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CHAPTER 59 ■ NEUROGENIC SHOCK
SUSANNE MUEHLSCHLEGEL r DAVID M. GREER
Neurologically injured patients, regardless of the nature of the
injury, frequently experience hypotension and shock. Neurogenic shock refers to a neurologically mediated form of circulatory system failure that can occur with acute brain, spinal
cord, or even peripheral nerve injuries. In this chapter, we
will explain the epidemiology, pathophysiology, clinical presentation, and management strategies for this special form of
shock.
Contrary to common belief, neurogenic shock is not a single entity due to one single pathologic mechanism. The term
is sometimes used in nonneuroscience intensive care units to
explain hypotension occurring in any brain-injured patient,
but neurogenic shock should be considered only after systemic
causes of shock have been carefully ruled out. Just like other
critically ill patients, neurologically ill patients are prone to developing systemic conditions, such as dehydration, congestive
heart failure, acute blood loss, sepsis, pericardial tamponade,
or massive pulmonary embolism.
SUBTYPES OF
NEUROGENIC SHOCK
Once other systemic reasons for shock have been ruled out,
neurogenic shock should be considered. Three mechanisms can
lead to neurogenic shock (Fig. 59.1):
■ Vasodilatory (distributive) shock from autonomic distur-
bance with interruption of sympathetic pathways, with associated parasympathetic excitation, which causes profound
vasodilatation and bradycardia, as seen in spinal cord injury
or diseases of the peripheral nervous system (Guillain-Barré
syndrome)
■ Cardiogenic shock, as frequently seen in subarachnoid hem-
orrhage (SAH) with stunned myocardium after a catecholamine surge or ischemic stroke, especially those involving the right insula
■ Hypopituitarism/adrenal insufficiency.
Although some subtypes of neurogenic shock occur more
frequently with certain disease entities—for example, cardiogenic neurogenic shock after SAH, vasodilatory neurogenic shock with spinal cord injury—significant overlap exists between different disease entities (intracerebral hemorrhage
[ICH], SAH, traumatic brain injury [TBI], ischemic stroke), and
one cannot establish a firm rule by which neurogenic shock occurs. Interestingly, only some patients with neurologic injuries
experience true neurogenic shock, and it remains difficult to
predict in whom this will be seen.
INCIDENCE OF
NEUROGENIC SHOCK
Due to the small number of prospective epidemiologic studies,
it is difficult to establish the natural incidence of neurogenic
shock. In a retrospective review of cervical spinal cord injuries,
Bilello et al. (1) reported a 31% incidence of neurogenic shock
with hypotension and bradycardia after high cervical spinal
cord injury (C1–C5) and 24% after low cervical spinal cord
injury (C6–C7).
Cardiogenic neurogenic shock has been studied foremost in
SAH and ischemic stroke. Banki et al. (2) prospectively studied
the incidence of left ventricular (LV) dysfunction with transthoracic echocardiography (TTE) in the first 7-day period after
SAH in 173 patients. Thirteen percent had a normal ejection
fraction (EF) but had regional wall motion abnormalities that
did not correlate with coronary artery territories, and 15% had
an LVEF of less than 50%. Others report a 9% incidence of
LV wall motion abnormalities, resulting in hypotension requiring vasopressor therapy, as well as pulmonary edema in most
(80%) of these patients (3). The spectrum of injury can range
from mild to severe systolic dysfunction—the latter defined as
an EF less than 30%. Polick et al. (4) observed LV abnormalities
on TTE in 4 of 13 patients (31%) studied within 48 hours of
SAH. Resolution of these neurologically mediated wall motion
abnormalities is usually seen (2,3,5).
The third subtype of neurogenic shock, adrenal insufficiency, has been studied primarily in traumatic brain injury.
In the largest study to date, adrenal insufficiency occurred in
about 50% of patients and led to hypotension in 26% (6). Although it has been documented in other cases of acute brain
injury, the exact incidence and relationship to outcome is not
clear (7).
PATHOPHYSIOLOGY OF
NEUROGENIC SHOCK
Vasodilatory Neurogenic Shock
This variation of neurogenic shock is commonly seen with
spinal cord injuries and Guillain-Barré syndrome (acute demyelinating peripheral neuropathy) but also with traumatic
brain injuries, large hemispheric ischemic strokes, and intracerebral hemorrhages. The hallmark of vasodilatory neurogenic shock is the combination of bradycardia with fluctuating
blood pressures and heart rate variability due to interruption of
sympathetic output and excitation of parasympathetic fibers.
