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Intracranial HypertensionNCT03409237

Coagulation Activation by Hyperosmolar Agents in Intracranial Hypertension

An observational study of Intracranial Hypertension and Cerebral Edema, run by Neuromed IRCCS at 1 site in Italy.

Withdrawn

Withdrawn. The study stopped before anyone enrolled.

Official record
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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… Read more about this study

Who is it for?
Ages 18 to 80 years
Conditions the study is for
Intracranial Hypertension, Cerebral Edema
What is being tested?
Mannitol and Hypertonic saline solution
Type of treatment
Injection or infusion
How many people
0 participants
Where
1 siteItaly
Study dates
3 Dec 2020to 31 Dec 2021
Phase
Observational
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 80 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Study population: Patients (men and women) with cerebral edema / intracranial hypertension (CT / MRI neuroradiological diagnosis) on a non-traumatic basis with indication to osmotic therapy, treated on the basis of clinical and radiological evidence according to current treatment standards and meeting the inclusion criteria.

Who may be able to join

  • 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

Who cannot join

  • 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)
Show all 12Show fewer
  • 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)

Trial locations and contacts

1 site in 1 country.

Italy1 site
  • IRCCS INM Neuromed, Department of Epidemiology and Prevention

    Pozzilli, IS, 86077

Other trials in Italy

About this study

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

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.

Read the detailed 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.

Being tested
Mannitol, Hypertonic saline solution
Medical subject headings
Intracranial Hypertension, Brain Edema

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • MannitolDrug

    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 solutionDrug

    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.

Study groups in NCT03409237
Study groupRoleWhat they receive
Group 1Mannitol 0.2-0.3 g/kg 4 times/day.
Receives: Drug: Mannitol
Group 2Hypertonic saline solution 3%. Continous infusion of 0,5 ml/kg/h. If necessary a loading dose of 2,5 ml/kg is administered.
Receives: Drug: Hypertonic saline solution
Group 3Hypertonic solution saline 4%. Continous infusion of 0,5 ml/kg/h. If necessary a loading dose of 2,5 ml/kg is administered.
Receives: Drug: Hypertonic saline solution
Group 4Hypertonic saline solution 7%. Continous infusion of 0,5 ml/kg/h. If necessary a loading dose of 2,5 ml/kg is administered.
Receives: Drug: Hypertonic saline solution

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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

    Measured: Before osmotic therapy (time 0), after 12 hrs infusion (time 1)

Secondary outcomes (1)
  1. Changes in inflammation markers

    Inflammation markers such as C reactive protein, interleukin 6, P-selectin. E-selectin will be measured in plasma

    Measured: Before osmotic therapy (time 0), after 12 hrs infusion (time 1)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted24 Jan 2018
  2. Study start3 Dec 2020 (estimated)
  3. Primary completion1 Jul 2021 (estimated)
  4. Study completion31 Dec 2021 (estimated)

Why it stopped: No participant enrolled. The human resources to perform the study also due to the COBID emegency

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Observational
Observational model
Case-control
Time perspective
Prospective
Enrolment
0 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03409237
Sponsor's protocol ID
NMD-50/18
Status last verified
Nov 2020
First submitted
9 Jan 2018
Last updated
19 Nov 2020
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • 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.

    PubMed 22090171
  • Ropper AH. Hyperosmolar therapy for raised intracranial pressure. N Engl J Med. 2012 Aug 23;367(8):746-52. doi: 10.1056/NEJMct1206321. No abstract available.

    PubMed 22913684
  • 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. doi: 10.1089/neu.2007.9994. No abstract available.

    PubMed 17511539
  • 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. doi: 10.1213/01.ane.0000217208.51017.56.

    PubMed 16717334
  • 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. doi: 10.1097/00000542-199108000-00021.

    PubMed 1677548
  • 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. doi: 10.1097/00005373-199112000-00007.

    PubMed 1749030
  • 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.

    PubMed 25535502
  • 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. doi: 10.1089/neu.2000.17.41.

    PubMed 10674757
  • 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.

    PubMed 1411892
  • 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. doi: 10.1016/s0049-3848(02)00335-3.

    PubMed 12479887
  • 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. doi: 10.1046/j.1365-2044.2002.02603.x.

    PubMed 12059821
  • 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. doi: 10.1097/00005373-199101000-00002.

    PubMed 1986137
  • 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.

    PubMed 25784523
  • 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. doi: 10.1093/bja/88.4.475.

    PubMed 12066721
  • 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.

    PubMed 20082712

Questions about this trial

What is this clinical trial studying?

An observational study of Intracranial Hypertension and Cerebral Edema, run by Neuromed IRCCS at 1 site in Italy.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 3 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: withdrawn, as of the sponsor's last update on 19 Nov 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

The study was withdrawn before enrolling participants, so there are no results.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Changes in coagulation parameters (time frame: Before osmotic therapy (time 0), after 12 hrs infusion (time 1)). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03409237, which also lists 18 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Nov 2020.

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