumatic Shock

Laurie Barclay, MD

April 6, 2009 Hypertonic saline administered acutely to patients in hemorrhagic shock provides no survival benefit, according to interim results of a large, multicenter trial stopped early by the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH).
Intravenous saline solutions are typically given as first-line therapy for shock patients to compensate for acute blood loss before transfusions can be safely administered. On the basis of preclinical testing and other evidence, the rationale for use of hypertonic saline instead of normal saline is that it is thought to more effectively compensate for blood loss through volume expansion, to reduce excessive inflammation, and to help prevent brain edema.

"Several prior studies suggested the potential for improved outcome for patients with shock treated with hypertonic saline," Eileen M. Bulger, MD, FACS, associate professor of surgery at the University of Washington in Seattle, and coprincipal investigator of the hypertonic saline studies for the Resuscitation Outcomes Consortium (ROC), told Medscape Emergency Medicine. "Hypertonic saline solutions had been shown to improve tissue perfusion and reduce the excessive inflammatory response early after injury which results in organ damage. These fluids may be particularly beneficial for patients with traumatic brain injury, as they maintain cerebral perfusion while reducing intracranial swelling."

The Resuscitation Outcomes Consortium (ROC), a network of 9 major regional clinical research centers in the United States and Canada, conducted this trial, as well as one that is still ongoing to determine the acute effects of hypertonic saline solutions in traumatic brain injury without shock. The ROC is also sponsoring other randomized trials in clinical practice settings of promising new therapies for cardiac arrest or life-threatening traumatic injury.

ROC clinical trials are performed under strict guidelines allowing for patients in life-threatening scenarios to participate in research protocols under an exception to informed consent, as permitted by US and Canadian law. Emergency medical services (EMS) providers enrolled in the ROC network administer standard emergency care to all patients, as well as experimental treatment to eligible patients.

Clear Benefit of Treatment Not Seen

"All studies done under exemption from informed consent have careful, frequent, and periodic monitoring of the results," George Sopko, MD, MPH, a cardiologist with NHLBI and the ROC program director, told Medscape Emergency Medicine. "Because of the higher ethical standards, the key premise in continuing a trial done under exemption from informed consent is that there has to be a clear benefit of the experimental treatment being studied. At the latest check, in August 2008, we observed that the hypertonic saline compared with normal saline had no significant effect on mortality at 28 days."

Scheduled interim analysis by ROC's independent data safety monitoring board (DSMB) showed that hypertonic saline solutions, with or without dextran, given in the ambulance before hospital arrival to trauma patients who sustained hemorrhagic shock did not improve survival in comparison with administration of normal saline.

"The primary reason for stopping the shock trial was that there was no difference in 28-day survival between the treatment groups, and continuing enrollment was thought to be futile," Dr. Bulger said. "Further data analysis in preparation for publication is underway to clarify the results in the patient subgroups. Ongoing data analysis will guide future research."

According to Dr. Sopko, ongoing analysis of patient subgroups will focus on any difference in outcomes between women and men, or in patients with different types of traumatic injury.

Overall 28-day mortality was the same in both treatment groups, but mortality before reaching the hospital or in the emergency department was higher in the hypertonic saline group. Mortality in the normal saline group was higher during the remainder of the 28-day follow-up period. On August 25, 2008, the NHLBI therefore suspended enrollment into the hypertonic shock trial.

"There is little evidence that the use of hypertonic saline is harmful in this setting," Conor Shields, BSc, MD, FRCSI, consultant surgeon at Mater Misericordiae University Hospital, in Dublin, Ireland, told Medscape Emergency Medicine when asked for independent comment. "The mortality data given in the press release is difficult to explain, and I look forward to reading the final manuscript. Indeed, the positive immunomodulatory effects of hypertonic saline would have been expected to yield a benefit in the treatment arm."

