Running head: USE OF MP IN SCI 1

Critical Assessment of the Use of Methylprednisolone in Spinal Cord Injury

Amy Crane and Jordan Polite

Trent University
USE OF MP IN SCI 2

Critical Assessment of the Use of Methylprednisolone in Spinal Cord Injury

Spinal cord injuries (SCI) affect hundreds of thousands of people around the world each

year (WHO, 2013). Devastating neurological impairment often accompanies SCI and thus,

patients likely require long-term care that is both complex and multidisciplinary (Evaniew et al.,

2015). SCI is, therefore, associated with a high degree of burden at both an individual and

societal level. For these reasons, research into SCI has emphasized the importance of identifying

interventions to reduce the negative impact of, and improve recovery from SCI (Evaniew et al.,

2015). Methylprednisolone (MP) was identified in early studies as an intervention to accomplish

this by inhibiting the inflammatory response to SCI, which is thought to be associated with

secondary injury after the initial trauma (Bracken et al., 1990; Evaniew et al., 2015). The purpose

of this paper is to examine the pathophysiology of SCI in detail, as well as the use of MP to treat

SCI. This will involve reviewing the literature to determine the advantages and disadvantages of

MP as a treatment for SCI, and the application of the findings to a case study involving an

individual who has experienced recent SCI.

Pathophysiology of SCI

The pathophysiology of SCI occurs in two phases, commonly known as the initial phase

and the secondary phase (Lewis et al., 2019). The initial phase, or primary injury, involves the

failure of the vertebral column either by fracture, compression, dislocation, or other mechanical

injury (Quadri et al., 2018). The force generated from this injury reaches the spinal cord,

affecting nerve cells, blood vessels, and disrupting cell membranes (Lewis et al., 2019). The

secondary phase, also known as secondary injury, is more complicated as it involves several

cascading events at both the metabolic and cellular levels, which can occur for months after the

initial injury (Lewis et al., 2019).

USE OF MP IN SCI 3

Initial and Secondary SCI Phases

In the initial phase of SCI, the primary injury occurs as a result of mechanical trauma

(Quadri et al., 2018). The same study explains that hemorrhage, edema, and ischemia at the site

of injury occur in the initial phase as early manifestations of SCI. Hemorrhage occurs as local

vasculature is disrupted, and can lead to clot formation. Edema results from an increase in blood-

spinal cord barrier (BSCB) permeability which allows fluid and potentially harmful substances to

enter the confined space of the spinal cord. With hemorrhage and edema occurring in this space,

pressure can increase and lead to ischemia. These mechanisms are ultimately responsible for the

initiation of the secondary phase and they continue to play a role in its progression in the days,

weeks, or months following the initial phase (Quadri et al., 2018).

Secondary injury involves the continuation of these early responses, as well as the

propagation of several other cascades of events at both local and systemic levels (Kwon et al.,

2004). Impacts at the cellular and tissue levels include vascular dysfunction, electrolyte shifts,

neurotransmitter toxicity, apoptosis, and free radical-mediated injury. Systemic impacts can

include spinal and neurogenic shock, and inflammation and immunologic responses. These

responses and cascades of events can result in widespread tissue damage and dysfunction (Kwon

et al., 2004). They are often the focus of treatment, as some of the mechanisms of the secondary

phase can be specifically targeted and their processes inhibited to prevent further activation and

damage (Lewis et al., 2019).

Vascular Dysfunction

Vascular dysfunction, specifically microvascular, is thought to be a key mechanism

involved in the progression of the secondary injury (Kwon et al., 2004). Beginning with the

mechanical injury in the initial phase, the microvasculature is damaged resulting in hemorrhage
USE OF MP IN SCI 4

and subsequent thrombosis. These events in combination with edema and vasospasm at the site

of injury can lead to extensive ischemia and reperfusion. The grey matter is primarily affected,

and due to its high metabolic needs, is highly susceptible to ischemic injury. Reperfusion of

ischemic tissue can be harmful as it can facilitate the formation of reactive oxygen species (ROS)

and reactive nitrogen species (RNS) also known as free radicals (Kwon et al., 2004).

