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ACUTE MANAGEMENT OF THE
BRAIN INJURY PATIENT
The Agony of Defeat. . . . . . . . . . . . . . . . . . . . . . . . . . . . Level III
Dennis Parker, Jr, PharmD
CASE SUMMARY
A 55-year-old unresponsive man is brought to the ED after a skiing
accident. Physical examination reveals facial lacerations and respiratory distress, and a head CT shows evidence of epidural hematomas. The patient is ultimately transferred to the neurointensive care
unit for monitoring after ventriculostomy placement for monitoring of intracranial pressure (ICP). The patient requires appropriate
fluid resuscitation and management of increased ICP. The comprehensive pharmaceutical care plan must also include measures
to prevent the medical complications of hyperglycemia, seizures,
protein breakdown and resultant malnutrition, stress ulceration,
electrolyte abnormalities, and venous thromboembolism. Close
monitoring of the patient is required because of the multiplicity of
medical complications that may occur.
QUESTIONS
Problem Identification
1.a.Could any of the patient’s prehospital medications have
contributed to the extent of the brain injury?
• Intracranial bleeding following fall while on clopidogrel plus
aspirin.1
✓As the population ages, it is becoming increasingly common to encounter older patients with traumatic brain injury
(TBI). With aging comes chronic disease problems, such as
cardiovascular disease (CVD), that often necessitate the use
of antithrombotic therapy. Additionally, patients with CVD
are encouraged to lead active lifestyles, which might also
increase the risk of accidents such as falls.
✓Clopidogrel inhibits platelet aggregation through antagonism of the adenosine diphosphate receptor, preventing
glycoprotein IIb/IIIa activation. It also reduces collagen- and
thrombin-induced platelet activation.
✓Clopidogrel reaches maximum effect (40–60% platelet inhibition) after 7 days, and it takes an estimated 5 days for
platelet aggregation and bleeding to normalize after drug
discontinuation due to the presence of an active metabolite.
✓Aspirin inhibits cyclooxygenase-1 (COX-1) in platelets,
which prevents the conversion of arachidonic acid to prostaglandin G2 and subsequently thromboxane A2.
✓The duration of action of aspirin is 36 hours after the last
dose; however, aspirin irreversibly inhibits COX-1 so aspirin
can prolong bleeding times for 5 days after drug discontinuation (until there is a 20% increase in new circulating
platelets).
• Corneal reflexes, pupillary response to light, and eye movement abnormalities are important parameters to evaluate
brainstem involvement. This patient had one dilated pupil and
pupils that were nonreactive to light bilaterally. This indicates
possible brainstem involvement of his injury.
• Arterial blood gases indicate poor oxygenation necessitating
intubation of the patient.
• The Glasgow Coma Score (GCS) was first published in 1974
and has been widely used to describe level of consciousness. It
is based on eye opening, motor response, and verbal response.
The GCS ranges from 3 to 15, with 15 corresponding to a
normal neurologic examination. The severity of TBI is classified based upon the GCS, and the GCS (particularly the
motor score) is a strong predictor of outcome. GCS scores
of 3–8, 9–12, and 13–15 correspond to severe, moderate, and
mild TBI, respectively. This patient has a GCS of 5 and would
be classified as a severe TBI. The change in GCS may also be
prognostic, with deterioration in GCS predicting the need for
urgent intervention.
1.c. What patient factors may complicate assessment of the neurologic examination?
• The timing of GCS assessment determines the scores obtained.
Hypotension and pharmacological sedation or paralysis all
reduce the GCS, although this may not be taken into account
by observers.
• The administration of sedatives and neuromuscular blocking
agents may affect the neurologic examination; assessment
of their administration times in relation to the timing of the
examination must be considered. The patient was started on
a midazolam infusion upon arrival to the ED. When given as
a single dose, midazolam has a rapid onset and short duration
of action. However, accumulation and prolonged sedative
effects have been reported in critically ill patients receiving
midazolam who are obese or have a low serum albumin or
renal failure. This prolonged effect likely results from the accumulation of an active metabolite, α-hydroxymidazolam, or its
conjugated salt, especially in patients with renal insufficiency.
Additionally, significant inhibition of midazolam metabolism
has been reported with hypothermia, propofol, macrolide antibiotics, and other inhibitors of cytochrome P450 isoenzyme
3A4, which could influence the duration of effect.
• The initial neurologic examination may be affected by the
preadmission use of alcohol and drugs. While this patient
had a negative alcohol level and urine drug screen, a recent
study found that 25% of all trauma patients had an alcohol
level exceeding 50 mg/dL, and one or more drugs were found
in one in five patients (Rundhaug et al., J Neurosurg, 2015).
Therefore, it is essential to consider this during the initial
assessment.
1.d. What poor prognostic indicators does this patient exhibit?
• The Brain Trauma Foundation (BTF) (www.braintrauma.org)
published a list of early prognostic indicators that predict outcome from brain injury. Five parameters have been identified,
Copyright © 2017 by McGraw-Hill Education. All rights reserved.
Acute Management of the Brain Injury Patient
Denise H. Rhoney, PharmD, FCCP, FCCM, FNCS
1.b. What information (signs, symptoms, and laboratory values)
indicates the severity of this patient’s brain injury?
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✓Literature suggests that prehospital use of antiplatelet agents
is associated with increased morbidity (eg, increased resource
utilization, increase in disposition to long-term care facility)
and potentially increased mortality. For instance, clopidogrel
use prior to TBI is associated with a 14.7-fold increase in
mortality (Wong DK et al., J Trauma, 2008).
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SECTION 6
including GCS, age, pupillary diameter and light reflex, hypotension, and CT scan features. This patient displays five of
these predictors.
✓If the initial GCS is obtained reliably, then there is an
increasing probability of poor outcome with a decreasing
GCS in a continuous and stepwise manner.
Neurologic Disorders
✓Bilaterally absent pupillary light reflex has at least a 70%
positive predictive value for poor outcome. A papillary size of
>4 mm is recommended as the measure for a dilated pupil. The
duration of papillary dilation and fixation should be recorded.
✓Hypotension (defined as systolic blood pressure [SBP]
<90 mm Hg) occurring at any time from injury through the
acute intensive care course has been found to be one of the
most powerful predictors of outcome. A single recording of a
hypotensive episode is associated with a doubling of mortality.
✓Several features on the CT scan are predictive of outcome.
Poor outcome is observed in those with abnormalities on
the initial CT (eg, hematoma), compressed or absent basal
cisterns, blood in the basal cisterns, or extensive traumatic
subarachnoid hemorrhage.
✓Prehospital use of antiplatelet agents maybe associated with
hematoma expansion, increased mortality, and poor functional outcome particularly in elderly patients.
Desired Outcome
2.a. What are the immediate goals of therapy for this patient?
• Unfortunately, there is no “magic bullet” that can reverse the
consequences of TBI. Thus, treatment of TBI should focus on
prevention, recognition, and treatment/prevention of conditions known to cause secondary brain injury. (Please refer to
the corresponding textbook chapter for a detailed discussion of
primary vs secondary brain jury.) Goals for the management of
this patient are known as “cerebral resuscitation” and include
the following:
✓Frequently monitor level of consciousness using the GCS
(combined with assessment of pupils).
✓Establish an adequate airway along with maintenance of
breathing and circulation.
✓Prevent hypotension (SBP <90 mm Hg) and hypoxia (PaO2
<90 mm Hg).
✓Maintain cerebral perfusion pressure (CPP) at 50–70 mm
Hg and ICP <20 mm Hg. CPP is defined as mean arterial
pressure (MAP) minus ICP (CPP = MAP – ICP).
✓Abolish and prevent seizure activity.
✓Maintain normothermia (core temperature ≤37.2°C).
✓Reverse coagulopathy.
✓Modify or reverse mechanisms of secondary injury (refer to
the textbook chapter for a complete discussion of secondary
injury).
