Progesterone

Progesterone

see also Progesterone receptor.

(pregn-4-ene-3,20-dione; abbreviated as P4) is an endogenous steroid hormone involved in the menstrual cyclepregnancy, and embryogenesis of humans and other species.

It belongs to a group of steroid hormones called the progestogens, and is the major progestogen in the body. Progesterone is also a crucial metabolic intermediate in the production other endogenous steroids, including the sex hormones and the corticosteroids, and plays an important role in brain function as a neurosteroid.


Dexamethasone (DEXA) is widely used in the management of peritumoral edema. DEXA, however, has many systemic side-effects, and may interact negatively with glioma therapy. Progesterone (PROG), on the other hand, is a well-tolerated and readily accessible antiinflammatory and anti-edema agent with potent neuroprotective properties.

Cheng et al., investigated if PROG can serve as a viable alternative to DEXA in the management of peri-tumoral brain edema.

They used an orthotopic C6 glioblastoma model with male Sprague Dawley rats. Tumor grafts were allowed to grow for 14 days prior to drugtreatment with (i) DEXA 1mg/kg, (ii) PROG 10mg/kg or (iii) PROG 20 mg/kg for five consecutive days. Overall animal survival and neurologic functions were evaluated. Mechanistic studies on blood brain barrier (BBB) permeability and angiogenic responses were performed on the ex vivo tumor grafts.

They found that all drug treatments prolonged overall survival to different extents. PROG 10mg led to significantly longer survival, and better preservation of neurologic functions and body weightBBB permeability was better preserved with PROG 10mg than DEXA possibly through the downregulation of MMP-9 and AQP-4 expressions; anti-angiogenic responses were also observed in the PROG group.

This proof-of-concept pilot study provides novel information on the use of PROG as a corticosteroids-sparing agent in brain tumor management. Further translational and clinical studies are warranted 1).

Progesterone for acute traumatic brain injury

1)

Cheng Y, Yeung WL, De Zhang P, Li N, Kiang MY, Leung KK. Progesterone is more effective than dexamethasone in prolonging overall survival and preserving neurologic functions in experimental animals with orthotopic glioblastoma allografts. World Neurosurg. 2019 Jan 30. pii: S1878-8750(19)30211-6. doi: 10.1016/j.wneu.2019.01.113. [Epub ahead of print] PubMed PMID: 30710720.

Effect of trauma center designation in severe traumatic brain injury outcome

Effect of trauma center designation in severe traumatic brain injury outcome

Trauma center designation is significantly associated with functional independence (FI) and independent expression (IE) (defined as a functional independence measure component of 4) after severe traumatic brain injury, but not moderate traumatic brain injuryProspective study is warranted to verify and explore factors contributing to this discrepancy 1).

Patients with severe traumatic brain injury treated in American College of Surgeons (ACS)-designated level 1 trauma centers have better survival rates and outcomes than those treated in ACS-designated level 2 trauma center2).

In 2019 a study showed superior functional outcomes and lower mortality rates in patients undergoing a neurosurgical procedurefor severe traumatic brain injury in level 1 trauma center3).

References

1)

Brown JB, Stassen NA, Cheng JD, Sangosanya AT, Bankey PE, Gestring ML. Trauma center designation correlates with functional independence after severe but not moderate traumatic brain injury. J Trauma. 2010 Aug;69(2):263-9. doi: 10.1097/TA.0b013e3181e5d72e. PubMed PMID: 20699734.
2)

DuBose JJ, Browder T, Inaba K, Teixeira PG, Chan LS, Demetriades D. Effect of trauma center designation on outcome in patients with severe traumatic brain injury. Arch Surg. 2008 Dec;143(12):1213-7; discussion 1217. doi: 10.1001/archsurg.143.12.1213. PubMed PMID: 19075174.
3)

Chalouhi N, Mouchtouris N, Saiegh FA, Starke RM, Theofanis T, Das SO, Jallo J. Comparison of Outcomes in Level I vs Level II Trauma Centers in Patients Undergoing Craniotomy or Craniectomy for Severe Traumatic Brain Injury. Neurosurgery. 2019 Jan 24. doi: 10.1093/neuros/nyy634. [Epub ahead of print] PubMed PMID: 30690608.

Hypernatremia

Hypernatremia

Hypernatremia, is a high concentration of sodium in the blood. Normal serum sodium levels are 135 – 145 mmol/L (135 – 145 mEq/L). Hypernatremia is generally defined as a serum sodium level of more than 145 mmol/L.

Hypernatremia is one of the most common electrolyte disturbances following aneurysmal subarachnoid hemorrhage (aSAH) and has been correlated with increased mortality in single institution studies. Both hyponatremia and hypernatremia during ICU management were significantly associated with unfavorable neurologic outcomes 1).

In neurosurgical patients, this is most often seen in the setting of diabetes insipidus (DI). Since normal total body water (TBW) is ≈ 60% of the patient’s normal body weight, the patient’s current TBW may be estimated by Eq.

Mild and moderate hypernatremia were significantly associated with increased early mortality in patients with severe TBI 2). Hypernatremia was associated also with poorer outcomes in patients with severe TBI. This finding warrants further investigation in a prospective, randomized study 3).

Electrolyte imbalances are common in traumatic brain injury. In a study Hypokalemia was the most common electrolyte imbalance at 65.5%. The results of the use of a multivariable logistic regression model showed that the odds of postoperative death in TBI patients were increased with high levels of blood glucose, hypernatremia, and acidosis.Hypokalemia was the most common electrolyte imbalance in TBI patients. Hypernatremia, acidosis, and hyperglycemia significantly increased the odds ratio of death in the first 24  hours post TBI 4).

