Table of Contents  
ORIGINAL ARTICLE
Year : 2015  |  Volume : 8  |  Issue : 3  |  Page : 301-307

Progesterone versus combination therapy of progesterone, ω3 fatty acids, glutamine and vitamin D 3 in improving clinical outcome in patients with traumatic brain injuries


Anesthesiology and Intensive Care Department, Faculty of Medicine, Minia University, Minia, Egypt

Date of Submission18-Apr-2015
Date of Acceptance16-May-2015
Date of Web Publication29-Jul-2015

Correspondence Address:
Omyma S Mohamed
190 El-Horria Street, Minia 61511
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1687-7934.161689

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  Abstract 

Introduction
Traumatic brain injury (TBI) is a major health problem. No single agent that can halt the progression of secondary injury exists. Progesterone, glutamine, ω3 fatty acids, and vitamin D 3 are all immune modulators, which can prevent secondary brain insult.
Aim
The aim of this study was to evaluate and compare the efficacy of progesterone alone with a half dose of progesterone plus vitamin D 3 , ω3 fatty acids, and glutamine (combination therapy) on the outcome of patients with acute TBI.
Settings and design
This was a randomized, prospective, controlled study.
Patients and methods
Sixty adult patients of both sexes, with moderate or severe TBI [Glasgow coma score (GCS) 4-12)] within 8 h of trauma, were equally randomly assigned to three groups: the control (C) group, which received the standard care and medications according to the guidelines of head trauma protocol; the progesterone (P) group, which received progesterone; and the combination therapy (T) group, which received a half dose of progesterone combined with vitamin D 3 , ω3 fatty acids, and glutamine. The GCS, ICU and hospital stay, computed tomography findings, mortality rate, and the Glasgow outcome scale (GOS) at 3 months after trauma were recorded and analyzed.
Results
Significant improvement in GCS and computed tomography findings, significantly shorter ICU and hospital stay, lower mortality rate, and more favorable GOS after 3 months were recorded among the therapeutic groups compared with the control group. Only ICU stay was significantly shorter on comparing the progesterone group with the T group.
Conclusion
Both progesterone and the combination therapy improved outcome in acute TBI, although progesterone dose was halved in the latter.

Keywords: combined therapy, progesterone, traumatic brain injury


How to cite this article:
Ali NS, Mohamed OS, Aead MS. Progesterone versus combination therapy of progesterone, ω3 fatty acids, glutamine and vitamin D 3 in improving clinical outcome in patients with traumatic brain injuries. Ain-Shams J Anaesthesiol 2015;8:301-7

How to cite this URL:
Ali NS, Mohamed OS, Aead MS. Progesterone versus combination therapy of progesterone, ω3 fatty acids, glutamine and vitamin D 3 in improving clinical outcome in patients with traumatic brain injuries. Ain-Shams J Anaesthesiol [serial online] 2015 [cited 2019 Jul 22];8:301-7. Available from: http://www.asja.eg.net/text.asp?2015/8/3/301/161689


  Introduction Top


Management of patients with traumatic brain injury (TBI) has changed over the last 20 years. Advancements in the treatment of TBI requires great understanding of the biochemical mechanisms of the brain during a normal resting state as well as the metabolism after a severe traumatic event [1] .

Neuroprotection methods to halt or mitigate secondary injury have been the subject of great interest because of their ability to limit the damage that follows TBI; however, clinical trials to test agents that could halt these cellular mechanisms have largely been met with failure [2] .

Although progesterone is best known for its effects on the female reproductive system, it also has abundant receptors in the CNS of men and women [3] . Progesterone influences the expression of ~500 genes involved in regulating inflammation, apoptosis, and vascular remodeling [4] . Its use in TBIs had been investigated and revealed that it can protect and reconstitute the blood-brain barrier, reduce cerebral edema through decreasing vasogenic and cytotoxic edema and modulating brain water regulation through aquaporin channels, downregulate the inflammatory cascade and proinflammatory cytokines in response to neurotrauma, reduce free radicals and lipid peroxidation, and decrease apoptosis [5] .

