NEJM Article Review

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List of contents

Table of Contents

The extended Glasgow outcome scale (GOSE) 3

Limitations of the GOSE tool 3

Key selection criteria for the trial 4

Blinding in research 4

Blinding 4

Level of blinding used in the study. 4

The potential risk of the approach taken by the investigators 4

Issues around the consenting process this study 4

Potential ethical considerations in planning this study. 5

Benefits and limitations of having a multicenter study. 5

Benefits: 5

Limitations: 5

Bias in Research 5

Bias 5

A potential example of bias in the study design. 5

Role of the steering committee 5

Internal validity 6

Internal validity 6

Things that can improve internal validity in a study. 6

Things that can have a negative impact validity of the study. 6

Specific exclusion criteria listed in the protocol. 6

Why the study recruitment was discontinued. 7

Open-label pragmatic study design. 7

16. Support or not support using therapeutic hypothermia is this 7

My hospital’s capacity to participate in the study. 8

List of abbreviations

GOSE- Extended Glasgow Outcome Scale

TBI- Traumatic Brain Injury

NEJM- The New England Journal of Medicine

The extended Glasgow outcome scale (GOSE)

The Glasgow Outcome Scale (GOSE) is a widely used instrument for assessing global functional disability and recovery outcomes after traumatic brain injury (TBI). It rates patient status into either of the five categories: dead, vegetative state, severe disability, moderate disability, or good recovery. The Extended Glasgow Outcome Scale provides a detailed categorization of the status of patients into eight groups by subdividing the categories based on severity. The lower scores indicate worse functional outcomes, while higher scores indicate better outcomes. The eight categories are: dead, vegetative state, lower severe disability, upper severe disability, lower moderate disability, upper moderate disability, lower good recovery, or upper good recovery, as shown in table 1. Most patients fall into a particular category, while some have outcomes falling on the borderline of categories, hence the need for the extension of this tool. A GOSE questionnaire is used to collect the outcome information, after which it is graded on the scale.

Limitations of the GOSE tool

1. The precision of outcomes is limited in cases that do not fall in a specific category.

2. Lack of patients in some categories could have led to biased results.

Key selection criteria for the trial

1. Patients with head injury experienced ten or fewer days ago.

2. Patients with abnormal brain computed tomographic scan.

3. Accessibility to a cooling technique for more than 48 hours.

4. The core temperature of 36⁰C and above during randomization.

5. Adults having a closed traumatic brain injury.

6. Above 20mmHg intracranial pressure for a minimum of five minutes after the first stage of treatment, without apparent reversible cause.

Blinding in research

Blinding

Blinding is the practice of preventing study participants from knowing information about their assigned treatment, which may alter the results.

Level of blinding used in the study.

The study followed an open-label design, where the patients, their families, and clinicians were informed about the treatments for each study group. Only the primary scoring outcome measure was blinded.

The potential risk of the approach taken by the investigators

Lack of blinding may have led to biased results, such as more severe events in the hypothermia group.

Issues around the consenting process this study

1. The participants were incapacitated and not able to give explicit consent.

2. The participants were assumed to be of the legal consenting age.

3. Inaccuracy of information given by the patient’s representative on the written informed consent.

Potential ethical considerations in planning this study.

1. Decision on what to tell the relatives regarding prognosis

2. Conducting patient education

3. Safety of procedures vs the benefits

4. Physician-assisted suicide in poor prognosis.

Benefits and limitations of having a multicenter study.

Benefits:

1. The study can enrol a large number of patients, which generates larger studies in a short duration.

2. More acceptable results due to their representative nature.

Limitations:

1. Ensuring uniformity in therapy timing is difficult.

2. The dosing of the research medications could vary widely across the centres.

Bias in Research

Bias

Bias skews a process towards a specified outcome when a systematic error is introduced into the sample data.

A potential example of bias in the study design.

The early termination of the trial due to safety concerns led to biased results.

Role of the steering committee

The steering committee conducts regular reviews on trial and assesses the trial’s conduct, development, and safety

Internal validity

Internal validity

Internal validity is the extent to which the outcomes represent the truth in the study population in relation to the treatments.

Things that can improve internal validity in a study.