The sympathetic fibers originate in the hypothalamus, giving rise to neurons projecting to autonomic centers in the
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Section VI: Shock States
Vasodilatory Shock
Cardiogenic Shock
due to autonomic dysfunction
with unopposed vagal tone
• Bradycardia, hypotension
• Seen in cervical and upper
thoracic spinal cord injury
due to stunned myocardium after
catecholamine surge
• Tachycardia, hypotension
• ↓CO, ↑CVP, ↑PCWP,
• Seen in SAH, ischemic stroke
involving the insula, TBI
Neurogenic Shock
Neuroendocrine Shock
due to pituitary or adrenergic
dysfunction after CNS injury
• Hypotension poorly responsive
to vasopressor therapy
• Seen in TBI, SAH, hypothalamic
stroke
FIGURE 59.1. Neurogenic shock consists of three pathomechanisms. CNS, central nervous system; CO,
cardiac output; CVP, central venous pressure; PCWP, pulmonary capillary wedge pressure; SAH, subarachnoid hemorrhage; TBI, traumatic brain injury.
brainstem—the periaqueductal gray matter in the midbrain, the
parabrachial regions in the pons, and the intermediate reticular formation located in the ventrolateral medulla. From here,
neurons project to nuclei in the spinal cord. The sympathetic
preganglionic neurons originate in the intermediolateral cell
column within the spinal cord gray matter between T1 and
L2 and are therefore called the thoracolumbar branches. From
here, they exit the spinal cord and project to 22 pairs of paravertebral sympathetic trunk ganglia next to the vertebral column.
The main ganglia within the sympathetic trunk are the cervical and stellate ganglia. The adrenal medulla receives preganglionic fibers and thus is equivalent to a sympathetic ganglion.
Blood pressure control depends on tonic activation of the sympathetic preganglionic neurons by descending input from the
supraspinal structures (8).
The parasympathetic nervous system consists of cranial
and sacral aspects. The cranial subdivision originates from the
parasympathetic brainstem nuclei of cranial nerves III, VII, IX,
X, and XI. The cranial parasympathetic neurons travel along
the cranial nerves until they synapse in the parasympathetic
ganglia in close proximity to the target organ. The sacral subdivision originates in the sacral spinal cord (S2–S4), forming
the lateral intermediate gray zone where preganglionic neurons
travel with the pelvic nerves to the inferior hypogastric plexus
and synapse on parasympathetic ganglia within the target organs.
Following a spinal cord injury, the sympathetic pathways
are interrupted with dissociation of the sympathetic supply
from higher control below the level of transection (9,10).
Parasympathetic fibers are usually spared. This results in autonomic hyperreflexia with associated hypertension or hypotension with bradycardia, all observed in human studies as well
as in animal models (10–13). Loss of supraspinal control of
the sympathetic nervous system leads to unopposed vagal tone
with relaxation of vascular smooth muscles below the level of
the cord injury, resulting in decreased venous return, decreased
cardiac output, hypotension, loss of diurnal fluctuations of
blood pressure, reflex bradycardia, and peripheral adrenoreceptor hyperresponsiveness (14). The latter accounts for the
excessive vasopressor response repeatedly seen in this clinical
scenario. The acute phase, also known as spinal shock, more
frequently consists of periods of hypotension. After the acute
phase, starting about 2 months after the injury, autonomic dysreflexia occurs in patients with lesions above T5 (15). This state
is characterized by sympathetically mediated vasoconstriction
in muscular, skin, renal, and presumably gastrointestinal vascular beds, induced by afferent peripheral stimulation below
the level of the lesion. For example, stimuli such as urinary
catheterization, dressing changes, or surgical stimulation can
lead to severe blood pressure spikes out of proportion to the
stimulus. In Guillain-Barré syndrome, the autonomic dysregulation is likely caused by acute demyelination not only of sensory and motor fibers, but also of autonomic fibers.
