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Cochrane Database of Systematic Reviews Protocol - Intervention

The Lund concept for severe traumatic brain injury

Authors' declarations of interest

Version published: 14 November 2012 Version history

https://doi.org/10.1002/14651858.CD010193

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view the current version 16 December 2013
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Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To assess the role of the Lund concept versus other treatment modalities such as intracranial pressure (ICP) targeted therapy, cerebral perfusion pressure (CPP) targeted therapy or other possible treatment strategies in the management of severe traumatic brain injury.

Background

Description of the condition

Severe traumatic brain injury is a significant cause of morbidity and mortality. The general incidence of traumatic brain injury in developed countries is estimated to be 200 per 100,000 population at risk per year (Bruns 2003). Historically, the Glasgow Coma Scale (Teasdale 1974) has been most widely used for the classification of traumatic brain injury severity. Patients with an admission Glasgow Coma Score of between three and eight are considered to have severe traumatic brain injury, and about 10% to 15% of all patients with head injuries are classified as such (Bruns 2003).

In past decades, it has been recognised that much of the neuronal damage following severe head injury does not occur instantaneously, but rather evolves over several hours and days after the impact (Chesnut 1993). A distinction is made between primary injury, which occurs as a direct result of the trauma, and secondary injury that develops over hours to days after the initial traumatic insult. Secondary injury is of particular importance because the process of its development is open to therapeutic interventions. Therefore, critical care management of such patients is extremely important.

Cerebral ischaemia is the most important consequence of secondary brain injury. The central pathophysiological problem in its development is disturbance in post‐traumatic cerebral blood flow caused by increased intracranial pressure (ICP) and the formation of brain oedema.

The traditional approach in the prevention of secondary brain injury is intracranial pressure (ICP) targeted therapy, characterised by the use of head elevation, sedation, active treatment of systemic hypertension, neuromuscular blockade, cerebrospinal fluid (CSF) drainage usually by external ventriculostomy, osmotherapy and induction of a barbiturate coma to reduce and control intracranial pressure (Miller 1993).

A similar approach, called cerebral perfusion pressure (CPP) targeted therapy, emphasises the role of CPP, a difference between mean arterial pressure (MAP) and ICP. It differs from the previously described model in terms of the flat head position, avoidance of sedation, hyperventilation and barbiturate coma, but similarly advocates the use of osmotherapy, CSF drainage and neuromuscular blockade (Rosner 1995) (Table 1).

Description of the intervention

In contrast to the previously described 'traditional' therapeutic approaches, the Lund concept emphasises a reduction in microvascular pressures to minimise cerebral oedema formation. Cerebral oedema occurs due to leakage of large molecules such as albumins from blood vessels through the damaged blood brain barrier. Water flows into the brain after the albumins by osmosis. This vasogenic oedema causes compression of and damage to brain tissue. The goals of the Lund concept approach are to preserve a normal colloid osmotic pressure (by infusion of the albumin and correction of anaemia), to reduce capillary hydrostatic pressure (by medical control of the blood pressure) and to reduce cerebral blood volume by vasoconstriction (Eker 1998). This is achieved by a flat head position, sedation, strict control of systemic hypertension (usually with metoprolol and clonidine) and avoidance of the neuromuscular blockade, hyperventilation, osmotherapy and barbiturate coma, i.e. all treatments that would favour the increased transcapillary filtration of the plasma (Grande 1997) (Table 1).

How the intervention might work

Maintenance of a normal colloid osmotic pressure retains intracapillary water content, and thereby reduces transudation and interstitial oedema formation. Keeping the MAP within a low normal range, and consequently maintaining the low capillary hydrostatic pressure, facilitates this effect. To enforce this concept, it is vital not to perform any procedure that counteracts the principles stated above. An efficient reduction in brain oedema formation improves cerebral blood flow and reduces the frequency, duration and magnitude of ischaemic episodes, as well as secondary brain injury sequelae. Consequently, this may lead to a more favourable management outcome, i.e. reduced mortality and long‐term disability in such patients.