Vitamin D (a steroid hormone) and ω3 fatty acids (an essential fatty acid) are both very powerful anti-inflammatory agents that reduce cerebral edema and swelling [6] .

Glutamine becomes an essential amino acid during stress and produces the extra glucose (through the Cori cycle) that is used by the injured brain and by the immune response system to fight off infection during stress [7] .

Glutamine, ω3 fatty acids, and vitamin D 3 are all immune modulators, which work synergistically to prevent secondary brain injury by limiting or decreasing inflammation. They are also neuroprotectors that make the neurons more resistant to stress, ischemia, hypothermia, hyperthermia, hypoglycemia, hyperglycemia, hypotension, and hypertension. Immune modulation with nutritional supplements is a rapidly advancing field with a very promising future in treating TBI as well as other critically ill patients [8] .

The aim of this research was to evaluate and compare the efficacy of progesterone alone with that of a half dose of progesterone plus vitamin D 3 , ω3 fatty acids, and glutamine (combination therapy) on the outcome of patients with acute TBI, with primary endpoints being detection of mortality rate and recovery [Glasgow coma score (GCS)] and secondary endpoints being duration of ICU and hospital stay, computed tomography (CT) findings, and Glasgow outcome scale (GOS) after 3 months.


  Patients and methods Top


This prospective randomized study was carried out at the ICU, Minia University Hospital, during the period from December 2013 to December 2014 after institutional approval and informed consent was obtained from all patients' relatives before enrollment in the study. It involved 60 adult patients of both sexes aged 18-60 years, with moderate to severe TBI within 8 h from the trauma either with or without surgical interference, with a GCS of 4-12 at admission. Patients who had received any investigational drugs before the enrollment, such as progesterone or estrogen, or those with known allergy to progesterone, unstable patients (e.g. partial pressure of oxygen <60 mmHg or a systolic blood pressure <90 mmHg, or both), presence of severe anoxic intracerebral damage, brain death, active myocardial infarction, ischemic stroke, pulmonary embolism, deep-vein thrombosis, pregnancy, lactation, spinal cord injury, status epilepticus, blood-clotting disorder, and a known history of reproductive cancer were excluded.

Patients were randomly divided into three equal groups of 20 patients each; randomization was based on computer-generated tables.

  1. The control group (C group): this group received the standard care and medications according to the guidelines of head trauma protocol [9] in terms of analgesia and sedation (e.g. fentanyl), mechanical ventilation (if needed), seizure prophylaxis (e.g. phenytoin), temperature modulation (e.g. paracetamol), hemodynamic support, antibiotic therapy, gastric ulcer prophylaxis (e.g. ranitidine), deep-vein thrombosis prophylaxis, dehydrating measures such as administration of mannitol 20% in cases of brain edema, neuroprotective drugs, and nutritional support.
  2. The progesterone group (P group): this group received 1 mg/kg intramuscular progesterone at enrollment into the study once per 12 h for 5 consecutive days (Prontogest Ampoule of 100 mg; Marcyrl Nile Company, El Obour city, Cairo, Egypt), in addition to the standard care and medications according to the guidelines of head trauma protocol.
  3. The combination therapy group (T group): this group received intramuscular 0.5 mg/kg progesterone at enrollment into the study once per 12 h for 5 days, 1 mic vitamin D 3 daily by means of direct intravenous injection over 30 s (one alpha ampoule; LEO Pharmaceutical, Ballerup, Denmark), 2 g enteral ω3 fatty acids daily by means of a nasogastric tube (two ω3 plus capsule 1 g; SEDICO Company, 6th of October, Giza, Egypt), and intravenous glutamine at 20 g per 12 h (Dipeptiven bottle; Fresenius Company, Bad Homburg, Germany), which was added to 350 ml saline 0.9% and infused slowly over 30 min, in addition to the standard care and medications according to guidelines of head trauma protocol.
Primary evaluation of the patients was carried out at the emergency department using vital signs, GCS, and revised trauma score (RTS).