Injury to the brain can also lead to vasodilatory neurogenic
shock. Certain cerebral structures, such as the insular cortex,
amygdala, lateral hypothalamus, and medulla, have great influence on the autonomic nervous system. Cortical asymmetry is present and is reflected in a higher incidence of tachycardia, ventricular arrhythmias, and hypertension with lesions
of the right insula—resulting in loss of parasympathetic input and thus sympathetic predominance—and a higher incidence of bradycardia and hypotension with injuries to the left
insula—resulting in a loss of sympathetic input and subsequent
parasympathetic predominance (16–18) (Fig. 59.2).
Cardiogenic Neurogenic Shock
This form of neurogenic shock is primarily encountered in SAH
and TBI but is also seen in ischemic stroke and intracerebral
hemorrhage. Cardiac dysfunction is a well-known complication of ischemic and hemorrhagic stroke, first described over
50 years ago (19). It is most often recognized on the electrocardiogram (ECG) as arrhythmias, QRS, ST-segment, and
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Chapter 59: Neurogenic Shock
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FIGURE 59.3. Contraction band necrosis. Histologic examination of
the myocardium, showing contraction band necrosis, see arrow. (Courtesy of Dr. James R. Stone, M.D., Ph.D., Department of Pathology,
Massachusetts General Hospital, Boston, MA.)
FIGURE 59.2. Example of a right ischemic stroke resulting in ventricular arrhythmias and cardiogenic shock. A 61-year-old man presents
with sudden onset of left hemiparesis affecting his face and arm, leftsided neglect, and a left hemianopia. He presented outside of any acute
treatment window and did not undergo thrombolysis. He was admitted
to the neurointensive care unit (NICU) for close monitoring of his cardiac and respiratory function. The noncontrast head CT shows a right
middle cerebral artery stroke and incidental hemorrhagic conversion.
Electrocardiogram on admission showed diffuse T-wave inversion in
all leads. Telemetry monitoring revealed frequent premature ventricular complexes and intermittent nonsustained ventricular tachycardia of
4 to 8 beats for the first 72 hours after stroke onset. His systolic blood
pressure on admission was elevated at 190 mm Hg but then dropped
to 85 mm Hg several hours after admission to the NICU, requiring
vasopressor support for 2 days. Troponin T levels were elevated in the
emergency room and peaked at 12 hours after stroke onset. Echocardiogram showed global hypokinesis and no regional wall motion abnormalities. No other causes for shock were found, so that the stroke
involving the right insula was the most likely cause. The shock slowly
resolved over 72 hours, and vasopressor infusion was weaned off successfully. A repeat echocardiogram 2 weeks later showed resolution of
the abnormalities.
T-wave abnormalities (20,21). Studies of SAH and cardiac injury have shown that the severity of SAH is an independent predictor of cardiac injury, supporting the hypothesis that cardiac
neurogenic shock is a neurally mediated process (22). Based
on the similarities observed between pheochromocytoma crisis and SAH, the cardiovascular changes have been linked to a
catecholamine surge.
This hypothesis has been confirmed by many studies. Patients with SAH can have a threefold increase in norepinephrine
levels that are sustained for 10 days or longer after SAH but
that normalize after the acute phase of injury (23). In an animal
model, an increase in plasma catecholamines after experimental SAH causes specific lesions on electron microscopy within
4 hours of SAH (24). Selective myocardial cell necrosis, also
known as contraction band necrosis, is the hallmark of catecholamine exposure (25–27). The same lesions can be found in
patients with pheochromocytoma (28) and SAH (29), underlining the pathologic mechanism of cardiac injury in SAH or other
neurologic injuries (Fig. 59.3). The cardiac dysfunction is not
related to coronary atherosclerosis, as normal coronary arteries have been documented in these patients studied at autopsy
or by coronary angiography (5,29–31). In fact, it appears that
pre-existing heart disease, such as hypertensive heart disease,
might even be protective of this form of neurogenic shock (32).
In a case series of 54 consecutive SAH deaths, 42 had myocardial lesions consisting of foci of necrotic muscle fibers, hemorrhages, and inflammatory cells, none of which were found
in the control group. Patients with a wider range of heart rate
and blood pressure fluctuations were more likely to have myocardial lesions. Pre-existing hypertensive heart disease led to
significantly fewer myocardial lesions, possibly reflecting a decreased sensitivity of these patients to the catecholamine surge
(32).