Management approach

Treatment

ICP targeted therapy

CPP targeted therapy

Lund concept

Head position

Elevation 15 to 30 degrees

Flat

Flat

Sedation

Morphine + lorazepam

None

Low‐dose thiopental

Treatment of systemic hypertension

Treat systolic blood pressure > 160 mm Hg using labetalol

No

Metoprolol + clonidine

Nutritional support

Yes, avoid hyperglycaemia

No

Yes, avoid hyperglycaemia

Neuromuscular blockade

Yes

Yes

No

CSF drainage

Yes

Yes

No

Osmotherapy

Yes

Yes

No

Barbiturate coma

Yes

No

No

Table 1. Management approaches in patients with traumatic brain injury (Eker 1998; Grande 1997; Miller 1993; Rosner 1995)

Why it is important to do this review

Despite the growing body of evidence in the research of traumatic brain injury, not all aspects of secondary brain injury are completely understood. Accordingly, the concepts supporting injury treatment differ, with ICP and CPP‐based therapies currently being the preferred treatment choices. However, the Lund concept offers an interesting theoretical background, which is confirmed in practice by some studies (Eker 1998). There is evidently a need to systematically evaluate this protocol and to compare it to the more established ones. If proved to be more efficient or at least equal to the other treatments, the Lund concept should be more frequently applied in the management of patients suffering severe traumatic brain injury. Therefore, the aim of this review is to point out the possible advantages as well as the limitations of the Lund concept in comparison to existing strategies.

Objectives

To assess the role of the Lund concept versus other treatment modalities such as intracranial pressure (ICP) targeted therapy, cerebral perfusion pressure (CPP) targeted therapy or other possible treatment strategies in the management of severe traumatic brain injury.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs, Level 1 evidence) exploring the efficacy of the Lund concept in the treatment of severe traumatic brain injury. Studies will be included irrespective of publication status, language or date.

Types of participants

Patients, irrespective of gender, age or race sustaining severe traumatic brain injury.

Types of interventions

We will include studies where at least one of the arms in the trial was treated by an intervention described as the Lund concept or modified Lund concept.

We will be looking for the following comparisons:

  • Lund concept versus ICP targeted therapy;

  • Lund concept versus CPP targeted therapy;

  • Lund concept versus any other possible treatment or combination of treatments.

Types of outcome measures

Primary outcomes

  • Mortality rate

Secondary outcomes

  • Treatment outcome, as expressed by the Glasgow Outcome Scale (GOS) or Extended Glasgow Outcome Scale (GOSE)

  • Treatment complications

Search methods for identification of studies

We will not restrict the search for trials by language, date or publication status.

Electronic searches

We will search the following electronic databases:

  • Cochrane Injuries Group Specialised Register (all years to present);

  • Cochrane Central Register of Controlled Trials (The Cochrane Library) (latest issue);

  • MEDLINE (Ovid) (1950 to present);

  • EMBASE (Ovid) (1980 to present);

  • CINAHL (1980 to present);

  • ISI Web of Science: Science Citation Index Expanded (SCI‐EXPANDED) (1970 to present);

  • ISI Web of Science: Conference Proceedings Citation Index ‐ Science (CPCI‐S) (1990 to present).

We will base the electronic database searches on the strategy below, which was formulated in MEDLINE and will be adapted as necessary for use in each of the other databases:

MEDLINE (Ovid) 1994 to May Week 1 2012

1. exp Brain Ischemia/
2. exp Intracranial Pressure/
3. exp Cerebrovascular Circulation/
4. exp Brain Edema/
5. exp Intracranial Hypertension/
6. exp Craniocerebral Trauma/
7. exp Brain Injuries/
8. exp Decompression, Surgical/
9. exp Monitoring, Physiologic/
10. ((Intracranial or Cerebr* or brain) adj3 Hypertens*).ab,ti.
11. (brain adj3 (isch?emia or pressure or perfusion or oedema or edema or injur* or trauma* or ICP or CCP)).ab,ti.
12. (cerebral adj3 (isch?emia or pressure or perfusion or oedema or edema or injur* or trauma* or ICP or CCP)).ab,ti.
13. or/1‐12
14. lund.mp.
15. 13 and 14
16. randomi?ed.ab,ti.
17. randomized controlled trial.pt.
18. controlled clinical trial.pt.
19. placebo.ab.
20. clinical trials as topic.sh.
21. randomly.ab.
22. trial.ti.
23. 16 or 17 or 18 or 19 or 20 or 21 or 22
24. (animals not (humans and animals)).sh.
25. 23 not 24
26. (rat or rats or rodent* or mouse or mice or murine or dog or dogs or canine* or cat or cats or feline* or rabbit or rabbits or pig or pigs or porcine or swine or sheep or ovine* or guinea pig*).ti.
27. 25 not 26
28. 15 and 27

