Is there a role for Progesterone in the treatment of severe head injury?
Date First Published:
January 27, 2015
Last Updated:
June 5, 2015
Report by:
Jack Macleod, Medical Student 3y (Manchester Medical School)
Three-Part Question:
In the treatment of [acute head injury] does the use of [progesterone] result in a [better outcome]?
Clinical Scenario:
A patient is brought into the emergency department with a severe acute head injury. You remember that there was recent trial in the hospital on the use of progesterone in head injury and wondered if it would be in the patients best interests?
Search Strategy:
Medline 1966- 01/15
(Head injury.mp. OR exp Craniocerebral trauma AND progesterone LIMIT English and human studies.)
Pubmed 1996-01/15
"Head injury" and "progesterone"
(Head injury.mp. OR exp Craniocerebral trauma AND progesterone LIMIT English and human studies.)
Pubmed 1996-01/15
"Head injury" and "progesterone"
Outcome:
Total articles found= 78
Duplicates= 6
Excluded= 65
Relevant articles= 7
Duplicates= 6
Excluded= 65
Relevant articles= 7
Relevant Paper(s):
| Study Title | Patient Group | Study type (level of evidence) | Outcomes | Key results | Study Weaknesses |
|---|---|---|---|---|---|
| Improved outcomes from the administration of progesterone for patients with acute severe traumatic brain injury: a randomized controlled trial Xiao G et Al 2008 China | 159 patients: progesterone (82) vs placebo (77): Inclusion Criteria: GCS<8, admitted within 8h of injury Exclusion Criteria: use of investigational drugs 30 days prior to the enrolment eg progesterone, oestrogen,patients with severe anoxic intracerebral damage or brain death, and patients whose clinical condition was unstable and pregnant patients |
Prospective randomised placebo controlled double blind trial. IV progesterone vs placebo. | Favourable GCS outcome at 3 months | progesterone 47% placebo 31% (p=0.032 | Low number of female participants (1/3 of total) Use of the GCS outcome scale results in low detail outcome measurements Although a total of 25 placebo and 15 progesterone patients died before discharge this was not accounted in results |
| Unfavourable GCS outcome at 3 months | progesterone 53% placebo 70%% (p=0.022) | ||||
| Favourable GCS outcome at 6 months | progesterone 58% placebo 42% (p=0.048) | ||||
| Unfavourable GCS outcome at 6 months | progesterone 41% placebo 57% (p=0.048) | ||||
| Women only, favourable GCS outcome at 6 months | progesterone 43% placebo 28% (p=0.044) | ||||
| Mortality within 6 months | progesterone 18% placebo 32% (p=0.039) | ||||
| A Clinical Trial of Progesterone for Severe Traumatic Brain Injury Skolnick B et Al 2014 Multi-national | 1195 patients: progesterone (591) vs placebo (588) 16 excluded Inclusion Criteria: 16 to 70 years of age, with Glasgow Coma Scale score ≤8, presenting within 8 hours of injury. Exclusion Criteria: GCS score of 3 and bilaterally fixed and dilated pupils, a life expectancy of less than 24 hours, prolonged or in-correctable hypoxaemia (partial pressure of arterial oxygen, <60 mm Hg), hypotension (systolic blood pressure, <90 mm Hg) at the time of randomisation, spinal cord injury, pregnancy. |
Multinational, prospective, double-blind, parallel-group trial. IV progesterone vs placebo. | Proportional-odds model | No effect of progesterone treatment in either unadjusted or adjusted analyses (adjusted odds ratio, 0.96; 95% confidence interval [CI], 0.77 to 1.18) | Low number of female patients within trial (78% male) No gender based results |
| Favourable GCS outcome at 6 months | 50.4% progesterone 50.5% placebo group | ||||
| Proportion of patients in a vegetative state or who died in 6 months | 22.2% progesterone 22.3% placebo | ||||
| Sliding dichotomy split based on baseline prognostic risk | No significant difference between progesterone and placebo outcome | ||||
| ProTECT: A Randomized Clinical Trial of Progesterone for Acute Traumatic Brain Injury Wright DN et Al 2007 Georgia, USA | 100 patients randomised: progesterone (77) vs placebo (23) Inclusion: GCS 4-12, within 11 hours of injury, Exclusion: Blood alcohol concentration greater than 250 mg/dL, penetrating brain injury, <18 years, GCS score <4 or >12, indeterminate time of injury, pregnant, history of active cancer, acute stroke or history of older stroke with residual motor deficits, acute or chronic spinal cord injury with neurologic deficits. |
Phase II, randomised, double-blind, placebo-controlled trial. IV progesterone vs placebo | % Death within 30 days | Progesterone (n=77) 13% Placebo (n=23) 30.4% | Small sample. High chance of type II error. Disproportionate numbers in control and treatment group. Use of those with GCS >8 in study as not severe head injury |