Pathologic studies link the central catecholamine release to
the posterior hypothalamus. Postmortem studies have found
microscopic hypothalamic lesions consisting of small hemorrhages and infarctions in those patients with typical myocardial
lesions as noted above (29,32–34). However, it appears that
raised intracranial pressure (ICP) is not responsible for these
hypothalamic changes, as the control group with elevated ICP
did not have any hypothalamic injury (32).
Overall, by the described pathomechanism, the catecholamine surge results in direct myocardial injury resulting
in decreased inotropy, and in addition an increase in cardiac
preload due to venous constriction and increased cardiac afterload by peripheral arterial constriction. As a consequence,
stroke volume diminishes, which cannot be compensated for by
reflex tachycardia, thus resulting in decreased cardiac output
and shock. This transient LV dysfunction with loss of myocardial compliance (stunning of the myocardium) is reflected by
a characteristic shape of the cardiac silhouette on a ventriculogram and on chest radiograph, which has given this disease
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Section VI: Shock States
C
A
B
FIGURE 59.4. Takotsubo cardiomyopathy. A: Japanese octopus fishing pot. B: CT brain of a 47-yearold woman with subarachnoid hemorrhage (SAH). C: Chest x-ray view of the same patient with typical
cardiac silhouette of Takotsubo cardiomyopathy. An echocardiogram revealed an ejection fraction of 29
degrees with apical ballooning, global hypokinesis, and sparing of the apex. The chest radiograph and
echocardiogram became normal within 1 week after her SAH.
entity its other name, Takotsubo cardiomyopathy, derived from
the Japanese word for the Japanese octopus fishing pot, takotsubo (35–37) (Fig. 59.4).
Pulmonary edema with concomitant hypoxia is frequently
encountered in this context and may result from cardiac congestion but can occur independently from the cardiac dysfunction as its own entity: neurogenic pulmonary edema. Massive
increases in pulmonary capillary pressures lead to pulmonary
edema and hypoxia, which in turn decreases the uptake of
oxygen in a high demand state, contributing to hemodynamic
instability. The Vietnam war era head injury series (38) reported the rapid onset of acute pulmonary edema after severe
head injury. In addition, experimental models as well as multiple human case reports of TBI and SAH have shown massive
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Chapter 59: Neurogenic Shock
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Acute Brain Injury
TBI, SAH, ICH,
ischemic stroke
Catecholamine Surge
α
Peripheral
vasoconstriction
α+β
Pulmonary
venous
constriction
Myocardial
contraction band
necrosis
Microemboli
↑Pulmonary
capillary
pressure
Neurogenic
pulmonary
edema
Platelet
aggregation
β
Damaged
endothelium
↑Pulmonary
permeability
sympathetic discharges as the primary cause of neurogenic pulmonary edema (39–41). Figure 59.5 summarizes the pathophysiology of cardiogenic neurogenic shock.
Overall, cardiac neurogenic shock, with or without neurogenic pulmonary edema, is usually transient, with resolution
within several days to 2 weeks (2–4). Prevention of secondary
brain injury from hypoxia and decreased cerebral perfusion
pressures should be the focus of care in the management of
this neurally mediated complication.
Neuroendocrine Neurogenic Shock
Insufficiency of the hypothalamic-pituitary-adrenal axis has
been recognized as an important cause for shock. Inappropriately reduced release of cortisol in stress situations can lead
to decreased systemic vascular resistance, reduced cardiac contractility, hypovolemic shock, or hyperdynamic shock that can
mimic septic shock. Secondary adrenal insufficiency due to
injury to the hypothalamic-hypopituitary feedback loop can
cause neuroendocrine neurogenic shock. Acute brain injury,
particularly TBI and SAH, can commonly lead to injury of
the hypothalamus, pituitary gland, or the connecting structures
(42). Cohan et al. (6) revealed that adrenal insufficiency after
traumatic brain injury occurred in about half of all patients
and led to a significantly higher rate of hypotension in these
patients. Most cases of adrenal insufficiency developed within
4 days of injury. Importantly, the authors defined adrenal insufficiency using a low random serum cortisol value and highlight
the fact that an increase in the cortisol level after a stimulation test does not rule out the presence of adrenal insufficiency.