Free Radical-Mediated Injury

The formation of free radicals and subsequent oxidative stress or damage is another key

aspect of SCI and specifically involved in the progression of the secondary injury (Kwon et al.,

2004). ROS and RNS formation results from periods of ischemia and reperfusion. The high

metabolic rate of the CNS, combined with its high level of transition metals, means that free

radicals can be constantly produced (Quadri et al., 2018). A major process that produces free

radicals is lipid peroxidation, in which free radicals attack fatty acids and produce more free

radicals. This continues in a self-propagating process which can eventually spread to healthy

tissue. Free radicals can damage proteins, nucleic acids, lipids, and inhibit the ability of the

sodium-potassium ATPase pump, all of which can be harmful to the healthy tissue surrounding

the site of injury (Quadri et al., 2018).

Neurotransmitter and Electrolyte Abnormalities

In SCI, glutamate is released and accumulates rapidly following the primary injury

(Kwon et al., 2004). The amount of glutamate can reach toxic levels quickly and contribute to

the progression of secondary injury. Glutamate causes an influx of calcium into cells and their

cytoplasmic compartments, which can alter cell metabolism and lead to cell apoptosis. Sodium

abnormalities can also occur from glutamate release, as an influx of sodium into the cells occurs,

and when combined with the inhibition of the sodium-potassium ATPase pump, can result in
USE OF MP IN SCI 5

toxic levels of sodium (Kwon et al., 2004). Other neurotransmitters are also released in SCI such

as norepinephrine, serotonin, and dopamine (Lewis et al., 2019). These substances are vasoactive

and at high levels can lead to vasospasms and ischemia, resulting in tissue damage or necrosis

(Lewis et al., 2019).

Inflammation and Immune System Response

The inflammatory and immunologic response to SCI also contributes to the progression

of secondary injury (Kwon et al., 2004). Kwon et al. (2004) elaborates that neutrophils are the

first cells to reach the site of injury, followed by macrophages and local microglia to phagocytize

damaged tissue. These cells release cytokines such as tumor necrosis factor (TNF) and

interleukins which induce COX 2 expression. This leads to the release of proinflammatory

mediators, such as prostaglandins and thromboxanes, increasing vascular permeability,

vasoconstriction, and platelet aggregation, each of which can potentiate the tissue damage

associated with SCI (Kwon et al., 2004).

Spinal and Neurogenic Shock

Spinal shock is another potential response to SCI and it involves a disruption in reflexes

and function below the site of injury (Lewis et al., 2019). The manifestations of this temporary

syndrome usually involve a loss of sensation, muscle tone, and the ability to control temperature

below the site of injury (Quadri et al., 2018). Neurogenic shock differs from spinal shock as it

results from injury at the fifth thoracic (T5) vertebrae or higher (Lewis et al., 2019). Injury to this

region of the spinal cord leads to the loss of sympathetic nervous system vasoconstrictor tone,

resulting in massive vasodilation and a loss of compensatory ability (Lewis et al., 2019).

Pharmacology of Methylprednisolone
USE OF MP IN SCI 6

SCI is a debilitating and life-altering injury, demanding research of potential

pharmacological treatments (Kwon et al., 2004). After the discovery of pathophysiology and

mechanisms of secondary damage, neuroprotective interventions have been the target of this

research. These interventions are aimed at minimizing secondary injury with SCI and protecting

the remaining functional aspects. High-dose corticosteroid therapy, specifically with MP, has

been explored extensively in the literature for use in SCI (Kwon et al., 2004).

Mechanism

When administered at high doses, glucocorticoids have effects on metabolism and

electrolytes, as well as the inflammatory and immune response (Lehne, Rosenthal, & Burchum,

2013). These effects include increased glucose levels, suppression of protein synthesis, chemical

mediator inhibition, and the accumulation of both phagocytes and lymphocytes (Lehne et al.,

2013). MP, specifically, is proposed to target the underlying pathophysiology of SCI (Kwon et

al., 2004). Kwon et al. (2014) suggest that the key mechanisms of MP are “inhibition of lipid

peroxidation and inflammatory cytokines, modulation of the inflammatory/immune cells,

improved vascular perfusion and prevention of calcium influx and accumulation” (p. 458).

