Coagulation Activation by Hyperosmolar Agents in Intracranial Hypertension

Intracranial Hypertension Clinical Trial

Official title:

Evaluation of Coagulation Activation in Patients With Intracranial Hypertension After Treatment With Mannitol or Hypertonic Saline Solution.

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT03409237
• Other study ID #: NMD-50/18
• Status: Withdrawn
• Start date: December 3, 2020
• Est. completion date: December 31, 2021

Study information

• Verified date: November 2020
• Source: Neuromed IRCCS
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

Osmotherapy consists in the therapeutic use of osmotically active substances with the aim of reducing the volume and therefore the intracranial pressure. It therefore represents an essential component in the clinical management of cerebral edema and intracranial hypertension, whether they are a consequence of head trauma, ischemic or hemorrhagic stroke, and neoplasm or neurosurgical procedures.

The current study aims at evaluating in vivo the effects on haemostasis parameters of hypertonic saline solutions at different concentration, as compared to mannitol, in patients with neuroradiological signs (CT / MRI) of cerebral edema / non-traumatic intracranial hypertension.

Description:

Osmotherapy is commonly used in the treatment of intracranial hypertension (ICH) due to a variety of causes, including head trauma, intracranial neoplasia, infection or hemorrhage, and status epilepticus. The principle goal of osmotherapy is to shift fluid from the intracellular into the extracellular compartment using intravenous hyperosmolar agents, thereby reducing brain edema and improving cerebral perfusion pressure. Although 10-20% mannitol is considered the gold standard hyperosmolar agent in the treatment of ICH, mannitol-induced osmotic diuresis may cause hypovolemia and reduction in cerebral perfusion pressure. In recent years, 3.0-7.5% hypertonic saline (HTS) has gained popularity in the treatment of ICH as it has less pronounced diuretic effects and therefore does not cause hypovolemia. Indeed, in the face of hypovolemic shock and traumatic brain injury, HTS provides the advantage of volume expansion, restoring adequate cerebral perfusion pressures, and reducing brain edema, which makes it superior to mannitol in trauma patients with shock.

Both mannitol and HTS have been shown to interfere with whole blood coagulation and platelet function. This is in part due to dilutional coagulopathy. Furthermore, 7.2% HTS may directly disturb both fibrin formation and platelet function, and mannitol may interfere with coagulation by reducing clot strength. In addition, hyperosmolarity is supposed to lead to impairment of both whole blood coagulation and platelet function . In consequence, the safety of using these agents in patients with ICH and intracranial hemorrhage remains unclear. Previous in vitro studies in humans have demonstrated anticoagulant effects of both mannitol and HTS, although one clinical study failed to demonstrate any negative effect on hemostasis using either solution in patients undergoing elective intracranial surgery. However, in vivo studies in a clinical setting are lacking.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: December 31, 2021
• Est. primary completion date: July 1, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria:

• Indication to osmotic therapy for cerebral edema / non-traumatic intracranial hypertension

• Age 18 - 80 years

• Body temperature between 35.5 ° C and 37.5 °C

Exclusion Criteria:

• Congenital or acquired disorders of hemostasis

• Clinical history of abnormal bleeding

• Hematologic or Renal diseases (acute or chronic renal failure II-III stage)

• Chronic or recent therapy with antiplatelet and/or anticoagulants

• Taking corticosteroids or nonsteroidal anti-inflammatory drugs (less than 4 weeks)

• Administration of macromolecular vascular filling solutions (less than 4 weeks)

• History of recent venous / arterial thromboembolic disease (less than three months)

• Moderate-severe liver dysfunction

• Anemia (hb <10 mg/dl)

• Recent transfusions (less than three months)

• Hyponatremia (Na <135 meq/l)

• Hypernatremia (Na> 155 meq/l)

Related Conditions & MeSH terms

• Brain Edema
• Cerebral Edema
• Hypertension
• Intracranial Hypertension

Intervention

Drug:
• Mannitol
Therapy is administered according to the clinical gold standard and until reaching and maintaining serum sodium levels between 145 e 155 meq/l and an osmolarity <320.
• Hypertonic saline solution
Therapy is administered according to the clinical gold standard and until reaching and maintaining serum sodium levels between 145 e 155 meq/l and an osmolarity <320.

Locations

Country	Name	City	State
Italy	IRCCS INM Neuromed, Department of Epidemiology and Prevention	Pozzilli	IS

Sponsors (1)

Lead Sponsor	Collaborator
Neuromed IRCCS

Country where clinical trial is conducted

Italy, 

References & Publications (18)

Brain Trauma Foundation; American Association of Neurological Surgeons; Congress of Neurological Surgeons; Joint Section on Neurotrauma and Critical Care, AANS/CNS, Bratton SL, Chestnut RM, Ghajar J, McConnell Hammond FF, Harris OA, Hartl R, Manley GT, Nemecek A, Newell DW, Rosenthal G, Schouten J, Shutter L, Timmons SD, Ullman JS, Videtta W, Wilberger JE, Wright DW. Guidelines for the management of severe traumatic brain injury. II. Hyperosmolar therapy. J Neurotrauma. 2007;24 Suppl 1:S14-20. Erratum in: J Neurotrauma. 2008 Mar;25(3):276-8. multiple author names added. — View Citation