This issue is particularly relevant in TBI patients, in whom
the hypothalamus and the pituitary gland are the likely affected organs, and the adrenal glands might well be expected
to mount an appropriate response when stimulated. When rec-
LVEF ↓
Shock
FIGURE 59.5. Summary of the pathophysiology of
the cardiogenic type of neurogenic shock. ICH, intracerebral hemorrhage; LVEF, left ventricular ejection
fraction; SAH, subarachnoid hemorrhage; TBI, traumatic brain injury.
ognized, primary and secondary adrenal insufficiency can easily
be treated.
In septic shock, a low-dose vasopressin infusion has been
shown to successfully restore blood pressure in hypotension
refractory to standard catecholamine therapy (43,44). Recent
studies in SAH have shown that endogenous vasopressin serum
levels are elevated during the first 2 days after SAH but decrease
to subnormal levels after 4 days (45–47). Arginine vasopressin
supplementation in SAH at low dose (0.01–0.04 units/min)
has been studied in only one single retrospective study (48).
The role of vasopressin in the setting of neurogenic shock remains to be studied in a prospective manner, but the changes in
endogenous vasopressin levels might indicate neuroendocrine
changes in neurogenic shock and potential new treatment options in SAH.
CLINICAL MANIFESTATIONS
Figure 59.6 illustrates the clinical manifestations and symptoms seen in neurogenic shock. Acutely, vasodilatory neurogenic shock presents with a “warm and dry” hemodynamic
profile. The patient is hypotensive and frequently bradycardic;
however, the peripheral vessels are dilated, leading to warm
limbs and a normal capillary refill time. Central venous pressure (CVP) is normal or low, and systemic venous resistance
(SVR) is always low. Stroke volume and cardiac output are
low due to the unopposed vagal tone. When a spinal cord injury is present, a difference in smooth muscle and vasculature
tone can be observed between the body parts above and below
the level of the injury. For example, in an injury at thoracic level
7 (T7), normal upper limb perfusion might be observed, while
vasodilatation below T7 leads to warm and dry lower extremities. Orthostatic hypotension without reflex tachycardia on
changing from a supine to an upright position—by standing
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Section VI: Shock States
Vasodilatory
Neurogenic Shock
Dry, warm skin
Bradycardia
Hypotension
SVR ↓
SV and CO ↓
CVP ↓ or normal
Cardiogenic
Neurogenic Shock
Dry, or wet, cold skin
Tachycardia (rarely bradycardia)
Hypotension
SVR ↑
SV and CO ↓
CVP ↑ or normal
PCWP ↑
EDVI ↑
Chest radiograph “Takotsubo”-shaped heart
Echo LVEF ↓ with global or segmental wall motion
abnormalities different from coronary artery territory
May have pulmonary edema
May have cardiac enzyme leak
Neuroendocrine
Neurogenic Shock
Hypotension not
responsive to vasopressors
SVR ↓
SV and CO ↓
CVP ↓ or normal
or with reverse Trendelenburg position—is common. When
treating this form of neurogenic shock with a vasopressor infusion (such as phenylephrine or other pressors), extreme caution
should be applied, as vasopressor hypersensitivity can lead to
severe rebound hypertension, which can be difficult to control.
Cardiogenic neurogenic shock manifests as hypotension and
tachycardia, with bradycardia seen rarely. Peripheral vessels are
often vasoconstricted, leading to a high SVR and cold and wet
skin. Vascular filling, as measured by CVP, pulmonary capillary wedge pressure (PCWP), and end-diastolic volume index
(EDVI), is normal or high, with low stroke volumes and cardiac output due to global myocardial dysfunction. Leaking of
cardiac enzymes—troponin, creatine kinase (CK), CK-MB—
may be seen, but frequently the peak levels are not as high as
one would find in myocardial infarction. It is difficult to establish a cutoff value that differentiates stunned myocardium from
myocardial infarction with atherosclerotic coronary artery disease. A retrospective study in SAH measuring troponin-I levels
has reported an appropriate cutoff value to be 2.8 ng/mL (49),
whereas CK-MB did not help differentiate between the two
kinds of myocardial injury. Higher levels of troponin should
raise the suspicion of true myocardial infarction, and ECG and
echocardiography correlation is important.
Neuroendocrine neurogenic shock presents with hypotension that does not respond well to vasopressor infusion. Hemodynamic signs of this category of neurogenic shock are low
CVP, SVR, stroke volume, and cardiac output. Low baseline
cortisol levels are the hallmark. A cosyntropin stimulation test
frequently leads to an appropriate increase in the cortisol level,
which does not rule out the presence of neuroendocrine neurogenic shock, as the adrenal gland is usually not the primarily
affected organ (6). For this reason, we do not find any clinical utility in this test when neuroendocrine neurogenic shock
is suspected. Resolution of the hypotension with the use of
hydrocortisone clinically confirms the presence of this shock
form.