The RTS consists of three categories: GCS, systolic blood pressure, and respiratory rate. The score range is 0-12. Patients with an RTS of 12 are labeled delayed, those with an RTS of 11 are labeled urgent, and those with RTS of 10-3 are labeled immediate. Those who have an RTS below 3 are declared dead and should not receive certain care because they are highly unlikely to survive without a significant amount of resources [Table 1].
Table 1: Revised trauma score [10]

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After head CT scanning and any necessary investigations, the patients were delivered to the ICU immediately, or following surgical interference. On arrival to the ICU all patients were monitored continuously with the bedside monitor apparatus (Hewlett Packard, Boblingen, Germany), including heart rate, respiratory rate, blood pressure, oxygen saturation, and body temperature. Insertion of intravenous lines with suitable-sized cannulae, central venous line, arterial cannula in the nondominant hand, and urinary catheter was carried out under complete aseptic conditions. Immediately, the standard treatment for management of TBI based on the guidelines for the management of head injury was started. Particular emphasis was placed on the prevention and treatment of secondary insults, avoidance of intracranial hypertension, maintenance of a normovolemic, normothermic as well as normoglycemic state, with mechanical ventilation (if needed). Daily evaluations of neurologic status were performed using the GCS. The score is composed of three tests: eye, verbal, and motor responses. The three values separately, as well as their sum, are considered. The lowest possible GCS (the sum) is 3 (deep coma or death), whereas the highest is 15 (fully awake person) [Table 2].
Table 2: Glasgow coma score (Quoted from Gill et al.[11])

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Moreover, all patients were followed up for evaluation of vital data (heart rate (HR), respiratory rate (RR), mean arterial blood pressure (MAP), central venous pressure (CVP), urine output, and temperature), arterial blood gas analysis, and the routine laboratory investigations every 48 h, but the previous follow-up parameters are not reported here. CT was performed at admission and then every 48 h, and the GOS at 3 months of trauma was evaluated, which is a five-point scale account of both physical and mental impairment. Points from 1-3 are considered unfavorable and from 4-5 are considered favorable outcomes [Table 3].
Table 3: Glasgow outcome scale [12]

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RTS at admission, GCS on days 1, 2, 3, 4, 5, 6, and 7, ICU and hospital stay, mortality rate, CT findings on days 1, 3, 5, and 7, and GOS after 3 months were recorded and statistically analyzed. In addition, the patients were followed up for any side effects related to the studied medications.

Statistical method

The collected data were coded, tabulated, and statistically analyzed using statistical package for the social sciences (SPSS program, version 20; SPSS Inc., Chicago, Illinois, USA) software. Descriptive statistics were determined for numerical data and were presented as mean, SD and minimum and maximum of the range, or median (interquartile range), whereas categorical data were presented as number and percentage.

Analyses were performed for quantitative variables using the one-way ANOVA test for parametric data between the three groups and post-hoc analysis for each group, and the Kruskal-Wallis test was used for analysis of nonparametric data between the three groups and the Mann-Whitney U-test was used for analysis of each group.

The paired sample t-test was used to compare parametric data between two variables in each group, and the Wilcoxon signed-rank test was used to compare nonparametric data between two variables in each group.

The χ2 -test was used to compare qualitative data between groups when the cell contains more than 5, and Fisher's exact test was used when the cell contains less than 5. The level of significance was taken at P value of 0.05 or less.

Sample size calculation

On the basis of a previous pilot study in our institute with study power 80%, the sample size was calculated by comparing the means of difference between groups with confidence interval 95%, margin of error ± 3, and α2 = 0.05; 20 patients in each group were required.


  Results Top


Patient characteristics were comparable among the study groups [Table 4].
Table 4: Patient characteristics at admission among the study groups

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As regards GCS, the three groups were comparable on first day of admission, but at days 2, 3, 4, 5, 6 and 7, a significant difference was detected between the group C and each of the P and the T group with no significant difference between the P and T groups.