Delano MJ, Rizoli SB, Rhind SG, Cuschieri J, Junger W, Baker AJ, Dubick MA, Hoyt DB, Bulger EM. Prehospital Resuscitation of Traumatic Hemorrhagic Shock with Hypertonic Solutions Worsens Hypocoagulation and Hyperfibrinolysis. Shock. 2015 Jul;44(1):25-31. doi: 10.1097/SHK.0000000000000368. — View Citation

Gatidis S, Borst O, Föller M, Lang F. Effect of osmotic shock and urea on phosphatidylserine scrambling in thrombocyte cell membranes. Am J Physiol Cell Physiol. 2010 Jul;299(1):C111-8. doi: 10.1152/ajpcell.00477.2009. Epub 2010 Mar 17. — View Citation

Hanke AA, Maschler S, Schöchl H, Flöricke F, Görlinger K, Zanger K, Kienbaum P. In vitro impairment of whole blood coagulation and platelet function by hypertonic saline hydroxyethyl starch. Scand J Trauma Resusc Emerg Med. 2011 Feb 10;19:12. doi: 10.1186/1757-7241-19-12. — View Citation

Luostarinen T, Niiya T, Schramko A, Rosenberg P, Niemi T. Comparison of hypertonic saline and mannitol on whole blood coagulation in vitro assessed by thromboelastometry. Neurocrit Care. 2011 Apr;14(2):238-43. doi: 10.1007/s12028-010-9475-6. — View Citation

Mojtahedzadeh M, Ahmadi A, Mahmoodpoor A, Beigmohammadi MT, Abdollahi M, Khazaeipour Z, Shaki F, Kuochaki B, Hendouei N. Hypertonic saline solution reduces the oxidative stress responses in traumatic brain injury patients. J Res Med Sci. 2014 Sep;19(9):867-74. — View Citation

Munar F, Ferrer AM, de Nadal M, Poca MA, Pedraza S, Sahuquillo J, Garnacho A. Cerebral hemodynamic effects of 7.2% hypertonic saline in patients with head injury and raised intracranial pressure. J Neurotrauma. 2000 Jan;17(1):41-51. — View Citation

Ng KF, Lam CC, Chan LC. In vivo effect of haemodilution with saline on coagulation: a randomized controlled trial. Br J Anaesth. 2002 Apr;88(4):475-80. — View Citation

Prough DS, Whitley JM, Taylor CL, Deal DD, DeWitt DS. Regional cerebral blood flow following resuscitation from hemorrhagic shock with hypertonic saline. Influence of a subdural mass. Anesthesiology. 1991 Aug;75(2):319-27. — View Citation

Rabinovici R, Yue TL, Krausz MM, Sellers TS, Lynch KM, Feuerstein G. Hemodynamic, hematologic and eicosanoid mediated mechanisms in 7.5 percent sodium chloride treatment of uncontrolled hemorrhagic shock. Surg Gynecol Obstet. 1992 Oct;175(4):341-54. — View Citation

Reed RL 2nd, Johnston TD, Chen Y, Fischer RP. Hypertonic saline alters plasma clotting times and platelet aggregation. J Trauma. 1991 Jan;31(1):8-14. — View Citation

Rhind SG, Crnko NT, Baker AJ, Morrison LJ, Shek PN, Scarpelini S, Rizoli SB. Prehospital resuscitation with hypertonic saline-dextran modulates inflammatory, coagulation and endothelial activation marker profiles in severe traumatic brain injured patients. J Neuroinflammation. 2010 Jan 18;7:5. doi: 10.1186/1742-2094-7-5. — View Citation

Ropper AH. Hyperosmolar therapy for raised intracranial pressure. N Engl J Med. 2012 Aug 23;367(8):746-52. doi: 10.1056/NEJMct1206321. Review. — View Citation

Schmoker JD, Zhuang J, Shackford SR. Hypertonic fluid resuscitation improves cerebral oxygen delivery and reduces intracranial pressure after hemorrhagic shock. J Trauma. 1991 Dec;31(12):1607-13. — View Citation

Tan TS, Tan KH, Ng HP, Loh MW. The effects of hypertonic saline solution (7.5%) on coagulation and fibrinolysis: an in vitro assessment using thromboelastography. Anaesthesia. 2002 Jul;57(7):644-8. — View Citation

Torre-Healy A, Marko NF, Weil RJ. Hyperosmolar therapy for intracranial hypertension. Neurocrit Care. 2012 Aug;17(1):117-30. doi: 10.1007/s12028-011-9649-x. Review. — View Citation

White H, Cook D, Venkatesh B. The use of hypertonic saline for treating intracranial hypertension after traumatic brain injury. Anesth Analg. 2006 Jun;102(6):1836-46. Review. — View Citation

Wilder DM, Reid TJ, Bakaltcheva IB. Hypertonic resuscitation and blood coagulation: in vitro comparison of several hypertonic solutions for their action on platelets and plasma coagulation. Thromb Res. 2002 Sep 1;107(5):255-61. — View Citation

* Note: There are 18 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Changes in coagulation parameters	Coagulation parameters such as thrombin and prothrombin time, fibrinogen, thrombin generation time will be measured in plasma by ELISA test or on whole blood by thromboelastography	Before osmotic therapy (time 0), after 12 hrs infusion (time 1)
Secondary	Changes in inflammation markers	Inflammation markers such as C reactive protein, interleukin 6, P-selectin. E-selectin will be measured in plasma	Before osmotic therapy (time 0), after 12 hrs infusion (time 1)