✓Protect uninjured tissue that is vulnerable to a secondary
insult.
✓Maintain a balance between cerebral oxygen delivery and
cerebral metabolic rate of oxygen (CMRO2) consumption.
✓Prevent and/or treat associated medical complications.
✓Frequently assess pain and sedation. For patients who can
assess their own pain, using the Numeric Rating Scale (NRS)
is recommended, and for those with an unreliable NRS, the
behavior-based pain scale (BPS) should be used. For patients
with severely impaired consciousness, the Nociception Coma
Scale-revise (NCS-R) is recommended. The assessment of
Copyright © 2017 by McGraw-Hill Education. All rights reserved.
sedation in brain injury is challenging since agitation and
sedation may be a consequence of the underlying disease.
Both the Richmond Agitation Sedation Scale (RASS) and the
Sedation–Agitation Scale (SAS) are recommended.2
2.b. What are the goals of fluid resuscitation and hemodynamic
monitoring for this patient?
• The goal of fluid therapy is to expand the patient’s circulatory
volume without reducing the plasma osmolality (euvolemia).
Although fluid restriction was recommended in the past, data
now suggest that this approach may cause systemic hypotension, which is associated with increased ICP and worse neurologic outcome. The target central venous pressure (CVP) is
5–10 mm Hg. The importance of fluid balance was illustrated
in a retrospective analysis of data from the National Acute
Brain Injury Study: Hypothermia, which sought to describe
critical thresholds of fluid balance, ICP, CPP, and MAP on
patient outcome (Clifton GL et al., Crit Care Med, 2002).
Independently, ICP >25 mm Hg, CPP <60 mm Hg, MAP
<70 mm Hg, and fluid balance lower than –594 mL had a
negative effect on outcome. Logistic regression identified variables that were associated with poor outcome, which included
(in order): GCS at admission, age, MAP <70 mm Hg, fluid
balance lower than –594 mL, and ICP >25 mm Hg. Reasons
for this negative association of fluid balance on outcomes were
not clear and did not appear to be related to low MAP, high
ICP, or low CPP. However, patients in the lowest quartile of
fluid balance received the highest total dosages of mannitol,
representing lack of appropriate fluid replacement. This study
illustrates that clinicians must pay close attention to fluid balance, particularly in patients receiving diuretic therapy.
• Brain injury patients require maintenance of systemic hemodynamics as well as attention to cerebral hemodynamics. The
BTF cites level II recommendations for monitoring blood pressure (BP) and avoidance of hypotension (SBP <90 mm Hg).
Most brain injury patients have increased metabolic oxygen
consumption, mild hypertension, and increased cardiac indices. A cardiac index of 4–5 L/min/m2 may be seen as normal
because of an increased metabolic rate. This patient has BP
87/60 mm Hg and heart rate (HR) 126 bpm upon admission.
The goals of hemodynamic monitoring are to:
✓Optimize volume status and cardiac function.
✓Maximize tissue perfusion (including the brain).
✓Avoid complications of fluid management and pharmacologic hemodynamic therapy.
✓ Preserve CPP (goal 50–70 mm Hg). Patients who have a sustained CPP >70 mm Hg have been shown to have decreased
morbidity and mortality due to increased risk of acute respiratory distress syndrome.
✓Maintain systemic oxygen availability because hypotension
and hypoxia are major factors contributing to secondary
injury. A single episode of hypotension with SBP <90 mm
Hg has been reported to result in a mortality rate of 85%.1
Administration of vasopressor agents may be needed to
maintain adequate systemic BP after intravascular volume is
restored. The association of hypoxia with outcome is not as
strong as hypotension but is still a significant predictor.
2.c. What are the goals of therapy for patients with traumatic
brain injury and prehospital use of antiplatelet medications?
• The goals of therapy are to:
✓Consider point of care (POC) tests of platelet activity to
quantify antiplatelet effects.
✓Minimize risk of further intracranial bleeding.
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• Currently available studies do not offer recommendations for
the use of reversal regimens. Additionally, clinicians must balance the risk of reversing the actions of antithrombotic therapy
(ie, vascular events) with the risk of not reversing the effects.
This complicates the understanding of appropriate therapeutic
interventions.
• Another complication is that standard laboratory investigations are insufficient to evaluate platelet activity. There are
a number of modalities available to evaluate platelet function, including bleeding time, platelet aggregometry, platelet
works, thromboelastograph platelet mapping, impact cone and
plate(let) analyzer, PFA-100, VASP phosphorylation state, and
platelet function assays. Each of these modalities has a number
of limitations and/or is time-consuming to conduct.
• Point of care (POC) tests of platelet activity enable quantification of antiplatelet effects on a patient-specific basis. This
allows for identification of “nonresponders” who may have
normal platelet activity despite treatment with antiplatelet
agents. Thus, POC testing can facilitate expedited treatment
decisions. The VerifyNow® rapid platelet function analyzer
is specifically designed to allow POC detection of aspirin or
clopidogrel resistance. The VerifyNow® rapid platelet function
analyzer Aspirin Response Test has been used as a guide for
platelet transfusion reversal of aspirin following TBI. The use
of this tool can assist in identifying patients who would benefit
from platelet transfusions and guide the adequate volume of
platelets need to correct the drug-induced dysfunction. The
recent consensus recommends the following:2
✓POC testing may help identify coagulopathy or antiplatelet
agents use in patients with TBI where there is a concern for
platelet dysfunction (strong recommendation, moderate
quality of evidence).
✓POC testing may be used to monitor the response to interventions intended to improve platelet dysfunction (strong
recommendation, moderate quality of evidence).
Therapeutic Alternatives
3.a. What therapeutic alternatives are available for reversal of
the antiplatelet effects of clopidogrel and aspirin?
• Prevention is key, and patients taking these agents should
be counseled on balancing a healthy lifestyle with proper
safety when engaging in physical activities, particularly those
with high risk of injury. The Centers for Disease Control and Prevention (CDC) provides TBI prevention strategies to assist in counseling the patients (http://www.cdc.gov
/traumaticbraininjury/prevention.html).
✓Platelet transfusions are considered a standard practice in
many trauma centers despite an overall lack of evidence and
there are concerns with adverse effects (Washington et al.,
J Trauma, 2011).
✓The American Association of Blood Banks guideline does
not recommend for or against platelet transfusion in patients
receiving antiplatelet therapy who have intracranial hemorrhage (traumatic or spontaneous).3
✓A case study described the successful reversal of clopidogrel
plus ASA antiplatelet effects with a 20-minute infusion of
desmopressin (0.3 mcg/kg).4
✓ More prospective studies are necessary to more clearly delineate the optimal intervention for patients with TBI who were
receiving antiplatelet agents.
3.b. What therapeutic alternatives are available for fluid resuscitation, and which would be the most appropriate for this
patient?
• The optimal fluid for fluid resuscitation in adult TBI patients
has yet to be determined. The use of hypertonic saline has been
hypothesized to improve outcomes by lowering ICP and optimizing cardiac output (ie, minimizing secondary neurological
injury). However, clinical trials demonstrated no overall difference compared with isotonic solutions on long-term neurological outcome. The options available include:
✓Isotonic solutions (0.9% sodium chloride [NaCl] = 308 mOsm/
kg) are the most appropriate solutions for TBI patients. Isotonic crystalloids are the most commonly used IV fluid for
both resuscitation and maintenance fluid support. Normal
saline is the preferred option in most patients because it is
inexpensive and is iso-osmolar with plasma.
✓Hypo-osmolar solutions (D5W, 0.45% NaCl) reduce serum
sodium and increase brain water and ICP. Lactated Ringer’s solution is more hypo-osmolar than its calculated
273 mOsm/kg and should not be used in patients with TBI.
The use of dextrose-containing solutions is also not recommended for these patients since they may exacerbate cerebral edema and hyperglycemia.