FIGURE 59.6. Clinical manifestations of
the different types of neurogenic shock.
CO, carbon monoxide; CVP, central venous
pressure; EDVI, end-diastolic volume index;
PCWP, pulmonary capillary wedge pressure;
SV, stroke volume; SVR, systemic vascular
resistance.
DIAGNOSTIC CONSIDERATIONS
In any case of hypotension and shock in the neurointensive
care unit, systemic causes for shock must be ruled out first.
Especially in the paralyzed patient (for example, one with a
high spinal cord injury), recognition of other life-threatening
injuries can be quite difficult. Signs of hypovolemic shock may
be absent, even in a patient with profound internal bleeding, because of the absence of sympathetic tone below the
level of injury. The usual pallor from vasoconstriction and reflex tachycardia might also be absent. The patient may even
be bradycardic while continuing to bleed. For the same reason, signs of peritoneal irritation may be absent in patients
with abdominal injuries. The reported incidence of pulmonary
embolism (PE) varies tremendously in the neurocritical care
patient population—ranging from 0.5% to 20% in ischemic
stroke (50,51), to 1% in intracranial hemorrhage (52), to 8.4%
in brain tumors (53)—and there are only limited data during
the acute phase of subarachnoid hemorrhage, traumatic brain
injury, and spinal cord injury (51). Interestingly, according to
the study by Skaf et al. (50) using the National Hospital Discharge Survey, the incidence of PE did not change in patients
with ischemic and hemorrhagic stroke between 1979 and 2003.
However, the death rate from PE in the subgroup with ischemic
stroke decreased, likely due to an increased use of antithrombotic prophylaxis over the last 20 years (54). Additionally,
over the last two decades, the methods of PE detection have
improved immensely—for example, pulmonary CT-angiogram
versus nucleotide scan—and autopsy studies report additional
asymptomatic cases. In our opinion, the true incidence of PE is
underestimated. Pulmonary embolism should always be considered in cases of refractory shock. If profound hypotension
is present, or hypotension becomes progressive, reasons other
than neurogenic shock should be suspected and thoroughly
ruled out.
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Chapter 59: Neurogenic Shock
Every patient should undergo serial ECGs, serial cardiac
enzyme measurements, and a chest radiograph. As previously
mentioned, pulmonary edema and neurocardiogenic injury
may occur together or separately, making chest x-ray films important diagnostic tools. In particular, one should look for pulmonary vascular congestion and evaluate the size and shape of
the cardiac silhouette. Hemodynamic monitoring with continuous blood pressure and central venous pressure (CVP) monitoring with an arterial line and central venous line (CVL) should
be undertaken. Blood pressure measurements should be done
continuously with an arterial line. Arteriosclerosis of the upper extremities is common and should be kept in mind either
when there is a large discrepancy between right- and left-sided
pressures or when the clinical appearance of the patient does
not match the readings from the arterial line. Central venous
access is key for determining CVP and for the administration
of fluids and medications, especially vasopressors. The site of
the placement of the central venous line (CVL) may play an
important role in the management of shock in a neurologically
injured patient. Subclavian vein catheters are the preferred site
in patients with elevated intracranial pressure (ICP), as there
is a theoretical risk of venous stasis within the internal jugular
vein with venous congestion and higher risk for venous sinus
thrombosis, which could result in increased ICP (55). In addition, trauma patients frequently have cervical spine injuries
and require cervical collars, making the internal jugular vein
accessible only with difficulty.