Within the individual group, significant progressive improvement in GCS was detected in the consecutive days compared with day 1 in the P and T groups, which was not present in the C group [Table 5].
Table 5: Glasgow coma score in different study groups (data presented as median ± interquartile range)

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Analysis of CT data showed that the three groups were comparable on day 1 as all had TBI. A significant difference was detected between the C group and the P group on days 3, 5, and 7 (P = 0.001, < 0.001, and < 0.001) and between the C and T groups on days 5 and 7 (P = 0.001 and 0.002), with no difference between groups P and T. Progressive improvement was detected in groups P and T in consecutive days in comparison with the day 1 of trauma, which was not detected in the C group [Figure 1]. For simplification, the CT findings of TBI were classified into four grades (worsened, as previous, improved, and resolution), in comparison with the findings of first day of admission.
Figure 1: Computed tomography (CT) changes among the studied groups. Data presented as percentage of patients in each grade of CT findings on days of follow-up. As pre, as previous – that is, the same finding as at admission.

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As shown in [Table 6], both ICU and hospital stays were significantly shorter in the progesterone and combined therapy groups compared with the control group. On comparing the two therapeutic groups, only ICU stay was significantly shorter in the progesterone group. The total mortality rate after 3 months was 45% and all deaths occurred during the hospital stay, with a significant difference detected between the three studied groups (P = 0.029). When compared with the control group, mortality rate in the progesterone group was significantly lower (30 vs. 0%, P = 0.008), with no significant difference on comparing the combined therapy group with the other two groups. No complications related to the studied drugs were recorded.
Table 6: ICU and hospital stay and mortality among the studied groups

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As regards the GOS after 3 months, there was a significant difference between the three groups, with the highest percentage of unfavorable outcome (death, persistent vegetative, and severe disability) recorded in the C group (70%), with a significant difference between the C group and each of the P group and the T group; however, a higher favorable outcome was detected in the P and T groups (100 and 85%, respectively), with no significant difference between them. Comparison of the individual grades of the scale showed significant difference between the three studied groups, C and P groups, C and T groups (except in terms of death and moderate disability), and between the P and T groups in the moderate disability, which was only detected in the P group (20%) [Table 7].
Table 7: Glasgow outcome scale after 3 months of trauma among the study groups

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  Discussion Top


TBI is a form of acquired brain injury. Over the past 30 years, considerable research effort has been directed at understanding the secondary injury cascade that is a consequence of the primary mechanical trauma to the head [13] . The use of combination therapy (progesterone, vitamin D 3 , ω3, and glutamine) in the management of TBI was proposed by Matthews et al. [14] , who called it neuroceutical augmentation for TBI and believed that it will have a very promising future in the treatment of TBI. In addition to the synergistic action, another rationale for using a drug combination is the well-known inverted U-shaped dose response (or hormesis) of steroid action in which the optimal result is obtained with a medium-range dosage, whereas increasing dosages decrease the effectiveness [15],[16] . Glutamine also works synergistically with vitamin D 3 to increase heat-shock proteins HSP70 and thus protect the injured brain from an ongoing insult [17],[18] .

In this research, to decide the doses of the studied drugs, the recommended international doses together with the previous studies had been reviewed [1],[19],[20] . The results of Goss et al. [21] suggest that low and moderate doses of progesterone are optimal for facilitating recovery of select behaviors, and that postinjury progesterone treatment permits a wider dose range compared with preinjury treatment. Moreover, Shear et al. [22] found that both the 3-day progesterone and the 5-day progesterone regimens reduced the size of injury-induced necrosis and cell loss, with the 5-day schedule being the most effective and the only regimen that resulted in improved spatial learning performance and reduced sensory neglect.

Our results revealed that both therapeutic groups were effective in improving the neurological outcome in patients with TBI, and their efficacy was not different statistically, although the progesterone dose was halved in the combination therapy group, except for significantly shorter ICU stay in the progesterone group. In comparison with the control group, better improvement and outcome were recorded in both therapeutic groups.

Thus, we found that GCS had a significant progressive improvement in the progesterone and combined therapy groups compared with the control group accompanied by a similar improvement in CT findings. In agreement with our findings, Ma et al. [23] concluded that progesterone may improve the GCS of patients suffering TBI. Moreover, Aminmansour et al. [20] , who were treating patients with TBI in less than 8 h of admission with either progesterone (1 mg/kg intramuscular every 12 h for 5 days), progesterone+vitamin D (1 mg/kg progesterone intramuscular every 12 h+200 IU/kg of vitamin D once-a-day for 5 days), or injection of placebo for 5 days, in their results showed that recovery rate in patients who received progesterone and vitamin D together was significantly higher than that of the progesterone group, which was in turn higher than that of the placebo group.