✓Hypertonic saline solutions (3% NaCl) can decrease brain
water and ICP. Several trials have evaluated hypertonic saline
as a resuscitation fluid in trauma patients. A meta-analysis
of six studies of TBI patients (223 patients) concluded that
hypertonic saline confers a twofold survival benefit over isotonic crystalloids in the setting of hypotensive resuscitation.
Unfortunately, a more recent trial failed to duplicate these
results; therefore, more data are needed before definitive
conclusions can be made.
✓Concentrations of 2–3% hypertonic saline have been used as
continuous infusions for resuscitation and maintenance fluids
a goal to maintain the serum sodium within 145–155 mEq/L.5
Hypertonic saline is sometimes prepared as a “hybrid”
solution of NaCl and sodium acetate to prevent acid–base
disturbances. The mixed solution is prepared with half of
the sodium content as NaCl and the other half as sodium
acetate in an attempt to prevent hyperchloremic acidosis with
solutions prepared with NaCl alone. There has been some
concern with the development of pulmonary edema (PE)
when these infusions were used long term, so patients have
to be followed closely. Generally, this approach might be used
in patients at risk for developing cerebral edema.
Copyright © 2017 by McGraw-Hill Education. All rights reserved.
Acute Management of the Brain Injury Patient
• Limited retrospective analyses have shown that prehospital
use of antiplatelet therapy in trauma patients is associated
with poor outcome. The exact contribution of the antiplatelet
regimen on the severity of the injury is poorly described. It
is theorized that prehospital use of antiplatelet agents may
convert a minor TBI into a progressive intracranial injury and
subsequently severe TBI. More recent observational studies
assessing preinjury use of antiplatelets and outcomes have
reported mixed results; however, in patients over 55 years
of age premorbid use of antiplatelet agents may be linked to
mortality.3,4
• Current strategies for reversal of antiplatelet therapy include
administration of platelets, desmopressin, and recombinant
activated factor VIIa (rFVIIa).
CHAPTER 68
• Treatment with antiplatelet agents can be commonly seen
in patients who present with TBI. Severe TBI itself may be
associated with reduced platelet activity. The degree of platelet
inhibition through intake of antiplatelet agents varies considerably among individuals and depends on several factors such
as compliance and genetic profile.
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SECTION 6
Neurologic Disorders
✓Complications reported with the use of hypertonic solutions have been rare, but it must be stressed that safety has
yet to be evaluated in large clinical trials. Several theoretical
concerns should be noted. First, abrupt changes in sodium
could cause seizures or even coma. Second, central pontine myelinolysis, a syndrome involving demyelination of
the pons, may develop and lead to quadriparesis and has
usually been associated with rapid correction of chronic
hyponatremia. Central pontine myelinolysis has never been
reported with the use of hypertonic saline in TBI, as most
trials have avoided large increases in serum sodium. Third,
“rebound” increase in ICP may occur while its mechanism is
unclear. An increase in ICP may simply be an indication of
a limited osmotic effect, or prolonged infusions in patients
with damaged blood–brain barrier (BBB) integrity may lead
to a reverse osmotic gradient. This reverse osmotic gradient
may also be a concern during withdrawal of therapy. If a
hypertonic saline infusion is stopped after prolonged administration, the brain interstitium may become hyperosmotic
relative to the intravascular space, creating an osmotic gradient that draws water into the brain. Therefore, it is advised to
wean hypertonic saline infusions slowly over 24–48 hours.
✓Rapid volume expansion could exacerbate PE in susceptible patients. Metabolic acidosis from hyperchloremia is
possible but can be partially combated with the addition
of acetate. Hypokalemia is common because the kidney
excretes potassium in response to reabsorption of sodium
in the distal tubule. Coagulopathy and bleeding complications may occur as a result of a dilutional effect, but this is
primarily a concern in patients who are actively bleeding.
Renal insufficiency is a relative contraindication to all hyperosmolar therapy. Unlike with mannitol, renal insufficiency
has not been associated with hypertonic saline in TBI. Renal
complications have been reported with hypertonic saline in
other patient populations. Therefore, it seems prudent to
use a maximum threshold of 320 mOsm/L as a guideline for
hypertonic saline use.
✓Albumin has a high molecular weight with low vascular
permeability, resulting in a longer intravascular retention
time and more sustained effect versus crystalloids. However,
the SAFE (normal saline vs albumin fluid evaluation) study
showed that albumin fluid resuscitation produced worse
outcomes than saline resuscitation in patients with TBI. In
the original SAFE study (2004), 6997 intensive care unit
(ICU) patients were randomized to fluid resuscitation with
albumin or normal saline. There were no significant differences between the groups in new single- or multiple-organ
failure, in mean days spent in the ICU, days spent in the
hospital, days of mechanical ventilation, or days on renalreplacement therapy. In the post hoc evaluation (2007),
comparing 231 TBI patients with albumin and 229 TBI
patients with saline, 33.2% of patients in the albumin group
versus 20.4% in the saline group had died at 24 months
(relative risk [RR], 1.63). Albumin resuscitation nearly
doubled mortality in the subgroup of patients with severe
brain injury (mortality rate, 41.8% with albumin vs 22.2%
with saline; RR, 1.88). There was no benefit from albumin in
any subgroup. Thus, there is currently no role for the use of
albumin as a resuscitation fluid after TBI.
✓Packed red blood cells are beneficial in patients with decreased
hemoglobin/hematocrit (hemorrhagic shock) to maximize
cerebral oxygen delivery. Although blood transfusion has
become a standard means of treating anemia (Hgb <9 g/dL)
in TBI patients, data have shown that transfusion could be
Copyright © 2017 by McGraw-Hill Education. All rights reserved.
associated with increased mortality, increased complications
including multiorgan failure, and may contribute to poor
long-term functional outcome (Warner MA, et al., J Neurosurg, 2010). Thus, transfusion strategies should be aimed at
patients with symptomatic anemia with minimized volume
of the transfusion.
3.c. What nondrug therapies may be useful for preventing or
treating increased intracranial pressure (ICP)?
• Head position. Elevating the head of the bed between 15° and
30° from horizontal is effective in lowering ICP by decreasing cerebral venous outflow resistance. However, euvolemia
must be established first to prevent decreases in MAP and
CPP. The neck must be maintained in a neutral position and
external compression of the jugular venous system (ie, tight
cervical orthosis or endotracheal tube stabilization tape) must
be avoided.
• Cerebrospinal fluid (CSF) drainage. The CSF may be drained if
a ventriculostomy is inserted as the ICP monitor as long as the
ventricles are not compressed.
• Prevention of hyperthermia. Fever is commonly observed in
brain-injured patients as a result of nosocomial infections,
atelectasis, or hypothalamic injury. In addition, blood present
in the subarachnoid space has been implicated in fever propagation. Fever confers detrimental effects in patients with acute
brain injury.
✓In both animal and clinical studies, fever was found to
increase toxic neurotransmitter release, free oxygen radical production, inflammatory cytokine production, and
cerebral metabolic demand, which ultimately increases
permanent neuronal damage. ICP will increase by several
mm Hg for every 1°C (1.8°F) increase in body temperature.
Furthermore, fever within 72 hours postinjury along with
GCS score, papillary response, age, and high ICP have been
significantly associated with poor neurologic outcomes in
patients with severe TBI. Therefore, aggressive measures to
prevent hyperthermia are indicated.
✓Pharmacologic means to control fever include the use of
antipyretic agents such as acetaminophen or ibuprofen.