He continued, "Hypertonic fluids have been successfully applied both in intensive care patients with hypovolemic shock refractory to conventional treatment and in previous randomized, prospective, double-blind trials in trauma patients with severe hypovolemia." Dr. Shields added, "Although many of the beneficial effects of hypertonic saline relate to improved hemodynamics, significantly fewer hyperinflammatory complications, such as acute respiratory distress syndrome (ARDS), have been described in trauma patients."

Further Analysis Confirmed Lack of Benefit

Further analysis of these findings, as requested by the DSMB, examined in-hospital data (after saline administration in the field) from 545 patients in the largest enrolling hospital from each site.

On February 25, 2009, the investigators again concluded that deaths occurred earlier in the hypertonic saline group but that there was no significant difference in cumulative mortality between the hypertonic and normal saline groups at 28 days. Because the additional analysis did not fully explain the mortality findings, further analyses are underway; these will subsequently be submitted to a peer-reviewed scientific journal.

"I believe that subgroups of trauma patients at risk from the consequences of hyperinflammatory states (ARDS, renal failure, cerebral edema, etc) may derive a benefit from hypertonic resuscitation," Dr. Shields said. "The immunomodulatory effects of hypertonic saline in the clinical environment remain largely unexplored. I believe that if hypertonic infusion is to establish itself as a viable clinical strategy, it will be as an agent to suppress the systemic inflammatory response, rather than [as] a simple volume expander."

Scheduled interim analysis of the traumatic brain injury trial did not show any evidence of earlier mortality with hypertonic saline. However, this trial was also temporarily and voluntarily suspended in August 2008, resuming in late November 2008, to allow retraining of EMS personnel to enroll only brain injury patients and not those with hemorrhagic shock. This trial will evaluate whether use of hypertonic saline with or without dextran, compared with normal saline, affects survival and brain function in patients at 6 months after traumatic injury.

"Both the DSMB and the [US Food and Drug Administration] reviewed the data for the traumatic brain injury cohort and found no concerns with continuing this arm of the study," Dr. Bulger said. "Patients with [traumatic brain injury] may benefit due to improved cerebral perfusion and reduced cerebral swelling. The primary endpoint for this cohort is neurologic function 6 months after injury."

Further Research

In terms of further research, Dr. Sopko noted that ROC is in the process of applying for grant renewal to study additional interventions in acute trauma.

"The primary question always comes up, What is the most effective way of stopping the bleeding, which is the cause of the hemorrhagic shock? And the second question is, what is the most effective way of replacing volume loss?" Dr. Sopko said. "Strategies could include using solutions that we already have, such as plasma, platelets, [and] packed red cells, in particular combinations or applications that would improve survival, or new solutions that mimic the functions of these natural solutions without some of the drawbacks."

Dr. Sopko noted that the NHLBI stopping the trial of hypertonic saline in hemorrhagic shock was a good example of the system at work, with very careful ongoing monitoring of available evidence.

"In order to advance the field, the only way we know to provide better treatment strategies and better survival for these patients is to provide treatment very early, which means that there is no opportunity to obtain individual informed consent," Dr. Sopko concluded. "However, we do have a system to notify each community about the available protocols."

ROC trials are primarily supported by the NHLBI, with additional funding from the NIH's National Institute of Neurological Disorders and Stroke, the Institute of Circulatory and Respiratory Health of the Canadian Institutes of Health Research, US Army Medical Research & Materiel Command, the American Heart Association, Defence Research and Development Canada, and the Heart and Stroke Foundation of Canada. Dr. Sopko, Dr. Shields, and Dr. Bulger have disclosed no relevant financial relationships.

Just when we thought they were on to something.........
Next study using a hetastarch product will hopefully show an outcomes difference......


04-15-2009, 16:16
Thanks for the info.

04-15-2009, 16:32

Thanks for posting this. Are you aware of any instances or ongoing studies using the hetastarch in hypertonic saline, and their M&M rates in comparison to this? Do you have any anecdotal clinical observation to add to the above posted study? Thanks in advance,