Inhibition of lipid peroxidation has been highlighted as the most important mechanism

for neuroprotection as it has been found to have multiple neurotoxic effects that contribute to

secondary injury (Kwon et al., 2004). Bracken et al. (1990) and Bracken et al. (1997) explore

this further by explaining the effect of lipid peroxidation on neuronal and microvascular

membranes. Lipid peroxidation and hydrolysis break down these membranes, therefore,

inhibiting these processes will maintain the structure of these membranes (Bracken et al., 1990;

Bracken et al., 1997). Kwon et al. (2004) discuss other neurotoxic effects of lipid peroxidation

including metabolic collapse and cell death, both of which would be targeted by inhibition of
USE OF MP IN SCI 7

lipid peroxidation. Additionally, other potential benefits resulting from inhibition of lipid

peroxidation include improved blood flow to site of injury secondary to reduced vasoreactive

byproducts from arachidonic acid metabolism (Kwon et al., 2004).

MP has other mechanisms which are presumed to play less of a contributing role for

neuroprotection (Kwon et al., 2004). These mechanisms include inhibition of inflammatory

cytokines and modulation of the inflammatory/immune cells, improved vascular perfusion, and

prevention of calcium influx and accumulation. Inhibition of inflammatory cytokines and other

inflammatory/immune cells will prevent these cells from taking effect at the action site, which

has been shown to have both neurotoxic and neuroprotective effects. Vascular perfusion is often

impaired in SCI leading to ischemia, which plays a key role in secondary injury. Ischemia can

lead to free radical formation followed by the aforementioned neurotoxic effects of lipid

peroxidation. Improved vascular perfusion would presumably inhibit the progression of these

mechanisms. Calcium influx and accumulation also plays a key role in secondary injury through

the dysregulation of oxidative phosphorylation. MP induced prevention of calcium accumulation

can prevent this alteration and thus, the apoptotic death that follows (Kwon et al., 2004).

Therapeutic Role

The key anticipated outcomes of MP was improved neurological function, specifically

sensory and motor improvement (Bracken et al., 1990). In the second national acute SCI study

(NASCIS), Bracken et al. (1990) explore general improvements on quality of life in dimensions

such as locomotor recovery and self-care, but draw no specific conclusions on functional

improvement. In NASCIS III, Bracken et al., (1997) further explore the role of motor and

sensory function improvement on functional independence, using the Functional Independence

Measure (FIM). This study showed improvements within various aspects of the FIM including
USE OF MP IN SCI 8

self-care, sphincter control, mobility, and overall score of function. These aspects, even with

small improvements, can greatly influence an individual’s quality of life (Bracken et al., 1997)

Risks

Although there are many proposed benefits with the use of MP, there are extensive risks

that must be carefully considered (Kwon et al., 2004). In the NASCIS II, Bracken et al. (1990)

make reference to findings from the NASCIS I such as increased rates of infection at the trauma

site and surgical wounds. This finding was confirmed in their study with “more patients treated

with MP [having] wound infections” (Bracken et al., 1990, p. 1409). Their study also showed

increased rates of gastrointestinal (GI) bleeding (Bracken et al., 1990). With glucocorticoids, the

mechanism of prostaglandin inhibition increases this risk of bleeding (Lehne et al., 2013). The

NASCIS III showed higher rates of severe sepsis and severe pneumonia with the increased

duration of MP treatment (Bracken et al., 1997). Kwon et al. (2004) acknowledge the risks

within these studies and make reference to additional adverse effects including increased rates of

pulmonary embolism and death secondary to respiratory complications. Evaniew and Dvorak

(2016) support these findings, linking the use of MP to sepsis, infections, GI bleeding, and death.