Physical means include both invasive and noninvasive
devices, with the goal of maintaining core body temperature <37.5°C (99.5°F). Invasive cooling devices use cooled
saline infused via heat-exchange catheters placed into the
superior vena cava. Adverse effects associated with this technique include infection, bleeding, vascular puncture, and
venous thromboembolism (VTE). Noninvasive approaches
include water blankets and surface cooling devices. Surface
cooling devices use self-adhesive pads with temperaturecontrolled water that flows continuously in an attempt to
mimic the heat exchange experienced upon water immersion. Brain temperatures are often higher than body temperatures, so optimal temperature measurement should
include monitoring of brain temperature when possible. A
potential complication of these devices is shivering; patients
should be monitored and treated accordingly since shivering
increases metabolic demands (see discussion below in the
“Hypothermia” section).
• Hyperventilation. This is an established and effective mechanism for decreasing ICP. CBF changes approximately 2–3%
for every 1 mm Hg change in CO2 from a PaCO2 of 40 mm
Hg. However, evidence suggests that inappropriate or excessive hyperventilation can produce or exacerbate cerebral
ischemia. The BTF treatment guidelines recommend that
PaCO2 be maintained near 35 mm Hg, especially during the
68-5
• Sedative agents are commonly administered to patients with
TBI for treatment of agitation and pain, facilitation of mechanical ventilation, and for improvements in ICP and CPP. These
agents are not without potential risk, especially hypotension,
which can further contribute to the secondary neurologic
injury process. A systematic review of randomized clinical
trials on sedation in TBI patients found no evidence that any
particular sedative agent is more effective than another for
improvements in outcome, ICP, or CPP, and advised caution with use of high-dose bolus opioids due to the risk for
deleterious effects on systemic BP and subsequently CPP and
ICP. Similarly, a recent meta-analysis comparing midazolam
versus propofol found no significant differences between these
two commonly used sedatives in terms of efficacy or safety
(Fraser GL et al., Crit Care Med, 2013). The Society of Critical
Care Medicine published guidelines in 2013, which provided
a roadmap for developing integrated, evidence-based, and
patient-centered protocols for preventing and treating pain,
agitation, and delirium.7
• Propofol is a 1% solution in a 10% lipid carrier emulsion.
Propofol decreases CBF, CMRO2, ICP, MAP, and CPP in a
dose-dependent fashion.7 It has a rapid onset of effect because
✓Current TBI guidelines recommend propofol for control of
ICP but not for improvement in mortality or 6-month outcome because high-dose propofol can produce significant
morbidity.6 Propofol is associated with hypotension and prolonged infusions can substantially elevate serum triglyceride
levels. Another concern with the use of propofol is development of “propofol-related infusion syndrome” (PRIS). This
syndrome is characterized by cardiovascular instability,
metabolic acidosis, hyperkalemia, and rhabdomyolysis. The
syndrome may be caused by either a direct mitochondrial
respiratory chain inhibition or impaired mitochondrial fatty
acid metabolism mediated by propofol. Predisposing factors
include young age, severe critical illness of central nervous
system or respiratory origin, exogenous catecholamine or
glucocorticoid administration, inadequate carbohydrate
intake, and subclinical mitochondrial disease. Propofol
should be used for sedation with caution in critically ill
children and adults, as well as for long-term anesthesia in
otherwise healthy patients. Doses exceeding 4–5 mg/kg/
hour for long periods (>48 hours) should be avoided. If PRIS
is suspected, propofol must be stopped immediately and
cardiocirculatory stabilization and correction of metabolic
acidosis initiated.
• Benzodiazepines (eg, lorazepam, midazolam) decrease CBF and
CMRO2 and are effective anticonvulsant agents.10 Decreases in
CBF following benzodiazepine infusions are not associated
with substantial changes in cerebral blood volume, which suggests that these agents are less effective in decreasing ICP in
patients with low intracranial elastance but may be effective
in patients with high intracranial elastance. The most commonly used agents are lorazepam (1- to 5-mg bolus doses or
0.5–5.0 mg/hour infusion) and midazolam (1- to 5-mg bolus
doses or 1–20 mg/hour infusion).
✓Propylene glycol is used as a diluent for IV lorazepam.
Reports have found toxic propylene glycol concentrations
and adverse effects (acute kidney failure and metabolic
acidosis) with a total daily lorazepam dose of 1 mg/kg. The
serum osmole gap is a common surveillance tool used to
monitor for propylene glycol toxicity. Midazolam may be
preferred over lorazepam because it does not contain propylene glycol as a diluent and has a shorter duration of effect
than lorazepam. However, midazolam has been reported to
become long-acting after continuous infusion for more than
24 hours due to accumulation of active metabolites. Note that
benzodiazepines have been reported to be an independent
risk factor for transitioning to delirium in the intensive care
unit. Reversal with flumazenil is not advocated because of the
possible risk of seizure activity and the risk of increasing ICP.
• Opioids have either no effect on or decrease CBF and CMRO2.
There has been controversy regarding the effects of opioids on
ICP. Any ICP changes that may be seen can be explained by
autoregulatory responses to decreased MAP. Providing adequate pain control in patients who cannot verbalize their needs
is very challenging, and analgesics may often be underutilized.
It is generally recommended that an “analgesic first” policy be
instituted in agitated TBI patients.
✓Remifentanil is a μ-opioid agonist that has a very short
elimination half-life and a context-sensitive half-time of
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Acute Management of the Brain Injury Patient
Sedation/analgesia:
of high fat solubility, crosses the BBB rapidly, and has a rapid
termination of sedation (5–10 minutes) after short-term infusions. The dose ranges from 5 to 50 mcg/kg/min. Nutrition
support must be adjusted to compensate for the amount of
lipid infused in propofol (1 kcal/mL).
CHAPTER 68
first 24 hours, and then in the range of 30–35 mm Hg if ICP
control is inadequate.6 It is also recommended to monitor
cerebral oxygenation, such as jugular venous oxygen saturation, to optimize the use of hyperventilation and prevent
cerebral ischemia.
• Hypothermia. Cerebral metabolism decreases with decreasing
brain temperature, which is thought to be a useful method of
maintaining cerebral oxygen supply/demand in the injured
brain. In addition, evidence suggests that hypothermia interrupts the secondary injury cascade. Induced hypothermia is
now standard practice for anoxic brain injury postcardiac
arrest. However, clinical trials and meta-analyses of the use
of hypothermia following TBI have yielded conflicting results
and the BTF guidelines provide a cautious (Level III) recommendation. Nonetheless, hypothermia is used in the treatment
of otherwise therapy-resistant increased ICP.
✓Hypothermia is also associated with severe complications
including coagulopathy, electrolyte disorders, infection, and
arrhythmias. Re-warming too rapidly has been associated
with adverse outcomes and increased intracranial pressure.
Shivering is very common as the body attempts to conserve
heat and may be detrimental because it can dramatically
increase oxygen consumption. Nonpharmacologic ways to
limit shivering include warming of the face with warmed
air or warming the extremities using boots or mittens.
Shivering can be counteracted by administration of sedatives, anesthetics, opioids, and/or paralyzing drugs, some of
which have also been found to be synergistic with buspirone.
Another important complication of hypothermia is the
effect on drug metabolism. In most cases, drug clearance is
reduced, and many of the commonly administered drugs in
the ICU are affected. Therefore, it is essential to monitor for
potential drug interactions.
• Surgery. Decompressive craniotomy with lobectomy and craniectomy (ie, leaving the skull plate off so that the brain has
room to expand) are methods of “giving room to the swelling
brain.” This is usually reserved for patients who are resistant to
pharmacologic therapy for increased ICP.
3.d.What pharmacotherapeutic alternatives are available for
treating increased ICP?
68-6
SECTION 6
3 minutes.7 It is a good option for patients with brain injury
because of its ultrashort duration of action in patients who
require frequent neurologic examinations. In patients who
do not require frequent neurologic checks, fentanyl would
be another option.