Searching other resources

We will search the reference lists of relevant studies and published reviews found with our search. We will contact experts in the field in order to identify any published or unpublished work not found with our electronic search. We will use the Google search engine to find online information relevant to this systematic review and we will search the following online trials registers:

Data collection and analysis

The Trials Search Co‐ordinator of the Cochrane Injuries Group will run the searches, collate the results and remove any duplicates before transferring the records to the authors for screening.

Selection of studies

Two members of the review team will independently select papers and make decisions about eligibility, based on the analysis of the title, abstract or MeSH terms. All disagreements will be resolved by discussion and consensus. We will consult a statistician in case of doubt about study inclusion or data extraction. If necessary, we will contact the authors of the original papers to get additional data or to clarify dubious issues in order to perform the systematic review. We will also translate studies published in languages other than English.

Data extraction and management

We will contact authors for clarification and further data if trial reports are unclear, and we will arrange translations of papers where necessary. We will extract the relevant data from the selected studies and record it in customised forms. Two members of the review team will perform the extraction, after determining the study eligibility. We will contact authors of the original article, if necessary.

We will extract the following data:

  • study design, setting and duration;

  • participants;

  • sample size;

  • inclusion and exclusion criteria;

  • details of the experimental intervention (protocol);

  • details of the control intervention;

  • outcome (the effect of treatment, described by GOS or GOSE);

  • presence of ethical approval;

  • funding sources;

  • conclusions as reported by the authors.

Assessment of risk of bias in included studies

Assessment of the risk of bias of the included trials will be undertaken independently by Dario Muzevic and Bruno Splavski with the following taken into consideration, as guided by the Cochrane Handbook for Systematic Reviews of Interventions (Handbook 2011):

  • sequence generation;

  • allocation concealment;

  • blinding;

  • incomplete outcome data;

  • selective outcome reporting; and

  • other sources of bias.

We will use the Cochrane ‘Risk of bias’ tool in the Review Manager software (version 5.1) (RevMan 2011), which involves describing each of these domains as reported in the trial and then assigning a judgement about the adequacy of each entry: 'low', 'high' or 'unclear' risk of bias. 

Measures of treatment effect

We will analyse data using Review Manager. We will analyse dichotomous data using risk ratio (95% confidence interval) and continuous outcomes by calculating means and standard deviations. We will either pool scores as continuous variables using weighted means or standardised means.

If the selection process identifies up to three studies, we will perform an additional analysis. We will contact the authors of the relevant studies to obtain data files. According to the method described by Hukkelhoven et al (Hukkelhoven 2005), we will calculate the likelihood of death and unfavourable outcome for each patient. For all groups of patients compared, we will calculate and compare observed versus expected ratios for death and unfavourable outcome.

Unit of analysis issues

The unit of analysis will be the individual patient.

Dealing with missing data

Missing summary data will not be a reason to exclude study from the review. If necessary, we will contact the authors of the original papers for more information on missing data.

Assessment of heterogeneity

We will test all included studies for clinical homogeneity. For studies considered as clinically homogeneous, we will test the statistical heterogeneity using the Chi2 test and I2 statistic. We will assume statistical significance of the Chi2 test if P < 0.10. We will consider an I2 value greater than 50% to be substantial.

Assessment of reporting biases

Aside from within‐study biases tested as described in the Assessment of risk of bias in included studies section, we will assess between‐study biases by comparing outcomes as stated in protocols to those reported or, where protocols are not available, by comparing outcomes listed in the methods section to those reported in the results section.

Data synthesis

We will use Review Manager to perform meta‐analysis if we identify at least three studies with comparable outcomes. We will use a fixed‐effect model for dichotomous data.

Subgroup analysis and investigation of heterogeneity

If feasible, we will separately analyse patients suffering isolated severe traumatic brain injury, in contrast to poly‐trauma patients.

Sensitivity analysis

If necessary, we will use allocation concealment (done versus not done/unclear) in sensitivity analysis.