Review of the Literature

Introduction

Early studies exploring the efficacy of MP for the treatment of SCI indicated that there

were clinical benefits to its use (Rogers & Todd, 2016). The majority of the clinical evidence to

support the use of MP for SCI has come from two studies: NASCIS II and III, and subgroup

analyses of them. Recent studies however, have highlighted flaws in the designs and results. The

use of steroids for SCI has since become a source of controversy and debate (Rogers & Todd,

2016).
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Data Supporting the Use of MP for SCI

The NASCIS II was an early, highly publicized study that explored the use of MP for the

treatment of SCI (Bracken et al., 1990). In this study, patients presenting with SCI received an

initial dose, followed by a 23-hour maintenance infusion of MP and were then assessed for

neurologic function at six weeks and six months after treatment (Bracken et al., 1990). The

results of this study indicated that MP could improve sensation and motor function in patients

with SCI, but only if the treatment began within eight hours of the injury. The NASCIS III is

another highly publicized study that was published soon after the NASCIS II (Bracken et al.,

1997). One aim of this study was to explore the effects of high doses of MP on SCI, continuing

the work of the NASCIS II (Bracken et al., 1997). Patients would receive an initial dose of MP,

followed by a maintenance infusion lasting 24 or 48 hours, and would then be assessed at six

weeks and six months after treatment (Bracken et al., 1997). The results of this study indicated

that high doses of MP received within three to eight hours of SCI and continuing for 48 hours

after the initial dose would produce a significant improvement in motor function (Bracken et al.,

1997). These results however, have generated controversy as subgroup analyses of the NASCIS

II and III have highlighted flaws in the methods and designs (Evaniew et al., 2015).

Data Against the Use of MP for SCI

Since the NASCIS II and III were published, there has been an increasing body of

literature opposing the use of MP to treat SCI. Evaniew et al. (2015) explored the effects of a

treatment regimen of MP that was consistent with the regimen used by the NASCIS II. This

cohort study used patient data that was collected by the Rick Hansen SCI Registry (RHSCIR), a

large multi-site study with various sites across Canada (Evaniew et al., 2015). The results of this

study indicated that an MP regimen consistent with the one used in the NASCIS II did not
USE OF MP IN SCI 10

significantly improve motor function in comparison with treatment that did not include steroids.

The MP group in this study also had a higher rate of total complications than the no steroid

group. Ultimately, the findings of this study support recommendations to avoid and decrease the

utilization of MP for the treatment of SCI (Evaniew et al., 2015).

Hurlbert et al. (2013) conducted a review of the literature on the use of MP for SCI and

analyzed several articles that supported its use. Studies that were analyzed in this review include

the highly publicized NASCIS II and III (Hurlbert et al., 2013). The authors explain that the

evidence generated by both the NASCIS II and III, was weakened by the lack of functional

outcome measurements, the arbitrary nature of the 8-hour window within which the MP

treatment could be started, and the inconsistency of reported benefit. Hurlbert et al. (2013) also

highlighted the higher rate of complications that were associated with MP treatment in the

NASCIS II and III. This included a higher rate of infection, GI bleed, and pulmonary embolus in

the NASCIS II and an increased chance to develop severe pneumonia and sepsis in the NASCIS

III. Hurlbert et al. (2013) explains that this data was not adequately presented by the authors of

these trials and only through subsequent analyses was the data clearly articulated. The evidence

generated by the NASCIS II and III, two fundamental studies supporting the use of MP for SCI,

is neither consistent nor compelling enough to support its use in practice (Hurlbert et al., 2013).

Manifestations of SCI in Dan

Upon Dan’s admission to the emergency room, SCI was probable due to the mechanism

of injury and the associated signs and symptoms (Lewis et al., 2014). SCIs present with various

clinical manifestations due to the underlying pathophysiology. Clinical manifestations result

from cord compression related to the initial trauma and can additionally be associated with

responses to this original injury. Symptoms and degree of paralysis are dependent upon the
USE OF MP IN SCI 11

location of injury (Lewis et al., 2014). Magnetic resonance imaging in Dan confirmed a

compression fracture at the 5th cervical vertebrae (C5).

SCIs present with systemic manifestations including impaired motor and sensory function

as well as impacts on the respiratory, cardiovascular, urinary, and GI systems (Lewis et al.,

2014). SCIs at C5 result in tetraplegia, or paralysis of all extremities, with partial movement

remaining in the shoulders and biceps as well as gross elbow movements (Lewis et al., 2014).

These symptoms are reflected in Dan’s lack of movement, lack of sensation, limited gross arm

movements, and sensation remaining in his shoulders and upper arms.