Neurologic Disorders
• Etomidate (0.1–0.3 mg/kg IV bolus) decreases ICP by decreasing CBF and CMRO2. It has limited hemodynamic effects
unlike the other sedative/analgesic agents, but it is unsuitable
for prolonged infusion because of inhibition of adrenal corticosteroid synthesis.7 Prolonged infusions should be avoided
since adrenal suppression has also been reported after bolus
administration for intubation and induction of anesthesia.
Another unfortunate property of etomidate is its poor water
solubility resulting in the need for a propylene glycol vehicle.
In a study comparing etomidate to pentobarbital for control of
refractory cerebral edema, renal compromise with a metabolic
acidosis was observed in patients who received etomidate.
• Dexmedetomidine is an α-2 adrenergic agonist that mediates
sedation via the α-2a receptor in the locus coeruleus, possessing analgesic and anxiolytic properties without producing
respiratory depression.10 The usual dose range is 0.1–0.7 mcg/
kg/hour; however, recent data from the SEDCOM trial indicate the need for higher dosing (up to 1.4 mcg/kg/hour)
because 61% of patients in this trial required doses greater than
0.7 mcg/kg/hour for effective sedation.
✓Limited information is available on its use in head-injured
patients although scattered case series suggest that it does
not negatively affect physiologic or cerebral hemodynamics.
Adverse effects include bradycardia and hypotension, which
are more pronounced when administering bolus doses. This
agent might also be beneficial for reducing shivering associated
with the new cooling devices or following anesthesia and for
paroxysmal sympathetic discharges (“sympathetic storming”).
The major benefits with dexmedetomidine in the ICU may
include a reduction in the incidence of delirium, a reduction
in the time on the mechanical ventilation, and a reduction in
tachycardia and hypertension. Studies including TBI patients
with dexmedetomidine are needed to confirm its benefit in
the population. The effects of these sedative/analgesic agents
on the neurologic examination must be considered, and there
may be a need to coordinate daily baseline neurologic exams
with sedative administration and/or to use short-acting agents.
Cost is another consideration when choosing a sedative agent.
Neuromuscular blockade:
• Paralysis is useful when added to sedation in patients with
refractory increased ICP, in patients who have ICP spikes with
posturing, or in patients resisting ventilatory support.
• Prophylactic paralysis is not recommended because of an
increased risk of complications and ICU length of stay.
Osmotic agents:
• Mannitol is a commonly used osmotic agent for reducing ICP.
It does not readily cross the BBB but remains in the intravascular compartment when the BBB is intact. The presence of
mannitol in the cerebral vasculature creates an osmotic effect
which is delayed for 15–30 minutes until gradients between
plasma and cells are established. Its effects are variable and
range from 90 minutes to 6 hours. Repeated doses will increase
serum osmolality which could reduce its effectiveness. The
BTF found insufficient evidence to establish a treatment standard with regard to mannitol use and suggested that mannitol
is effective for control of raised ICP at doses of 0.25–1 g/kg and
infused over 15–30 minutes and can be dosed every 4–6 hours.
Copyright © 2017 by McGraw-Hill Education. All rights reserved.
Arterial hypotension (SBP <90 mm Hg) should be avoided.
Serum osmolality should be monitored and maintained below
320 mOsm/L. Other potential complications with mannitol
are hypovolemia and subsequent effects on BP, acute renal
failure, and the potential for rebound increases in ICP. A
Cochrane systematic review concluded that mannitol for
treating increased ICP may have beneficial effects on mortality
when compared with pentobarbital but may have a detrimental effect on mortality when compared with hypertonic saline.8
• Hypertonic saline is used as a hyperosmolar agent for the
treatment of cerebral edema and works similarly to mannitol
by establishing an osmotic gradient between the intravascular
space and cerebral tissue. Hypertonic saline is an effective
plasma volume expander, enhances cardiac output, increases
cerebral perfusion, and normalizes resting membrane potentials by restoring normal intracellular electrolyte balances.
Several clinical investigations also support its efficacy in concentrations ranging from 3.0 to 23.4% for the treatment of
intracranial hypertension.5 These studies found that boluses
(7.2% infused over 15 minutes and 7.5% at 2 mL/kg infused at
20 mL/min) produced a temporary reduction in ICP without
compromising the hemodynamics of the patients. Continuous
infusions (3% titrated to increase serum sodium concentrations to 145–155 mEq/L) have also been administered to
patients with severe TBI with significant decreases in ICP
and increases in CPP. A direct comparison of mannitol 20%
and 7.5% hypertonic saline with refractory increases in ICP
found a significant improvement in the number and duration
of ICP elevations in patients treated with hypertonic saline.
Other comparisons find that hypertonic saline is associated
with fewer treatment failures and reductions in the need for
additional therapies to reduce ICP. A recent systematic review,
due to limited data, did not find differences in outcomes but
reported fewer ICP treatment failures with hypertonic saline
(Burgess S et al., Ann Pharmacother, 2016). Adverse effects
of hypertonic saline include rebound increases in ICP upon
discontinuation, PE, hypokalemia, acute renal failure, and
hyperchloremic metabolic acidosis.
Diuretics:
• Furosemide is also effective in lowering ICP but to a lesser
extent than mannitol. Unlike mannitol, furosemide actually
decreases production of CSF. When used in combination
with mannitol, furosemide (0.1–1.0 mg/kg given after mannitol) enhances the degree and duration of ICP reduction and
may decrease the risk of rebound increases in ICP. The major
concern with the use of furosemide is massive diuresis that
results in hypovolemia and increases the risk of hypotension.
Therefore, furosemide should be reserved for patients who do
not exhibit a satisfactory response to mannitol.
Barbiturates:6
• High doses of barbiturates have been used since the 1970s for
refractory ICP control because they reduce CMRO2 and CBF
by as much as 50%. The response rate ranges from 27 to 80%
with a significantly increased mortality rate in nonresponders.
BP may need to be supported during barbiturate therapy,
and patients must be ventilated before instituting therapy.
Other potential complications are impaired tracheobronchial
mucociliary clearance and leukocyte function. In addition,
barbiturates are potent inducers of the cytochrome P450 system, so patients should be monitored for potential drug interactions. Because clinical studies have not shown an impact of
barbiturate therapy on patient outcome, their use should be
limited to patients with otherwise intractable ICP elevation.
68-7
Optimal Plan
4.a. Develop an optimal pharmacotherapeutic plan to treat the
patient’s increased ICP.
• Ventriculostomy opened to drain CSF.
• Elevation of the head of the bed from 15° to 30° horizontal and
head in midline position.
• Acetaminophen 500–1000 mg PO for T >37.5°C (99.5°F) and
other aggressive nonpharmacologic cooling strategies (note:
alternative dosing route is through the use of intravenous
acetaminophen 1 g IV Q 8 H).
• Optimize analgesia/sedation, titrated until the patient is no
longer agitated using one or a combination of the options
listed below:
✓Remifentanil IV infusion at 0.025–0.2 mcg/kg/min;
✓Morphine 1 mg IV push Q 1–2 H PRN; or
✓Fentanyl 0.7–10.0 mcg/kg/hour.
Plus:
• Propofol IV infusion given initially at 5 mcg/kg/min; or
• Dexmedetomidine infusion starting 0.1–0.2 mcg/kg/hour.
✓Because this patient develops hypernatremia, the hypertonic
saline should be discontinued and osmotic therapy should
not be recommended to treat increased ICP at this point.
✓ If this plan fails, then consider hyperventilation, pentobarbital coma, induction of therapeutic hypothermia, or surgical
intervention.
4.b.Outline a pharmacotherapeutic plan for prevention of
medical complications that may occur in this patient.
• Hyperglycemia. Hyperglycemia is associated with increased
mortality and poor neurologic outcomes after TBI. It is unclear
if the rise in serum glucose reflects a response to injury or
rather acts to promote further insult to the brain. In addition,
little is known regarding the effects of reducing blood glucose
(BG) to improve outcome after TBI.
