Podcast #42 - Is Shenfu Injection a Cure for Sepsis?

Today we are covering a study on a medication not commonly used in the United States or most of the world: Shenfu.  It is not discussed much but does have implications as a potential cure for sepsis and has been used in China for the last two decades.  Given the recent discussions about cures for sepsis based on other studies, it seemed appropriate to talk about something with a growing body of evidence that most of the world may be ignoring without a good reason.

Title:
Shenfu injection for improving cellular immunity and clinical outcome in patients with sepsis or septic shock
 
Case:
A 36 y/o male comes from home for fever with pneumonia.  During his stay he deteriorates to septic shock and the plan is for admission to your facility.  As you discuss with the patient and family the plan for treatment, a family member asks you about a recent medication she read about on an alternative medicine website where they used Shenfu in sepsis.
 
Background:
Shenfu injection originates from Shenfu decoction.  This traditional Chinese formula is used to restore “Yang” from collapse and tonify “Qi” for relieving desertion.  It is prepared in ginseng and aconite.  Ginsenosides and aconite alkaloids are the main ingredients in Shenfu.  Ginsenosides provide vasodilatory effects while alkaloids contribute to cardiac electrophysiological effects by blocking ion channels.  Shenfu has been used to provide a treatment for septic shock in China for more than two decades.
 
Clinical Question:
Does Shenfu injection enhance cellular immunity and improve clinical outcomes in patients with septic shock?
 
Reference:

• Population: Patients aged 18 years or more and onset of sepsis/septic shock within the previous 24 hours.  They defined sepsis using the Third International Consensus Definitions for Sepsis and Septic Shock with sepsis defined as a life-threatening organ dysfunction cause by dysregulated host reponse to infection, and septic shock clinically identified by vasopressor requirement to maintain a mean arterial pressure of 65 mm Mg or greater and serum lactate level greater than 2 mmol/L in the absence of hypovolemia.      
  • Exclusion Criteria: Patients with known hypersensitivity to Shenfu injection, pregnancy, systemic autoimmune disease, hematologic disease (neoplasm, acute leukemia, etc), transplant patients, known HIV infection, and moribundity. 
• Intervention: 100ml of Shenfu injection in 250ml of 5% glucose intravenously every 24 hours for 7 consecutive days. 
• Comparison: Placebo but was not specified how it was performed.
• Outcome: This study used co-primary outcomes of length of ICU stay, duration of vasopressor use, illness severity (assessed via APACHE II score), and degree of organ dysfunction (assessed via Marshall score).

 
Author’s Conclusions:
These findings suggest that Shenfu injection can enhance the cellular immunity of patients with septic shock and could be a promising adjunctive treatment for patients with septic shock.
 
Quality Checklist for Randomized Clinical Trials:

1. The study population included or focused on those in the ED. No, this study was performed on ICU patients
2. The patients were adequately randomized. Yes
3. The randomization process was concealed. Yes
4. The patients were analyzed in the groups to which they were randomized. Yes, modified intention to treat analysis
5. The study patients were recruited consecutively (i.e. no selection bias). Yes
6. The patients in both groups were similar with respect to prognostic factors. Yes
7. All participants (patients, clinicians, outcome assessors) were unaware of group allocation. Yes
8. All groups were treated equally except for the intervention. Yes
9. Follow-up was complete (i.e. at least 80% for both groups). Yes
10. All patient-important outcomes were considered. Yes, but death probably should have been the primary outcome
11. The treatment effect was large enough and precise enough to be clinically significant. No

 
Key Results:
A total 157 patients were included in the study with 78 in the Shenfu injection group and 79 in the placebo group.  Follow-up was at least 28 days.  Three patients were excluded (after allocation) with one being due to protocol violation and two from withdrawal of consent.  Patients were matched with respect to demographics and clinical characteristics. Shenfu injection increased CD4+ and CD8+ T cells and up-regulated HLA-DR expression in monocytes. Shenfu injection was also found to restore ex vivo monocytic tumor necrosis factor α and interleukin 6 prinflammatory cytokine release in response to the endotoxin.  Shenfu injection showed better clinical outcomes compared to placebo in regards to vasopressor use, APACHE II score, Marshall score, and length of ICU stay.  However, the 28 day mortality rate did not significantly decrease between Shenfu injection (20.5%; 16/78) and placebo (27.8%; 22/79).
 