Clinical features

Early symptoms may include a strong feeling of thirstweaknessnausea, and loss of appetite.

Severe symptoms include confusion, muscle twitching, and bleeding in or around the brain.

Severe symptoms typically only occur when levels are above 160 mmol/L.

Treatment

The free water deficit to be replaced is given by a Eq. Correction must be made slowly to avoid exacerbating cerebral edema. One half the water deficit is replaced over 24 hours, and the remainder is given over 1–2 additional days. Judicious replacement of deficient ADH in cases of true DI must also be made.


The aim of a work of Vassilyev was to evaluate the effectiveness of Sterofundin in the framework of complex therapy of hypernatremia in neurosurgical patients after removal of brain tumors. They analyzed the dynamics of the concentrations of sodium, potassium, chorus of the plasma, anion gap and buffer bases in the postoperative period of these patients. For obtaining reliable results, the patients were divided into groups according to the nature of the treatment: Sterofundin and symptomatic correction of hypotonic solution of sodium chloride, saluretic and Spironolactone respectively. In a comparison between the groups, a distinct difference in the speed of regression of hypernatremia and durability of the achieved effect was observed. In case of treatment with Sterofundin there was a significant decrease of hypernatremia by the end of the second day of the postoperative period without tendency to re-raise. The prevalence of hypotonic solutions of sodium chloride and potassium-sparing saluretics in intensive care allowed reducing the sodium concentration non-persistently to the fourth day on the background of significant fluctuations in its concentration. The use of Sterofundin in complex therapy of electrolyte disturbances, particularly of hypernatremia in neurosurgical patients after removal of brain tumors, is reflected in the form of significant regression of increased sodium concentration in plasmacompared with the method of use “hypotonic” hemodilution, saluretics and potassium-sparing diuretics 5).

Complications

Coma.

Pulmonary complications and acute kidney injury were more common in hypernatremia 6).


Hoffman et al., from the Upstate Medical University performed a retrospective analysis of adults between 2002 and 2011 with a primary diagnosis of aneurysmal subarachnoid hemorrhage (aSAH) using the Nationwide Inpatient Sample (NIS). Patients were grouped according to whether or not an inpatient diagnosis of hypernatremia was present. The primary outcome was the NIS-SAH outcome measure. Secondary outcomes included in-hospital mortalitylength of stay (LOS), and non-routine hospital discharge. Outcomes analyses adjusted for SAH severity using the NIS-SAH Severity Score, Charlson Comorbidity Index, and the presence of cerebral edema.

A total of 18,377 patients were included in the study. The incidence of a poor outcome as defined by the NIS-SAH outcome measure was 65.9% in the hypernatremia group and 33.4% in the normonatremia group (OR 1.96, 95% CI 1.68 – 2.27). There was higher mortality in the hypernatremia group (OR 1.60, 95% CI 1.37 – 1.87). Patients with hypernatremia had a significantly higher rate of non-routine hospital discharge and gastrostomy. The incidences of poor outcome, in-hospital mortality, and non-routine disposition were higher in the hypernatremia group regardless of treatment type (clipping vs. endovascular embolization). Pulmonary complications and acute kidney injury were more common in the hypernatremia group as well.

In patients with aSAH, hypernatremia is associated with poorer functional outcomes regardless of SAH severity 7).

References

1)

Okazaki T, Hifumi T, Kawakita K, Shishido H, Ogawa D, Okauchi M, Shindo A, Kawanishi M, Tamiya T, Kuroda Y. Target Serum Sodium Levels During Intensive Care Unit Management of Aneurysmal Subarachnoid Hemorrhage. Shock. 2017 Nov;48(5):558-563. doi: 10.1097/SHK.0000000000000897. PubMed PMID: 28498294.
2)

Vedantam A, Robertson CS, Gopinath SP. Morbidity and mortality associated with hypernatremia in patients with severe traumatic brain injury. Neurosurg Focus. 2017 Nov;43(5):E2. doi: 10.3171/2017.7.FOCUS17418. PubMed PMID: 29088954.
3)

Hoffman H, Jalal MS, Chin LS. Effect of Hypernatremia on Outcomes After severe Traumatic Brain Injury: A Nationwide Inpatient Sample analysis. World Neurosurg. 2018 Oct;118:e880-e886. doi: 10.1016/j.wneu.2018.07.089. Epub 2018 Jul 18. PubMed PMID: 30031178.
4)

Pin-On P, Saringkarinkul A, Punjasawadwong Y, Kacha S, Wilairat D. Serum electrolyte imbalance and prognostic factors of postoperative death in adult traumatic brain injury patients: A prospective cohort study. Medicine (Baltimore). 2018 Nov;97(45):e13081. doi: 10.1097/MD.0000000000013081. PubMed PMID: 30407307; PubMed Central PMCID: PMC6250545.
5)

Vassilyev D. [MODERN APPROACHES TO CORRECTION OF HYPERNATREMIA IN NEUROSURGICAL PATIENTS]. Georgian Med News. 2016 Nov;(Issue):12-16. Russian. PubMed PMID: 28009309.
6) , 7)

Hoffman H, Verhave B, Chin LS. Hypernatremia is associated with poorer outcomes following aneurysmal subarachnoid hemorrhage: a nationwide inpatient sample analysis. J Neurosurg Sci. 2018 Dec 5. doi: 10.23736/S0390-5616.18.04611-8. [Epub ahead of print] PubMed PMID: 30514071.
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