✓Aggressive lowering of BG in these patients can cause
hypoglycemia, resulting in altered mental status or seizures.
Furthermore, there is evidence of alterations in glucose
✓Intensive insulin therapy became a standard of care in critically ill patients after a landmark prospective, randomized
study in critically ill surgical patients found that very tight
BG control (<110 mg/dL) with insulin infusions significantly reduced mortality and other complications compared
to patients who received standard treatment (Van den
Berghe et al., New Engl J Med, 2001). A subgroup analysis
of brain-injured patients (n = 63) found that patients who
received intensive insulin treatment had a lower incidence
of seizures, spent less time mechanically ventilated, and had
lower ICP values. In addition, more patients in the intensive
insulin group were living functionally independent at 1 year.
However, this subgroup analysis included a small number
of patients, most of whom had strokes, and it was not clear
if any patients in this cohort had a history of TBI. A subsequent study by the same group in medical ICU patients
showed a reduction in morbidity (shorter length of stay,
fewer ventilator days) but not mortality, suggesting that
the benefits of intensive insulin may not be applicable to all
patients.
✓A small retrospective study examined the effects of intensive
insulin therapy (target BG range 90–120 mg/dL) compared to conventional glucose control in a small group of
head injury patients (Vespa P et al., Crit Care Med, 2006).
The results revealed no difference in mortality between the
intensive (n = 14) and conventional groups (n = 33), but the
study was not powered to do so. However, all markers of
cellular distress (brain ECF glucose, glutamate, and lactate/
pyruvate ratio) were significantly elevated for longer periods
of time in the intensive insulin group. The same investigators
substantiated their findings in a randomized within-subject
crossover trial of eight patients with severe TBI. They compared tight glycemic control (BG 80–110 mg/dL) to loose
glycemic control (BG 120–150 mg/dL) on brain glucose
metabolism, and found that tight glycemic control resulted
in increased global glucose uptake and increased cerebral
metabolic crisis after severe TBI.
✓A large multicenter, prospective, randomized trial has suggested that the practice of intensive insulin therapy is not
beneficial and is potentially dangerous. The NICE-SUGAR
trial studied the effects of intensive insulin therapy (goal BG
81–108 mg/dL) versus conventional therapy (goal BG 140–
180 mg/dL) in a mixed population (surgical and medical) of
6104 patients. At 90 days, there were more deaths in patients
treated with intensive insulin therapy (absolute increased
risk of death = 2.6%). The rationale for this detrimental
effect is likely severe hypoglycemia (BG <40 mg/dL), which
was 13-fold higher in the intensive-treated group. Although
the study did not provide specific information regarding
the number of TBI patients enrolled, a more conservative
approach to glucose control in this population is prudent.
✓This patient’s glucose is over 200 mg/dL, so administration
of insulin is warranted. A BG goal of 140–180 mg/dL is reasonable based on the above discussion.
• Seizure prophylaxis is recommended even though the overall
incidence of post-traumatic seizures (PTS) is relatively low
(<5%) because seizures greatly increase CMRO2. However,
prophylaxis of PTS has not been shown to reduce morbidity
or mortality following severe TBI. PTS may be categorized as
early (<1 week postinjury) or late (>1 week postinjury). The
majority of early PTS occur in the first 24 hours. Risk factors
Copyright © 2017 by McGraw-Hill Education. All rights reserved.
Acute Management of the Brain Injury Patient
✓Pentobarbital is the most common barbiturate used because
of predictable metabolic clearance (t1/2 = 24 hours), availability of serum concentration monitoring, and lack of active
metabolites. Patients should be normovolemic prior to initiating therapy. Pentobarbital administration can begin with
a 10 mg/kg loading dose over 30 minutes followed by 5 mg/
kg/hour for the next 3 hours. The loading dose is followed
by a maintenance infusion of 1–3 mg/kg/hour. Supplementation with 200 mg of pentobarbital may be necessary to
achieve burst suppression. Weaning of pentobarbital should
be done slowly (usually halving the daily dose every 24 hours
for 3–4 days) to prevent rebound intracranial hypertension.
It is important to monitor for hypotension during pentobarbital treatment, and vasopressor agents should be available
to support MAP and maintain CPP >60 mm Hg.
utilization after brain injury. Thus, aggressive lowering of BG
could lead to detrimental consequences in the injured brain.
CHAPTER 68
Current treatment guidelines do not recommend the prophylactic administration of barbiturates to induce burst suppression EEG but acknowledge that high-dose barbiturate
administration is recommended to control elevated ICP
refractory to maximum standard medical and surgical treatment. Hemodynamic stability is essential before and during
barbiturate therapy.
68-8
SECTION 6
for early PTS include: GCS <10, cortical contusion, depressed
skull fracture, subdural or epidural or intracerebral hematoma,
penetrating injury, or seizure within first 24 hours. This patient
has three of these risk factors (skull fracture, epidural hematomas, and GCS <10). The BTF guidelines do not recommend
use of prophylactic antiepileptic agents beyond 7 days.6
Neurologic Disorders
✓Phenytoin is the most commonly used anticonvulsant agent
for PTS prophylaxis. A randomized, placebo-controlled trial
documented a significantly lower incidence of early PTS
in patients receiving prophylactic phenytoin (3.6%) versus
placebo (14.2%). No difference in the incidence of late PTS
was observed between the two patient groups, suggesting
that prophylaxis beyond the first week is not warranted.
Phenytoin has several well-described serious adverse effects,
significant drug interactions, and a narrow therapeutic window necessitating serum concentration monitoring. Additionally, recent data have found that prolonged exposure to
phenytoin following subarachnoid hemorrhage is associated
with poor neurological and cognitive outcomes.9
✓Carbamazepine and sodium valproate have shown similar
prophylactic efficacy to phenytoin; however, valproate was
associated with a higher mortality than phenytoin.
✓The second-generation anticonvulsants is used due to their
favorable pharmacokinetic profile and the lack of negative
consequences on cognition. There is mounting beneficial
evidence for levetiracetam, but the sample sizes of studies are small. Nonetheless, the published data suggest that
levetiracetam is an effective alternative to phenytoin for PTS
prophylaxis. In a small prospective randomized trial, the use
of levetiracetam compared to phenytoin showed improved
long-term outcomes in patients who were randomized to
levetiracetam. The dosing regimen for levetiracetam used
in the prospective randomized trials was a loading dose of
20 mg/kg IV (rounded to the nearest 250 mg) over 60 minutes followed by a maintenance dose of 1000 mg IV Q 12 H
(the dose was adjusted to 1500 mg IV Q 12 H if the patient
experienced a seizure). The use of other newer IV secondgeneration agents such as lacosamide is also being explored.9
✓Aggressive therapy is recommended for patients having
documented seizures.
• Nutritional intervention is necessary because moderate or
severe brain injury results in a generalized hypermetabolic and
hypercatabolic state. In the absence of adequate nutritional
support, the resulting hypercatabolic state causes endogenous
protein breakdown to amino acids, ultimately resulting in
multiorgan dysfunction and an immunocompromised state.
Enteral nutrition results in improved mesenteric blood flow
and prevents gut atrophy and mucosal breakdown that promotes bacterial translocation. The most recent guidelines
for providing and assessing nutrition support therapy in
adult critically ill patients suggest that enteral nutrition is
the preferred method and should be started within the first
24–48 hours after admission and advanced toward goal over
the next 48–72 hours.10 In patients who are hemodynamically
unstable, enteral nutrition should be withheld until the patient
is stable. The BTF guidelines recommend that patients should
attain full caloric replacement by day 7 postinjury.6 Brain
injury patients are reported to have gastric hypomotility following injury that may last for 4–5 days. In this setting, early
gastric feeding may be poorly tolerated. On the other hand,
early jejunal feedings can begin shortly after injury even when
bowel sounds are absent. Ideally, feeding should begin within
24–48 hours of injury. Most critically ill TBI patients expend
Copyright © 2017 by McGraw-Hill Education. All rights reserved.