Key Points of Debate:

• This is a single-center trial in another country
  • As a single center trial, this is set with its own limitations as the population can be different from our own.
  • Given that the trial was exclusively in China, the population and practices are likely to be different from people we are seeing on a daily basis which could influence these results.
• The sample size was small and underpowered.
  • 160 patients are not enough for this type of study especially with the numbers that could be obtained for sepsis, but it is preliminary research.
  • There were 160 patients of which three were dropped from the study.
  • Since the study needed a minimum of 160 for analysis, one could argue that this already small study did not have power to detect a difference, even if there had been a mortality difference that they were calculating.
• Mortality was not a primary outcome.
  • Although this is not necessarily a problem by itself, the co-primary outcomes that were used are not necessarily all patient oriented.
  • Mortality though is a very important patient-oriented outcome and one easy to use as a single primary outcome.
  • It is important when introducing research such as this that we focus on mortality when possible, especially if it could have been used as a single primary outcome versus a secondary outcome when other co-primary outcomes were used.
• Decrease in mortality is not statistically significant, but could be clinically significant.
  • Even though this was a secondary outcome and not statistically significant, this could be valuable.
  • An absolute difference in mortality of 7.3% would be clinically important if it held up with more robust research.
  • Again, this is all the more reason why another study should use mortality as a primary outcome with possibly a small difference measured.
• Placebo was not specified.
  • Although this may not be important, depending on how this was done it could lead to bias.
  • If the placebo was obviously different from the treatment, this could influence potential bias.

 
Comparing Conclusions:
Although limited, we agree with the conclusion that patients given Shenfu injection did enhance cellular immunity of patients with septic shock and that this Shenfu injection could be a promising adjunctive treatment for patients with septic shock.
 
Our Bottom Line:
We agree that based on the current evidence available, Shenfu injection is potentially a promising adjunctive treatment for patients with septic shock but that further research is needed. 
 
Case Resolution:
You discuss with both the patient and the family that there is limited evidence to Shenfu injection and that it is currently not available at your facility.  You explain how you will continue to provide other mainstays of treatment for sepsis that does have more evidence and is commonly used in order to provide the best care.  They agree to this plan of treatment and your patient improves throughout their admission.  He is discharged home after making a full recovery.
 
Clinical Application:
At this time, further research is needed to identify if Shenfu injection could potentially be used more broadly in sepsis.  Although it is commonly used in China, there could be differences in local populations that may not make this as effective a treatment.
 
What do I tell my patient?
There is a promising new treatment call Shenfu injection that is being used in China.  We do not have it here and are waiting for more trials to be performed.  It is possible that in the future this could be used but quality data is limited at best.  We hope that, like many other treatments, it will be part of the cure.  However, we must be cautious with using any of these types of treatments without better research as they could carry negatives that we do not detect.
 
Conclusion:
The American Journal of Emergency Medicine has made this article's full text available for free here and would be well worth the read.  EM Lit of Note has also made a review of this same article and is available on their monthly podcast.

As was mentioned in the actual podcast, another reason for discussing this paper is given the recent discussion of "cures" for sepsis with the main discussion being around Paul Marik's paper.  This paper on the use of hydrocortisone, vitamin C, and thiamine has been widely discussed including a very detailed post by PulmCrit's Josh Farkas on the science behind this management.  The SGEM critiqued the paper in great detail and it is worth listening to the arguments.  Overall, the point remains that we must be cautious about any "cure" for sepsis.  If we are looking for cures, we should not stop with this idea combining hydrocortisone, vitamin C, and thiamine but press forward with other thoughts such as this Shenfu injection.

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