1. Random selection of the participants to make them representative of the study population.

2. Following a specified study protocol for treatment administration to ensure uniformity.

3. Random assignment of treatments to participants without any systematic bias among the groups.

Things that can have a negative impact validity of the study.

1. Experimental bias involves the researcher behaving differently with different study groups.

2. Participants dropping out of a study, introducing bias in the study results.

3. Diffusion, where one treatment spreads to the control group when participants interact.

Specific exclusion criteria listed in the protocol.

1. Intracranial pressure of 20mm Hg or less.

2. Lack of survival likelihood for the next 24 hours.

3. Patients currently receiving therapeutic hypothermia.

4. Barbiturate infusion administration before randomization.

5. 34^oc or less temperature.

Why the study recruitment was discontinued.

The recruitment was discontinued because of observed signs of harm from the treatment under study. According to Andrews et al. [3], the steering committee examined the expected primary outcome and concluded that the continuation of the trial would result in futility.

Open-label pragmatic study design.

A pragmatic study design is used to assess the effectiveness and safety of a treatment. By combining randomization with real-world evidence, this study design can be used to inform healthcare decisions after measuring treatment outcomes. Open-label pragmatic design is where all the participants in a study are aware of the assigned treatment. In the NEJM study, no blinding was introduced, and the patients, their families, and the participating clinicians were aware of the treatments received in all the groups as seen in Andresen et al. [1].

16. Support or not support using therapeutic hypothermia is this case?

Therapeutic hypothermia is the intentional reduction of a patient’s core temperature to improve neurological recovery. Induced hypothermia provides substantial neuroprotection and reduces secondary cerebral damages after traumatic brain injury. When used to regulate oedema in the brain, therapeutic hypothermia can reduce the elevation of intracranial pressure. There are, however, safety concerns for this treatment. The NEJM study found that therapeutic hypothermia, combined with standard care, aggravated neurological outcomes, increasing the risk of patients’ death. I would therefore not recommend its use in this case. The lack of significant improvement in functional recovery compared to standard care treatment alone shows the ineffective nature of therapeutic hypothermia in treating patients with traumatic brain injury. More research should be conducted on this treatment to establish the most effective levels of hypothermia.

My hospital’s capacity to participate in the study.

I work in a level 1 trauma centre where we receive patients with all kinds of physical trauma. Brain injury traumas are received, though in small numbers. The hospital provides complete care for TBI, including preventing further damage and rehabilitation. In TBI treatment, standard care is normally applied, with ventilation and circulation being the primary concerns. Therapeutic hypothermia for managing patients with TBI has been used for a long time, but the hospital started modernizing the procedure recently.

The efficiency of TH largely depends on factors such as cooling modes, implementation ease, patient tolerance and safety, cooling duration, and monitoring for complications as Dash & Chavali [2] explains. Surface cooling is normally applied in this facility, including convective air blankets, ice packing, and cooling jackets. Surface cooling requires less advanced equipment and expertise. It is, however, slow, and cooling must be combined with paralysis and sedatives to reduce shivering and discomfort. Proliferating temperature control technologies such as intravascular cooling catheters were introduced in this facility a few years ago. Through TH, we can stabilize the blood-brain barrier and reduce cerebral oedema in a number of patients. The efficacy of this procedure has, however, been consistently low.

Therefore, the hospital would not have the capacity to participate in this study since the study requires more advanced endovascular cooling. This level of cooling involves an invasive procedure using catheters coated with antithrombotic factors. This would require high-level specialization due to its extreme sensitivity; we lack the advanced skills required to manage TBI effectively.

References:

1. Andresen M, Gazmuri JT, Marín A, Regueira T, Rovegno M. Therapeutic hypothermia for acute brain injuries. Scandinavian journal of trauma, resuscitation and emergency medicine. 2015 Dec;23(1):1-7. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4456795/

2. Dash HH, Chavali S. Management of traumatic brain injury patients. Korean Journal of anesthesiology. 2018 Feb;71(1):12. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5809702/

3. Andrews PJ, Sinclair HL, Rodriguez A, Harris BA, Battison CG, Rhodes JK, Murray GD. Hypothermia for intracranial hypertension after traumatic brain injury. New England Journal of Medicine. 2015 Dec 17;373(25):2403-12.

Appendix

Table 1: GOSE table