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Severe cerebral emergency: aspects of treatment and outcome in the intensive care patient
Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Anesthesiology and Intensive Care. Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Neurosurgery.
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Severe Traumatic Brain Injury (TBI) and aneurysmal Subarachnoid Hemorrhage (SAH) are severe cerebral emergencies. They are common reasons for extensive morbidity and mortality in young people and adults in the western world. This thesis, based on five clinical studies in patients with severe TBI (I-IV) and SAH (V), is concentrated on examination of pathophysiological developments and of evaluation of therapeutic approaches in order to improve outcome after cerebral emergency.

The treatment for severe TBI patients at Umeå University Hospital, Sweden is an intracranial pressure (ICP)-targeted therapy according to “the Lund-concept”. This therapy is based on physiological principles for cerebral volume regulation, in order to preserve a normal cerebral microcirculation and a normal ICP. The main goal is to avoid development of secondary brain injuries, thus avoiding brain oedema and worsened microcirculation.

Study I is evaluating retrospectively 41 children with severe TBI, from 1993 to 2002. The boundaries of the ICP-targeted protocol were obtained in 90%. Survival rate was 93%, and favourable outcome (Glasgow Outcome Scale, score 4+5) was 80%.

Study II is retrospectively analysing fluid administration and fluid balance in 93 adult patients with severe TBI, from 1998 to 2001.The ICP-targeted therapy used, have defined fluid strategies. The total fluid balance was positive day one to three, and negative day four to ten. Colloids constituted 40-60% of total fluids given/day. Severe organ failure was evident for respiratory insufficiency and observed in 29%. Mortality within 28 days was 11%.

Study III is a prospective, randomised, double-blind, placebo-controlled clinical trial in 48 patients with severe TBI. In order to improve microcirculation and prevent oedema formation, prostacyclin treatment was added to the ICP-targeted therapy. Prostacyclin is endogenously produced, by the vascular endothelium, and has the ability to decrease capillary permeability and vasodilate cerebral capillaries. Prostacyclin is an inhibitor of leukocyte adhesion and platelet aggregation. There was no significant difference between prostacyclin or placebo groups in clinical outcome or in cerebral microdialysis markers such as lactatepyruvate ratio and brain glucose levels.

Study IV is part of the third trial and focus on the systemic release of pro-inflammatory mediators that are rapidly activated by trauma. The systemically released pro-inflammatory mediators, interleukin-6 and CRP were significantly decreased in the prostacyclin group versus the placebo group.

Study V is a prospective pilot study which analyses asymmetric dimethylarginine (ADMA) concentrations in serum from SAH patients. Acute SAH patients have cerebral vascular, systemic circulatory and inflammatory complications. ADMA is a marker in vascular diseases which is correlated to endothelial dysfunction. ADMA concentrations in serum were significantly elevated seven days after the SAH compared to admission and were still elevated at the three months follow-up.

Our results show overall low mortality and high favourable outcome compared to international reports on outcome in severe TBI patients. Prostacyclin administration does not improve cerebral metabolism or outcome but significantly decreases the levels of pro-inflammatory mediators. SAH seems to induce long-lasting elevations of ADMA in serum, which indicates persistent endothelial dysfunction. Endothelial dysfunction may influence outcome after severe cerebral emergencies.

Place, publisher, year, edition, pages
Umeå, 2009. , 83 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1244
Keyword [en]
severe traumatic brain injury, intracranial pressure-targeted therapy, albumin, prostacyclin, endothelial dysfunction, pro-inflammatory cytokines, subarachnoid haemorrhage, asymmetric dimethylarginine
National Category
Anesthesiology and Intensive Care
Research subject
Anaesthesiology
Identifiers
URN: urn:nbn:se:umu:diva-21065ISBN: 978-91-7264-725-1 (print)OAI: oai:DiVA.org:umu-21065DiVA: diva2:210575
Distributor:
Anestesiologi och intensivvård, 901 87, Umeå
Public defence
2009-04-24, Sal B 9tr, Tandläkarhögskolan, Norrlands Universitetssjukhus, Umeå, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2009-04-09 Created: 2009-04-02 Last updated: 2010-01-18Bibliographically approved
List of papers
1. Severe traumatic brain injury in pediatric patients: treatment and outcome using an intracranial pressure targeted therapy–the Lund concept
Open this publication in new window or tab >>Severe traumatic brain injury in pediatric patients: treatment and outcome using an intracranial pressure targeted therapy–the Lund concept
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2005 (English)In: Intensive Care Medicine, ISSN 0342-4642, E-ISSN 1432-1238, Vol. 31, no 6, 832-839 p.Article in journal (Refereed) Published
Abstract [en]

Objective: This study evaluated the outcome of treatment according to the Lund concept in children with severe traumatic brain injury and investigated whether the preset goals of the protocol were achieved.

Design and setting: A two-center retrospective study in neurointensive care units at university hospitals.

