Therapeutic hypothermia improving post–cardiac arrest care what is anoxic brain injury

US pharm. 2013;38(3):epub.

ABSTRACT: cardiac arrest is a leading cause of

Mortality and morbidity in the united states, the majority secondary to

Neurologic injury. Lowering the body temperature post–cardiac arrest has

Been shown to improve morbidity and mortality, and it has become the

Gold standard of care. Methods to induce and maintain therapeutic

Hypothermia include invasive and noninvasive techniques. Adverse effects

During therapeutic hypothermia are shivering, fluid and electrolyte

Shifts, bradycardia, and infection. The pharmacokinetics and

Pharmacodynamics of multiple medications are altered during hypothermia.

Pharmacists can help play a role in adverse-effect prevention and

Medication management.What is anoxic brain injury

Every year in the united states, an estimated 300,000 patients experience an out-of-hospital cardiac arrest. 1 ultimately, only 7.9% of those patients survive to discharge. 1 the rate of survival of an in-patient cardiac arrest is also low at approximately 33%. 1 upwards of 90% of survivors experience permanent neurologic injury. 2

The utilization of therapeutic hypothermia to improve

Patient outcomes after cardiac arrest dates back over 200 years to

Russia, when patients were covered in snow to attempt to return

Circulation. 3,4 from the 1800s to the 1960s, therapeutic

Hypothermia was investigated for multiple indications ranging from

Cancer prevention to decreasing intracranial pressure during cardiac

what is anoxic brain injury

Surgery. Due to complications, the use of hypothermia was abandoned

Until the 1980s. Starting with successful animal trials followed by

Human clinical trials led to our current improved post-resuscitative

Efforts. 5

Post–cardiac arrest brain injury

During cardiac arrest, there is a total lack of perfusion

To the brain, which initiates a complex cascade of events. A key aspect

Of these events is that they are all temperature dependent. There are

Two main components of post–cardiac arrest brain injury: ischemia and

Reperfusion. Due to the lack of blood flow during cardiac arrest, there

Is a loss of adenosine triphosphate (ATP) production in the brain

Causing the release of glutamate, which is responsible for neuronal

what is anoxic brain injury

Injury. An influx of intracellular calcium causes an increase of cell

Permeability that contributes to brain cell death. After return of

Spontaneous circulation, reperfusion injury can occur from free radicals

And mitochondrial injury. 6,7

There are multiple proposed mechanisms by which

Therapeutic hypothermia protects against neurologic injury. Hypothermia

Decreases neuronal metabolism, glucose and oxygen consumption, glutamate

Release, and blood-brain barrier breakdown. Overall, the neurologic

Cell death is decreased with hypothermia. 8

Supporting clinical data

In 2002, the first two randomized, controlled trials

Investigating use of therapeutic hypothermia after out-of-hospital

Cardiac arrest were simultaneously released. 9,10 these two trials were landmark studies that have revolutionized post–cardiac arrest care.What is anoxic brain injury

Bernard et al conducted a trial in australia to

Investigate the impact of therapeutic hypothermia on neurologic outcomes after cardiac arrest due to ventricular arrhythmias. 9

There were 77 patients included in the study who were randomized to

Hypothermia (33°C for 12 hours) or normothermia. In the hypothermia

Group, 49% survived with a good neurologic outcome (discharged home or

To rehabilitation facility), while only 26% in the normothermia group

Survived with good neurologic outcome ( P = .046). There was also a decrease in mortality in the hypothermia group; however, it was not statistically significant. 9

The hypothermia after cardiac arrest study group conducted a similar trial in europe. 10

The 275 patients included in the study were randomized to hypothermia

what is anoxic brain injury

(32°C-34°C for 24 hours) or normothermia. In the hypothermia group, 55%

Survived with good neurologic outcome at 6 months, while only 39% in the

Normothermia group had a good neurologic outcome at 6 months ( P = .009). There was a statistically significant ( P = .02) decrease in mortality in the hypothermia group (41%) compared to the normothermia group (55%). 10

Based on the clinical data, the advanced life support task

Force of the international liaison committee on resuscitation (ILCOR)

And the american heart association (AHA) both strongly recommend mild

Therapeutic hypothermia after cardiac arrest for out-of-hospital

Ventricular cardiac arrest. 11-13 there are limited data

Supporting the use of cardiac arrest in nonshockable rhythms.What is anoxic brain injury A recent

Cohort review of 437 patients with pulseless electrical activity or

Asystole showed no benefit with the use of therapeutic hypothermia. 14 A possible benefit for therapeutic hypothermia has been seen with in-patient cardiac arrest ( TABLE 1). 13

Temperature management

There are several methods that may be utilized to induce

And maintain hypothermia. They can be divided into two categories:

Noninvasive and invasive. Noninvasive methods include exposure of skin

To cold water, fans, ice packs, and gel-circulating cooling blankets or

Pads ( FIGURE 1). Invasive methods include infusion of ice-cold

Fluids, intravascular catheters, and extracorporeal circulation. Each

Method has its own advantages and disadvantages. 15 A combination of methods may be a more effective tactic to achieve goal temperature. 16

what is anoxic brain injury

Temperature management during therapeutic hypothermia can

Be divided into three phases: induction, maintenance, and rewarming. In

The induction phase, the goal of treatment is to decrease the patient’s

Temperature below 34°C as quickly as possible. During this phase, the

Patient is the most unstable due to hypovolemia, electrolyte

Abnormalities, and hemodynamic disturbances. This instability can be

Minimized with a rapid induction to goal temperature. During the

Maintenance phase, the patient becomes more stable, and the focus should

Be on prevention of long-term complications. The rewarming phase can be

Problematic, with electrolyte abnormalities, hypoxia, and

Cardiovascular instability. However, these effects may be mitigated with

what is anoxic brain injury

A slow, controlled warming ( TABLE 2). 15

Management of adverse effects

Shivering is the most common side effect during the

Induction phase. Shivering is an involuntary muscle response that

Increases heat production to restore normal body temperature. The

Response typically begins at 35.5°C and diminishes at 33.5°C. This

Reaction can lead to increased metabolism and oxygen consumption and a

Stress-like response. Shivering can be negated in several different

Ways. Surface counter warming, which is the warming of the face, hands,

And feet, may be utilized to decrease the sensation of cold. Multiple

Pharmacologic agents have been used to abate shivering; however, no one

Agent has been shown to be superior.What is anoxic brain injury the most commonly used medications

Are opioids, sedatives, anesthetics, magnesium, and neuromuscular

Blockers. Paralyzing agents are the most effective agents for shivering

Cessation; however, their use should be minimized due to adverse

Effects. 15,17

Fluid and electrolyte disturbances are common during

Hypothermia, prominently during the induction phase. Hypovolemia caused

By hypothermia diuresis typically requires volume resuscitation.

Hypokalemia frequently occurs due to cold diuresis and intracellular

Shifting. Potassium should be aggressively replaced during the cooling

And maintenance phase. Due to the possibility of electrolyte shifts

During the rewarming phase, conservative potassium replacement

what is anoxic brain injury

Strategies should be employed. 18 hyperglycemia is also

Observed during the cooling and maintenance phase, as there is a

Decrease in insulin secretion and sensitivity. Use of an insulin drip

May be required to maintain an appropriate blood glucose range. 19

Bradycardia is observed in most patients undergoing

Therapeutic hypothermia, which decreases cardiac output. Heart rates can

Drop as low as 40 beats per minute (bpm); however, this typically does

Not require treatment. Arrhythmias are uncommon, unless the temperature

Drops below 30°C. 15

Rarely, therapeutic hypothermia can lead to coagulation abnormalities. 15

Patients who are actively bleeding may require less aggressive

Hypothermia, as clotting factors are not affected until the temperature

what is anoxic brain injury

Is less than 35°C. 20

Patients’ inflammatory response is suppressed during

Hypothermia. A retrospective review of 537 patients undergoing

Therapeutic hypothermia showed frequent infections (67%). 21

The most frequent was pneumonia, followed by bacteremia and line

Infections. Despite an increase in infection rates, there was not an

Increase in mortality or favorable neurologic outcomes. 21 empiric broad-spectrum antibiotics may be considered. 15

Medication management

Therapeutic hypothermia can lead to alterations in the pharmacokinetics and pharmacodynamics of multiple medications. 22

For example, there is decreased receptor response to morphine during

Hypothermia. During the cooling phase, the morphine dosage may need to

what is anoxic brain injury

Be escalated to achieve adequate effect. However, during the rewarming

Phase, if the morphine dosage is not titrated downward, toxicity may

Occur. 23 there is a lack of clinical studies describing the

Clinical effects of hypothermia on medications. Pharmacists should be

Aware of potential effects and monitor for ineffectiveness and toxicity.

Additional indications

Based on the success of therapeutic hypothermia in cardiac

Arrest, its use has expanded to multiple other indications. Hypothermia

Has shown a reduction of morbidity and mortality in perinatal asphyxia.

Several studies have evaluated the effect of hypothermia on traumatic

Brain injury. While no benefit in mortality was observed, hypothermia

Was able to decrease intracranial pressure.What is anoxic brain injury therapeutic hypothermia has

Also been investigated to treat ischemic and hemorrhagic stroke, spinal

Cord injury, and hepatic encephalopathy; however, currently the data do

Not support or refute its use. 24


Therapeutic hypothermia is becoming the standard of care

For post–cardiac arrest care. Understanding temperature management,

Adverse effects from hypothermia, and potential medication alterations

Are key to pharmacist participation. Pharmacists can play a vital role

In managing adverse effects and preventing medication errors.


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