In the respiratory system, the phrenic nerve is important for respiratory function (Lewis et

al., 2014). Although this nerve is spared in C5 injuries, associated spinal edema and hemorrhage

resulting from SCI can cause respiratory insufficiency (Lewis et al., 2014). Respiratory function

is also affected due to paralysis of the intercostal muscles, which are important in facilitating

respirations (Lewis et al., 2014). This impairment in the intercostal muscles can lead to

diaphragmatic breathing, consisting of diaphragm contraction and abdominal distension during

inhalation (Lewis et al., 2014). These symptoms are reflected in Dan’s breathing patterns,

consisting of decreased chest expansion and increased abdominal distension. This decreased

chest expansion results in less air inhalation and impaired gas exchange (Lewis et al., 2014). This

impaired gas exchange is manifested in Dan’s decreased oxygen saturation of 86% on room air.

This decreased oxygen saturation causes increased respiratory rate as a compensatory

mechanism in an attempt to inhale more oxygen, resulting in Dan’s rate of 28 respirations per

minute (Lewis et al., 2014).

In terms of cardiovascular function, cervical spine injuries cause decreased sympathetic

nervous system influence (Lewis et al., 2014). This decreased influence results in hypotension
USE OF MP IN SCI 12

secondary to peripheral vasodilation as well as bradycardia (Lewis et al., 2014). These symptoms

are reflected in Dan’s blood pressure of 80/48 mm Hg and his heart rate of 52 bpm. This

hypotension can also be attributed to neurogenic shock induced vasodilation (Lewis et al., 2014).

Additionally, the urinary and GI system are affected in SCI. Bladder dysfunction occurs

with various characteristics in SCI (Lewis et al., 2014). In Dan, this bladder dysfunction presents

as urinary incontinence. GI system function is affected primarily through hypomotility which can

progress to paralytic ileus (Lewis et al., 2014). These symptoms are reflected in Dan with the

absence of bowel sounds.

Many of the clinical manifestations presenting in Dan can be attributed to the temporary

neurological syndrome of spinal shock (Lewis et al., 2014). Spinal shock is characterized by

“decreased reflexes, loss of sensation, and flaccid paralysis” (p. 1771), all of which Dan is

experiencing (Lewis et al., 2014). The integumentary system is affected in spinal shock

manifesting as Dan’s cool extremities, which are a result of poikilothermism or the inability to

control temperature below the injury site (Lewis et al., 2014).

The return of reflexes occurs after spinal shock resolves and can contribute to autonomic

dysreflexia (Lewis et al., 2014). Autonomic dysreflexia is a life-threatening reaction mediated by

the sympathetic nervous system. This response occurs with visceral stimulation after resolution

of spinal shock (Lewis et al., 2014). Manifestations that Dan is presenting with include severe

hypertension (287/126) and throbbing headache. The dizziness that Dan is experiencing may be

attributed to the common symptom of blurred vision (Lewis et al., 2014).

Priority Concerns and Interventions with Methylprednisolone Use in Dan

The priority concerns around the use of MP in Dan correlate with the definite associated

risks, as found in the literature. Dan is at an increased risk of infection with potential progression
USE OF MP IN SCI 13

to sepsis, GI bleeding, and respiratory complications (Kwon et al., 2004; Evaniew & Dvorak,

2016). Nursing roles with the use of MP include prevention of these complications, continuous

patient monitoring, and interventions if indicated.

There is an increased risk of infection and subsequently septic shock in patients receiving

MP due to the immunosuppression with corticosteroid treatment (Lehne et al., 2013; Lewis et al.,

2014). In addition to being immunocompromised, Dan is at an increased risk of infection due to

invasive procedures (catheter insertion and intravenous therapy), potential skin breakdown

secondary to immobility, and lack of adequate oxygenation. Healthcare providers should be

implementing precautions to prevent introducing any infection to Dan. Standard precautions such

as hand hygiene and proper personal protective equipment should be strictly adhered to in order

to prevent the introduction of infectious agents. Reducing Dan’s risk factors for infection include

preventing skin breakdown with frequent repositioning and pressure relieving surfaces. Oxygen

therapy should be considered with inadequate O2 saturation. Monitoring for manifestations of

inflammation and infection allows for early recognition and treatment if indicated. Classic

manifestations such as fever may be masked in Dan due to MP induced immunosuppression,

older age, and poikilothermism (Lewis et al., 2014).