| All other adverse effects | No significant difference | ||||
| Average coma length | Progesterone 10.1 days [95% CI 7.7 to 12.5 days] Placebo 3.9 days [95% CI 2.5 to 5.4 days]) | ||||
| Mortality of those with GCS 4-8 after 30 days | Progesterone 13.2% Placebo 40% RR 0.33; 95% CI 0.13 to 0.83 | ||||
| GCS Outcome of moderate/good after 30 days | Progesterone 21.2% Placebo 26.7% RR for moderate or good recovery 0.79; 95% CI 0.29 to 2.13 | ||||
| Effect of progesterone administration on prognosis of patients with diffuse axonal injury due to severe head trauma Shakeri M et Al 2013 Iran | 76 Patients: progesterone (38) vs control (38) Inclusion Criteria: male patients with a diffuse axonal injury, GCS ≤8, admitted within 8h of injury, over 18y Exclusion Criteria: Female patients, male patients <18y |
Single blinded randomised control trial. Oral progesterone VS control. | Good GOS outcome in 5 ≤ GCS ≤ 8 | progesterone (31.67%) vs control (18.33%) (p=0.03) | Weaknesses: - No placebo for control group - Small sample size,especially after such a large mortality percentage. Increased chance of T2 errors - Only male sample - Focuses solely on diffuse axonal injuries To note: -Mean GCS score on admission = progesterone (5.74±1.4) & control (5.79±1.2) p = 0.86 -defined "good outcome" as a Glasgow outcome score of moderate disability or good recovery after 3 months. |
| Good GOS ourcome in GCS <5 | no patients in either group had favourable outcome | ||||
| Mortality | progesterone (44.7%) control (31.6%) (p>0.05) | ||||
| Very early administration of progesterone for acute traumatic brain injury. Wright, David W, et al. 2014 USA | 17,681 screened, 882 randomised. Overall 73.7% male, 15,2% Black race, 14.2% Hispanic race. 53.5% moderate GCS (GCS of 6-8.) Minutes to study treatment 218.1m (±37.2) Inclusion criteria: Severe, moderate-to-severe, or moderate TBI due to a blunt mechanism, a Glasgow Coma Scale score of 4 to 12 and treatment could be initiated within 4 hours after injury. Exclusion Criteria: A patients injury sustained was non-survivable, pregnancy, status as a prisoner or ward of the state, severe intoxication (ethanol level, >249 mg per decilitre), a known history of reproductive cancer, allergy to progesterone or a fat-emulsion vehicle, a blood-clotting disorder. myocardial infarction, ischemic stroke, pulmonary embolism, or deep-vein thrombosis. |
Multi-centre, phase 3, randomized, double-blind, placebo-controlled clinical trial. IV progesterone in ethanol vs placebo (ethanol alone.) | Outcome at 6months (±30days) based on GOS-E | The trial was stopped due to futility after a second interim analysis. After 6months favourable outcome in placebo = 55.5% in progesterone = 51.0%. Model estimating a relative benefit of 0.95% (95% CI, 0.85-1.06, P=0.35.) Indicating fewer favourable outcomes in trial group to placebo. This was confirmed after secondary analysis of GOS-E. No significant difference in mortality between groups (hazard ratio for death, 1.19; 95% CI, 0.86 to 1.63) | Strong trial with thorough methods to cross barriers such as the low sensitivity of GOS, e.g. using GOS-E. The majority of the patient population is male leading to weaknesses in any gender based results. However they did provide subgroup analysis to show trends within groups. |
Author Commentary:
There is limited evidence in regards to the efficacy of progesterone in the treatment of head injury at the moment in time. The three largest papers indicate no link between progesterone and outcome. There is an obvious difficulty in both replicating animal based experiments in humans and the heterogeneity of head injury in trials, and hence further papers looking into this topic would to overcome these barriers to progress from our current stage. Progress may be made looking into Dual therapy , suggested as another stage in this research in the reviewed articles due to the complex neuro-metabolic cascade after head injury. Further research is needed with large sample sizes.
Bottom Line:
Currently not enough evidence supporting progesterone use in severe head injury.
References:
- Xiao G et Al . Improved outcomes from the administration of progesterone for patients with acute severe traumatic brain injury: a randomized controlled trial
- Skolnick B et Al. A Clinical Trial of Progesterone for Severe Traumatic Brain Injury
- Wright DN et Al. ProTECT: A Randomized Clinical Trial of Progesterone for Acute Traumatic Brain Injury
- Shakeri M et Al. Effect of progesterone administration on prognosis of patients with diffuse axonal injury due to severe head trauma
- Wright, David W, et al.. Very early administration of progesterone for acute traumatic brain injury.