Patients: Forty-one children with severe traumatic brain injury from blunt trauma and arriving at hospital within 24 h after injury. Median age was 8.8 years (range 3 months–14.2 years), Glasgow Coma Scale 7 (3–8), and Injury Severity Score 25 (16–75). All children had pathological findings on initial computed tomography. All developed intracranial hypertension, and survivors required intensive care longer than 72 h.

Interventions: Treatment according to the principles of the Lund concept.

Measurements and results: Neurosurgery was required in 46% of the children. Survival rate was 93% and favorable outcome (Glasgow Outcome Score 4 or 5) was 80% at long-term follow-up (median 12 months postinjury, range 2.5–26). The preset physiological and biochemical goals were achieved in over 90% of observations.

Conclusions: Treating pediatric patients with severe traumatic brain injury, according to the Lund concept, results in a favorable outcome when the protocol is followed.

Place, publisher, year, edition, pages
Heidelberg: Springer-Vlg, 2005
Keyword
adolescent, algorithms, brain injuries/mortality/physiopathology/therapy, child, child; preschool, female, humans, infant, intensive care units, intracranial pressure, male, retrospective studies, statistics; nonparametric, survival rate, Sweden/epidemiology, wounds; nonpenetrating/mortality/physiopathology/therapy
Identifiers
urn:nbn:se:umu:diva-5854 (URN)10.1007/s00134-005-2632-2 (DOI)15838678 (PubMedID)
Available from: 2008-01-11 Created: 2008-01-11 Last updated: 2011-04-01Bibliographically approved
2. Fluid therapy and the use of albumin in the treatment of severe traumatic brain injury
Open this publication in new window or tab >>Fluid therapy and the use of albumin in the treatment of severe traumatic brain injury
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2009 (English)In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 53, 18-25 p.Article in journal (Refereed) Published
Abstract [en]

Background: Evidence-based guidelines for severe traumatic brain injury (TBI) do not include strategies for fluid administration. The protocol used in this study includes albumin administration to maintain normal colloid osmotic pressure and advocates a neutral to slightly negative fluid balance. The aim of this study was to analyze the occurrence of organ failure and the mortality in patients with severe TBI treated by a protocol that includes defined strategies for fluid therapy.

Methods: Ninety-three patients with severe TBI and Glasgow Coma Score ≤ 8 were included during 1998–2001. Medical records of the first 10 days were retrieved. Organ dysfunction was evaluated with the Sequential Organ Failure Assessment (SOFA) score. Mortality was assessed after 10 and 28 days, 6 and 18 months.

Results: The total fluid balance was positive on days 1–3, and negative on days 4–10. The crystalloid balance was negative from day 2. The mean serum albumin was 38 ± 6 g/l. Colloids constituted 40–60% of the total fluids given per day. Furosemide was administered to 94% of all patients. Severe organ failure defined as SOFA ≥ 3 was evident only for respiratory failure, which was observed in 29%. None developed renal failure. After 28 days, mortality was 11% and, after 18 months, it was 14%.

Conclusions: A protocol including albumin administration in combination with a neutral to a slightly negative fluid balance was associated with low mortality in patients with severe TBI in spite of a relatively high frequency (29%) of respiratory failure, assessed with the SOFA score.

Keyword
severe traumatic brain injury, albumin
National Category
Anesthesiology and Intensive Care
Research subject
Anaesthesiology
Identifiers
urn:nbn:se:umu:diva-21052 (URN)10.1111/j.1399-6576.2008.01798.x (DOI)
Available from: 2009-04-02 Created: 2009-04-02 Last updated: 2012-08-16Bibliographically approved
3. Prostacyclin treatment in severe traumatic brain injury: a microdialysis and outcome study
Open this publication in new window or tab >>Prostacyclin treatment in severe traumatic brain injury: a microdialysis and outcome study
2009 (English)In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 26, no 8, 1251-1262 p.Article in journal (Refereed) Published
Abstract [en]

Prostacyclin (PGI2) is a potent vasodilator, inhibitor of leukocyte adhesion, and platelet aggregation. In trauma the balance between PGI2 and thromboxane A2 (TXA2) is shifted towards TXA2. External provided PGI2 would, from a theoretical and experimental point of view, improve the microcirculation in injured brain tissue. This study is a prospective consecutive double blinded randomised study on the effect of PGI2 versus placebo in severe traumatic brain injury (sTBI). All patients with sTBI were eligible. Inclusion criteria: verified sTBI, Glasgow Coma Score (GCS) at intubation and sedation ≤8, age 15 - 70 years, a first recorded cerebral perfusion pressure (CPP) of ≥ 10mmHg, and arrival within 24h of trauma. All subjects received an intra-cranial pressure (ICP) measuring device, bilateral intracerebral microdialysis catheters, and a microdialysis catheter in the abdominal subcutaneous adipose tissue. Subjects were treated according to an ICP targeted therapy based on the Lund concept. 48 patients, mean age of 35.5 years, and a median GCS 6 (3-8) were included. We found no significant effect of epoprostenol on either the lactate pyruvate ratio (L/P) at 24 hours or the brain glucose levels. There was no significant difference in clinical outcome between the two groups. The median Glasgow Outcome Score (GOS) at 3 months was 4, and mortality was 12.5%. The favourable outcome (GOS 4-5) was 52%. The initial L/P did not prognosticate for outcome. Thus our results indicate that there is no effect of PGI2 at a dose of 0.5 ng/kg/min on brain L/P, brain glucose levels or outcome at 3 months. The treatment seemed to yield a high number of favourable outcome and low mortality