There is an increased risk of GI bleeding, often occurring secondary to bleeding ulcers in

patients receiving high-dose corticosteroids such as MP (Lehne et al., 2013). Patients who have

sustained severe trauma are at an increased risk for physiological stress ulcers (Lewis et al.,

2014). Dan is at an increased risk of stress ulcers due to his SCI, physiological stress, and the use

of MP. Prophylactic medications such as H2-receptor blockers or proton pump inhibitors can be

considered to decrease hydrochloric acid secretion (Lewis et al., 2014). Dan was recently

exhibiting signs of bleeding such as dizziness and rapid, shallow respirations. If GI bleeding is
USE OF MP IN SCI 14

suspected, laboratory or diagnostic studies should be done in order to assess for the presence of

bleeding and conduct timely interventions (Lewis et al., 2014).

MP has been associated with higher rates of respiratory complications such as pulmonary

embolism, pneumonia, and death (Kwon et al., 2004). Pulmonary embolism can result from

venous thromboembolism (VTE), which are seen in the highest rate among patients with SCIs

(Lewis et al., 2014). Dan should be monitored for signs of pulmonary embolism, however,

symptoms are generally vague. Manifestations of pulmonary embolism, such as Dan’s

presentation of dyspnea and hypoxemia, may be indications to conduct diagnostic studies.

Monitoring for these manifestations allows for proper interventions to be undertaken if indicated.

With the use of MP, anticoagulant medications for VTE prophylaxis should be considered

(Lewis et al., 2014). Additionally, the use of MP places Dan at an increased risk for pneumonia

(Lewis et al., 2014). Dan should be monitored for manifestations of pneumonia for early

detection and treatment if indicated. Both of these respiratory complications can get

progressively worse, and could lead to death (Kwon et al., 2004).

Conclusion

SCI begins with the primary injury, consisting of the direct trauma to the spinal cord

(Lewis et al., 2014). Following this phase, secondary injury occurs through processes such as

vascular dysfunction, free radical-mediated injury, neurotransmitter and electrolyte

abnormalities, and inflammation/immune responses (Lewis et al., 2014). Many potential

pharmacological treatments, such as MP, attempt to target this secondary injury (Kwon et al.,

2004). MP is proposed to protect against further nerve injury through lipid peroxidation and

inflammatory cytokine inhibition, inflammatory and immune cell modification, improved

vascular perfusion, and inhibition of calcium accumulation (Kwon et al., 2004). The widespread
USE OF MP IN SCI 15

use of MP in the treatment of SCI is primarily supported by clinical evidence that arose within

the second and third National Acute SCI Studies (NASCIS II-III) (Kwon et al., 2004; Falavigna

et al., 2018). Subsequent research on the use of MP in SCI had led to controversy on this topic.

Much of the recent literature does not recommend the use of MP due to the evidenced risk of

complications but lack of clinical efficacy (Falavigna et al., 2018). With the clinical

manifestations that Dan is presenting with, there is concern for the occurrence of these

complications.

Based on the analyzed clinical data, the use of MP was not justified in Dan. Although

many surgeons choose MP treatment based on the presumed benefits, other reasons include fear

of legal action and presence of a hospital protocol at specific facilities (Falavigna et al., 2018).

This often leads to lack of critical analysis or awareness of the limitations to the NASCIS studies

and subsequent use of MP (Falavigna et al., 2018). The benefits of MP are still debated,

however, the risks are strongly supported by the literature. MP increases the risk of infection and

septic shock, GI bleeding, and respiratory complications - all of which can progress to death. As

mentioned, Dan is already at risk for these complications with SCI. Additionally, it is probable

that Dan is experiencing spinal shock in response to his SCI (Lewis et al., 2014). Spinal shock is

known to potentially mask neurological function post injury, making it hard to determine Dan's

motor and sensory function at the time MP was administered (Lewis et al., 2014). This impedes

the ability to make an informed decision regarding the potential benefits resulting from MP over

the definite associated risks.

USE OF MP IN SCI 16

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