25–35 kcal/kg per day and need 1.5–2.0 g/kg per day of protein. Patients with abdominal trauma or who are unable to
tolerate enteral feedings should receive TPN. The most recent
guidelines indicate that parenteral nutrition should only be
initiated after the first 7 days in otherwise healthy patients
and as soon as necessary if there is evidence of protein–calorie
malnutrition at admission.10
✓This patient should receive jejunal feedings if possible or
administration of gastric feedings while monitoring for
residuals. The patient should be fed 2000–2500 kcal per day
and 120–160 g of protein. The appropriate enteral formula
with additional protein added should be chosen to meet
these goals.
• Stress ulcer prophylaxis is recommended for all patients with
mechanical ventilation, coagulopathy, TBI, and major burns.
Thus, the patient in this case clearly has indications to receive
prophylaxis. Options include:
✓Cimetidine 900–1200 mg per day either orally or by continuous or intermittent infusion
✓Ranitidine 150 mg per day IV either by continuous infusion
or intermittent infusion, or 150 mg PO Q 12 H
✓Famotidine 40 mg per day either orally or by continuous or
intermittent infusion
✓A proton-pump inhibitor given per NG tube once daily
(omeprazole 20 mg, lansoprazole 30 mg, esomeprazole
20 mg, pantoprazole 40 mg, rabeprazole 20 mg, or dexlansoprazole 30 mg). Pantoprazole may be given IV instead
of via the NG tube. (Note: data have shown clinically significant drug interactions between proton-pump inhibitors
and clopidogrel, so use PPIs with caution and monitor for
potential loss of clopidogrel effectiveness.)
✓There is currently no guideline recommendation on a preferred agent or the length of therapy. Standard practice is
generally to continue prophylaxis for the duration of the
critical illness or for the ICU stay.
• Electrolyte abnormalities are common after brain injury.
✓Hyponatremia (serum sodium <135 mEq/L) lowers seizure
threshold and can exacerbate cerebral edema. The most
common cause is the administration of hypotonic fluids.
Other causes include syndrome of inappropriate antidiuretic
hormone (SIADH) and cerebral salt wasting (CSW), which
are characterized by low serum sodium and serum osmolality and high urine sodium and urine osmolality in a setting
of normal renal, adrenal, and thyroid function. Treatment
of SIADH is fluid restriction to 500–1000 mL per day until
serum sodium normalizes. Refractory or severely low serum
sodium may respond to 3% NaCl infusion and occasionally
demeclocycline. Treatment of CSW includes fluid and salt
supplementation. Accurate diagnosis is important as treatments differ and improper fluid restriction in the presence
of CSW can result in additional morbidities.
✓Aquaretic agents (arginine vasopressin antagonists):
Conivaptan, an intravenous V1A and V2 vasopressin receptor antagonist, and tolvaptan, an oral V2 receptor antagonist
promote free water excretion while sparing electrolytes
including sodium. Observational studies of conivaptan for
acute hyponatremia in the neurologically injured population
have demonstrated a 6 mEq/L rise in serum sodium within
8 hours of drug administration. Conivaptan is given as a
20-mg IV bolus over 30 minutes followed by a continuous
IV infusion of 20 mg over 24 hours. The infusion can be
increased to 40 mg over 24 hours if the initial response is
68-9
✓Hypernatremia is commonly associated with seizures and
coma depending on the rapidity of increased serum sodium.
Hypernatremia (serum sodium >160 mEq/L) has been
associated with increased morbidity and mortality. Patients
with TBI have a number of reasons for developing hypernatremia, including direct trauma to the posterior pituitary or
indirect trauma due to brain herniation syndromes resulting
in neurogenic diabetes insipidus (DI), and administration
of hyperosmolar therapy. Neurogenic DI, also referred to as
central DI, is a failure of adequate release of AVP from the
posterior pituitary. Clinical manifestations include excessive
excretion of inappropriately dilute urine (>30 mL/kg per day
or >250 mL/hour), low urine osmolality (<300 mOsm/kg
and specific gravity <1.005), high serum osmolality, and
subsequent elevations in serum sodium levels. Risk factors for developing DI after TBI include GCS ≤8, cerebral
edema, and penetrating injuries. Careful monitoring of fluid
balance, urine specific gravity, and serum sodium concentrations are vital for rapid diagnosis and treatment. Treatment
focuses around IV fluids and/or exogenous vasopressin
if the polyuria and/or polydipsia become excessive and
difficult to manage. Hormone replacement should be considered in patients with acute DI when the urine output
is >8 L per day. Options include aqueous vasopressin or
its analog 1-desamino-D-arginine vasopressin (dDAVP).
dDAVP dosing is typically 0.5–4 mcg subcutaneously. The
antidiuretic effect of dDAVP may last for 8–12 hours, so
this longer-acting agent should be used cautiously because
the hypernatremia may be transient and the drug is not
titratable. Aqueous vasopressin is shorter acting and may
be given intermittently (2–10 units subcutaneously every
3–6 hours) or as a continuous infusion starting at 2.5 units/
hour titrating to achieve normal urine output and serum
sodium concentrations. Concurrent IV fluids are necessary
to replace urinary losses. In this patient, hypernatremia
appears to be a result of administration of hypertonic saline
and thus should be discontinued and the patient reassessed
before administering vasopressin or its analog dDAVP.
✓Hypomagnesemia lowers seizure threshold, complicates
alcohol withdrawal, and (in experimental brain injury)
hinders neurologic recovery. It appears reasonable and safe
to maintain serum magnesium levels in the upper range of
normal. This patient’s magnesium level is already low and
needs supplementation. This patient’s magnesium can be
repleted with magnesium sulfate 2 g IV.
• Prophylaxis of thromboembolism (deep vein thrombosis
[DVT]/PE) should be initiated because the incidence of thromboembolic complications is 6–58% in brain injury patients. TBI
is an independent risk factor for developing DVT. A number
✓Pneumatic compression boots, which resulted in clinically
evident DVT in 2.3% and PE in 1.8% of patients.
✓Low-dose heparin (5000 units subcutaneously Q 12 H) has
been studied for prophylaxis starting on postoperative day 1
(or postinjury day 1), but there is no universal standard in
clinical practice.
✓Low-molecular-weight heparin (eg, enoxaparin, dalteparin)
is another option and theoretically should be associated
with fewer hemorrhagic complications. Small studies have
suggested a favorable risk-to-benefit ratio when utilized
postoperatively or in patients who have shown no interval
increases in bleeding on imaging for 24 hours.
✓If full anticoagulation with IV heparin is needed, the ideal
timing for safe anticoagulation is unclear but should be at
least 7–14 days postinjury.
✓This patient should be started on pneumatic compression
devices along with either heparin 5000 units SC Q 8 H,
enoxaparin 30 mg subcutaneously Q 12 H, or dalteparin
2500 IU subcutaneously once daily.
Outcome Evaluation
5.What monitoring parameters should be instituted to ensure
efficacy and prevent toxicity for the therapy recommended for
increased ICP and other medical issues?
• Maintain CPP. Implement continuous monitoring of ICP and
MAP for maintenance of CPP >60 mm Hg. The goal for CPP
is 50–70 mm Hg. ICP can be measured either by an intraventricular catheter or fiberoptic intraparenchymal device with
the goal to maintain ICP <20 mm Hg. MAP can be monitored
by an intra-arterial catheter. Drugs may have to be titrated to
achieve the desired effect on ICP, or vasoactive agents may
have to be added in addition to IV fluids for BP support.4
• Monitor sedation/analgesia:
✓Propofol: The most common adverse effect of propofol is
hypotension, so frequent assessment of BP is essential to
maintain target CPP goals. Serum triglyceride levels should
also be monitored. Unexplained metabolic acidosis; elevated
serum lactate, creatine kinase, and myoglobin levels; or
hyperlipidemia may all be early indicators for the onset of
PRIS, so daily monitoring is essential while receiving propofol. Monitor continuous electrocardiogram and intermittent
serum bicarbonate levels. Monitor sedation with a validated
and reliable scale such as SAS (3–4) or RASS (goal 0 to –3)
and avoid sedation interruptions or wake-up.2
Copyright © 2017 by McGraw-Hill Education. All rights reserved.