Identifiers
urn:nbn:se:umu:diva-3600 (URN)10.1089/neu.2008.0605 (DOI)19226191 (PubMedID)
Available from: 2008-11-07 Created: 2008-11-07 Last updated: 2010-06-03Bibliographically approved
4. Prostacyclin modulates the systemic inflammatory response in traumatic brain injury: a randomised clinical study
Open this publication in new window or tab >>Prostacyclin modulates the systemic inflammatory response in traumatic brain injury: a randomised clinical study
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(English)In: Article in journal (Other academic) Submitted
Abstract [en]

Purpose:

Systemic inflammatory response is common in patients with severe traumatic brain injury (TBI), and may contribute to a less favourable outcome. The aim was to evaluate the effect of prostacyclin on systemic inflammation.

Methods:

This study is part of a prospective, randomised, clinical trial on the effect of prosta­cyclin (epoprostenol, Flolan®) in patients with severe TBI. Epoprostenol/placebo was given during 72 hours and then de-escalated. Interleukin-6, interleukin-8, soluble intracellular adhesion molecules-1 (sICAM-1) and C-reactive protein (CRP) were sampled daily.

Results:

46 patients were included and randomised to 23 of each group (epopros­tenol/placebo). Interleukin-6 was statistically lower within 96 hours (p = 0.04), and CRP within 96 and 120 hours (p = 0.04 and p = 0.008 respectively) after trauma in the epoprostenol group compared to the placebo group. No significant differences were detected between the groups in the levels of interleukin-8 and sICAM-1 or in outcome.

Conclusions:

Administration of the prostacyclin analogue epoprostenol, compared to placebo significantly decreased interleukin-6 and CRP levels in patients with severe TBI. The beneficial effect of this decrease is further to investigate.

Keyword
traumatic brain injury, prostacyclin, interleukin-6, C-reactive protein, interleukin-8, intracellular adhesion molecules
National Category
Anesthesiology and Intensive Care
Research subject
Anaesthesiology
Identifiers
urn:nbn:se:umu:diva-21054 (URN)
Available from: 2009-04-02 Created: 2009-04-02 Last updated: 2011-04-11
5. Subarachnoid haemorrhage induces a long-lasting increase of asymmetric dimethylarginine, ADMA, in serum
Open this publication in new window or tab >>Subarachnoid haemorrhage induces a long-lasting increase of asymmetric dimethylarginine, ADMA, in serum
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(English)Article in journal (Other academic) Submitted
Abstract [en]

Background and Purpose: Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase (NOS), inhibiting nitric oxide (NO) production and thus induces vasoconstriction and endothelial dysfunction. ADMA might therefore be involved in the cerebral vasospasm and cardiovascular complications observed after subarachnoid haemorrhage (SAH). The aim of this study was to evaluate whether ADMA was increased in subjects during the acute phase (first week) and non-acute phase (three months later) after SAH.

Methods: Prospective clinical study of 20 subjects with SAH. ADMA in serum (ADMA/s) at admission was compared to sex and age matched controls. ADMA/s and ADMA in cerebrospinal fluid (ADMA/csf, from subjects with ventriculostomy) were determined by HPLC-based separation and detection.

Results: There was no significant difference in ADMA/s the day after SAH (day 2) between SAH subjects and controls (0.22±0.10 vs. 0.25±0.12 µmol/L). ADMA/s increased by 68% during the first week after SAH (day 2; 0.22±0.10 vs. day 7; 0.37±0.34 µmol/L, p<0.05) and remained elevated at a three-month follow-up (0.36±0.10 µmol/L). ADMA/csf was significantly lower than ADMA/s throughout the study period.

Conclusion; ADMA/s in SAH subjects increased significantly during the first week after SAH and remained elevated at a three-month follow-up. This might indicate that reduction of the available NO is involved in long-term effects after SAH.

Keyword
asymmetric dimethylarginine
National Category
Anesthesiology and Intensive Care
Research subject
Anaesthesiology
Identifiers
urn:nbn:se:umu:diva-21057 (URN)
Available from: 2009-04-02 Created: 2009-04-02 Last updated: 2010-02-10Bibliographically approved

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