In the present study, lack of difference between the progesterone group and the combination therapy group in GCS may be attributed to the administration of half dose of progesterone (0.5 mg/kg) in the combination therapy group aiming to decrease the incidence of any side effects associated with the hormonal therapy. However, the result may be different if 1 mg/kg was used.

In contrast, Wright et al. [24] performed a trial in patients with moderate-to-severe acute TBI, who received intravenous progesterone (0.7 mg/kg/h) or placebo within 4 h after injury for a total of 96 h. This clinical trial did not show any benefit of progesterone over placebo.

Moreover, our results showed that the 3-month mortality rate was significantly higher in the control group (30%). All deaths occurred during the hospitalization period due to the severity of trauma. In accordance with our results, Xiao et al. [19] , in a study conducted on a total of 159 patients who arrived within 8 h of injury with a GCS of 8 or less, reported lower mortality rate in patients who received progesterone compared with those who received placebo. Wright et al. [25] proved that progesterone may improve the neurologic outcome of patients suffering TBI and reported a lower 30-day mortality rate compared with controls. However, mortality rate in the combination therapy group was significantly low compared with that in other groups in the study conducted by Aminmansour et al. [20] . In the current research, although three patients died in the combined therapy group with no deaths in the progesterone group, it was statistically insignificant. This may be attributed to the lower dose of progesterone used by us in comparison with that used by Aminmansour et al. [20] .

On following up the patients at 3 months after trauma, we detected a significant increase in favorable GOS among patients in the progesterone and combined therapy groups (100 and 85%, respectively) compared with the control group (30%), whereas unfavorable GOS was found in 70% of control group patients. Although the two therapeutic groups were statistically comparable as regards the GOS at 3 months, a better degree of scoring has been achieved in the combined therapy group, as all 17 patients who survived (100% survival) showed good recovery, which is the best grade of GOS, whereas 20% of patients who survived in the progesterone group still showed moderate disability and 80% showed good recovery. Thus, even though treatment with progesterone alone showed an early better progress as regards ICU stay and incidence of mortality, combination therapy was promising in long-term follow-up and we anticipate that if the dose of progesterone is increased in this group, the results will be more favorable.

Our results are in agreement with those of Xiao et al. [19] , who reported a better survival rate and a significant increase in the proportion of patients with a favorable outcome in the progesterone group compared with the placebo group up to 6 months. Shakeri et al. [26] also recorded a better recovery rate and GOS for the patients who received progesterone compared with those in the control group during a 3-month follow-up period, especially those with 5 ≤ GCS≤ 8 (50 vs. 21%).

In contrast, the study by Aminmansour et al. [20] showed that GOS and recovery rate in the progesterone and vitamin D group was higher compared with the progesterone or placebo groups.

In this research, we recorded GOS at 3 months only, but many studies proved that the GOS at 3 months is a best predictor of 12-month outcomes. This is in agreement with that reported by King et al. [27] , who assessed the GOS at 3 months and long-term outcomes at 12 months after TBI; the logistic regression model showed that GOS at 3 months was a best predictor of 12-month outcomes.

Some limitations are observed in this research; serum progesterone level and its correlation with the clinical data were not followed. Moreover, we used only GOS to evaluate the outcome after 3 months. GOS, although useful, provides only a global assessment of function and dependence and may not differentiate the difference in cognitive function, motor function, or daily activities, and thus modified functional independence measure scores may be useful if used together with GOS. Lastly, our results could be influenced by a single-center trial on a limited number of patients; thus multicenter study on a larger population is recommended.

In conclusion, both progesterone and neuroceutical augmentation TBI regimen are promising treatment modalities for severe and moderate TBI patients as they are relatively inexpensive, widely available, and have a long track record of safe use in humans.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

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    Figures

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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]



 

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