Acute Management of the Brain Injury Patient
✓The etiology of hyponatremia is best investigated by assessing volume status as well as serum and urine osmolality.
This will provide the clinician with information to exclude
iatrogenic causes or to differentiate between SIADH and
CSW. Volume status should be accessed via CVP (or PCWP)
monitoring and close attention should be paid to fluid balance and urinary output.
of studies have suggested that delays past 4 days resulted in
a threefold increased risk of VTE. However, another study
found that irrespective of the time to initiation of pharmacologic prophylaxis, TBI patents have a three- to four-fold
increased risk of DVT compared with other trauma patients.
The challenge of VTE prophylaxis is balancing the risk of VTE
with the risk of bleeding complications from pharmacologic
agents. Smaller studies have shown limited bleeding complications when pharmacologic prophylaxis was initiated within
48 hours of injury in patients with a stable CT scan. There
are no clear guidelines for best practices in preventing VTE.
The current approach is to initiate mechanical prophylaxis
upon admission (unless lower extremity injuries prohibit use)
and then initiate pharmacologic prophylaxis when there is no
interval increase in intracranial bleeding 24 hours after injury
or on postoperative day 1 if the patient is stable. Prophylactic
options include:
CHAPTER 68
inadequate. Injection site reactions are very common, and
there is potential for serious drug interactions because the
drug is a substrate and inhibitor of cytochrome P450 3A4.
There have also been reports of benefit with use of tolvaptan
in TBI patients with SIADH. Clinicians should use tolvaptan
cautiously in critically ill patients due to a paucity of information related to absorption.
68-10
SECTION 6
✓Dexmedetomidine: Monitor BP and HR continuously while
receiving dexmedetomidine infusion.
✓Opioids: Monitor BP, HR, and any physical signs of pain
(eg, facial grimacing). Assessment of pain using the NCS-R
using a threshold of 4 or BPS <5 should also be a standard
practice.2
✓Ensure that an appropriate bowel regimen has been
instituted.
Neurologic Disorders
• Monitor hyperventilation. Arterial blood gases should be monitored at least every 6 hours to specifically assess PaCO2, which
should be maintained near 35 mm Hg if ICP is adequately
controlled and should always be maintained at 35 mm Hg in
the first 24 hours following injury. Thereafter, PaCO2 may be
lowered to 30–35 mm Hg if ICP is not controlled.
• Monitor hypertonic saline. Monitor serum osmolality and
sodium every 6 hours, and do not administer hypertonic saline
if osmolality is >320 mOsm/L or serum sodium is >155 mEq/L.
Continuously monitor fluid status (CVP or PCWP) and fluid
intake/output. Also measure serum electrolytes, BUN, and
serum creatinine at least once daily but optimally every 6 hours
until the patient’s ICP and/or sodium are stabilized. A chest
X-ray can be evaluated for the presence of pulmonary edema.
• Monitor barbiturate coma:
✓Continuous monitoring of electroencephalogram (EEG) to
evaluate for burst suppression is necessary to guide titration
of therapy.
✓Serum pentobarbital concentrations may be evaluated every
24 hours. Serum concentrations of 25–40 mcg/mL are
associated with barbiturate-induced coma, electrically silent
EEG, and a maximal reduction in metabolic rate. One to
three bursts per minute are common at serum levels of
30–40 mcg/mL. Supplementation with 200 mg of pentobarbital may be necessary to achieve burst suppression.
✓CPP may decrease, especially during loading-dose administration as a consequence of decreases in cardiac output and
systemic vasodilation. The loading infusion may need to be
slowed if CPP falls below 60 mm Hg.
✓BP may need to be supported during barbiturate therapy,
and patients must be ventilated before instituting therapy.
Vasoconstrictors, inotropes, and volume expansion may be
required to support the patient. Cardiac output monitoring
is recommended, particularly in patients with a history of
cardiac disease.
✓Continuous assessment of body temperature is necessary
because pentobarbital may cause hypothermia.
✓The bispectral index (BIS) is a technology developed originally for the operating room to assess the depth of anesthesia
and is another option for monitoring barbiturate coma. It
utilizes the raw EEG signal in combination with a software
algorithm to report a numeric BIS score corresponding to
the level of consciousness in patients, with 0 being completely comatose and 100 being fully awake. The system also
reports the suppression ratio (SR) score, a value representing the percentage of the completely suppressed EEG in
the last 63 seconds. Therefore, the SR and BIS scores are
inversely related; the higher the SR, the lower the BIS score
and patients are more likely to be in a comatose state. The
SR is believed to be superior to burst suppression because it
represents not only the frequency of the burst suppression
but also the duration of the suppression, which may be more
accurate in assessing patients on barbiturate coma for intractable ICP control. The BIS monitor is smaller and easier to
Copyright © 2017 by McGraw-Hill Education. All rights reserved.
use at the bedside than the EEG, so there is increased interest
in studying the correlation of BIS scores and burst suppression in patients with brain injury. Studies suggest a BIS of
10–20 and SR of 71% quantified the burst suppression of
3–5/min well in patients on barbiturate infusion.
• Monitor nutrition. During feedings, monitor blood glucose
and serum electrolytes to prevent hyperglycemia and electrolyte deficiency or excess. Monitor for adequacy of nutritional
regimen including indirect calorimetry, 24-hour urine urea
nitrogen studies, and prealbumin.
• Monitor seizure prophylaxis. Assess for factors that may
decrease seizure threshold (ie, electrolyte abnormalities, drugs,
hypoxia, and infection) and signs/symptoms of seizures or
reduced neurologic functioning, which would suggest the need
for electroencephalography.
• Monitor stress ulcer prophylaxis. Monitor hematocrit, hemoglobin, and other signs and symptoms of GI hemorrhage (ie,
melena, hematemesis).
• Monitor VTE prophylaxis. Monitor for signs and symptoms of
DVT and/or PE and platelet counts.
Patient Education
6.What medication education should this patient receive if he is
discharged on clopidogrel and aspirin?
• Prevention of head injury is key, especially when you are taking
drugs that might cause increased bleeding if you hit your head.
It is important to still have a healthy active lifestyle, but just be
cautious of activities that might place you at high risk for falling
or hitting your head. The Centers for Disease Control and Prevention (CDC) provides TBI prevention strategies (http://www
.cdc.gov/TraumaticBrainInjury/index.html) including:
✓Wear a seat belt every time you drive or ride in a motor
vehicle.
✓Never drive while under the influence of alcohol or drugs.
✓Make your living areas safer by: (1) removing tripping
hazards such as throw rugs and clutter in walkways;
(2) using nonslip mats in the bathtub and on shower floors;
(3) installing grab bars next to the toilet and in the tub or
shower; (4) installing handrails on both sides of stairways;
(5) improving lighting throughout the home.
✓Wear a helmet when riding a bike, motorcycle, snowmobile,
scooter, or all-terrain vehicle, playing contact sports, skiing
or snowboarding, riding a horse, or using in-line skates.
• It is extremely important that you do not miss a dose of these
two medications and that you do not start or stop taking
other medicine without talking to your doctor or pharmacist,
because other drugs may affect the way these drugs work or
enhance their bleeding risk. This includes over-the-counter
products you may buy.
• Monitor for signs and symptoms of bleeding and for symptoms of chest pain.
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Acute Management of the Brain Injury Patient
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