In patients with cardiogenic neurogenic shock, more extensive hemodynamic monitoring may be necessary with either
noninvasive cardiac monitoring devices or a pulmonary artery
catheter (PAC). Echocardiography is very important to understanding the etiology of shock. In most cases, a transthoracic
echocardiogram is sufficient. The typical echocardiographic
appearance is that of apical ballooning, which results from
global hypokinesis sparing the apex (56). This part of the heart
is devoid of sympathetic nerve terminals, supporting the hypothesis that cardiac injury in SAH is neurally mediated by a
sympathetic storm. Segmental wall motion abnormalities not
conforming to distinct coronary artery territories is another
characteristic echocardiographic finding. However, myocardial
infarction from ischemic coronary disease is frequently seen in
brain-injured patients, just as in any critically ill patient, and
should always be ruled out first as a cause of shock. In the setting of fever and shock, blood cultures must be obtained and the
patient appropriately covered with antibiotics until the cultures
yield results. However, older and immunosuppressed patients
may not mount an appropriate febrile response, and thus sepsis should still be considered in these patients even when they
are afebrile, especially in the setting of a rising white blood cell
(WBC) count. Cerebral spinal fluid cultures are very important in the neurointensive care unit, with antibiotic coverage
of potential central nervous system CNS infections, especially
in patients after head trauma with skull fracture or sinus disease, after instrumentation of the head or spinal canal, or in
immunocompromised patients. Placement of intracranial pressure measurement devices do not contribute to the diagnostic
workup of shock, but they are important tools in the management of neurogenic shock, such as when the goal mean arterial
pressure (MAP) is being titrated to the cerebral perfusion pressure. Finally, adrenal insufficiency should always be considered.
Random serum cortisol levels should be obtained in the early
stages of shock, keeping in mind that in some forms of brain
931
injury, low random serum cortisol levels, and thus adrenal insufficiency, may be encountered for several days after injury (6).
Many neurologically injured patients, especially those with
spinal cord injuries, receive steroids while in the neurointensive care unit. The doses administered may be high enough to
alter the result of a random serum cortisol level, but often the
dose is not enough to treat true adrenal insufficiency appropriately. In these cases, one could either empirically treat with
higher doses of steroids that also treat adrenal insufficiency—
hydrocortisone, with or without fludrocortisone—or, keeping
the potential adverse effects of steroids in acute injury in mind,
one could withhold the administration of steroids for 12 hours,
then obtain a random cortisol level and resume steroid treatment right after the blood draw. However, hypotension is frequently severe enough that immediate treatment is warranted,
and withholding steroids often is not an option. Dexamethasone, which is frequently used in the neurointensive care unit, is
the steroid that interferes the least with the cortisol assay after
a corticotropin stimulation test and therefore allows for such a
test. In cases of high suspicion, a random cortisol level is often
preferred because of its simplicity. The cortisol level should be
drawn immediately before the steroid dose. However, given the
lack of mineralocorticoid activity of dexamethasone, changing
to hydrocortisone with or without fludrocortisone is recommended when adrenal insufficiency is suspected.
MANAGEMENT
Two important reasons for early and proactive treatment of
patients in neurogenic shock are as follows:
1. Prevention of secondary brain injury from hypoxia and hypotension
2. The fact that neurogenic shock, especially cardiogenic and
neuroendocrine forms, is easily treatable and transient, with
potentially good outcomes despite the moribund appearance
of the patient in the acute phase.
Identifying patients at risk has been very difficult, but at least
in SAH it appears that poor neurologic grade, age older than
30 years, and ventricular repolarization abnormalities are risk
factors for neurogenic shock (57).
Once the diagnosis of neurogenic shock has been established
and the pathophysiology (subtype) has been understood, treatment tailored to the specific subtype is initiated. In all cases,
euvolemia is of utmost importance and must be achieved before
any other treatment can be successful. In general, vasopressor
treatment as a continuous infusion is initiated and titrated to a
goal MAP and cerebral perfusion pressure (CPP). As an important management tool, an intracranial pressure measurement
device is very helpful, allowing the indirect measurement of
CPP. We recommend a goal CPP of greater than or equal to 65
mm Hg. The optimal CPP is not known. Data regarding the
minimum tolerable CPP comes from TBI patients, in whom
the ICP is often elevated. Several studies have suggested an improved outcome when CPP is maintained at greater than 70 mm
Hg (58,59). Other studies using physiologic measurements,
such as cerebral blood flow and brain tissue PO2 (Pbt O2 ), indicate that adverse changes do not occur unless the CPP is below
50 to 60 mm Hg (60,61).
Vasodilatory neurogenic shock can be difficult to treat.
In general, vagal tone predominates; however, in this state,
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patients frequently have peripheral α-adrenoceptor hyperresponsiveness, limiting the use of norepinephrine, epinephrine,
ephedrine, and phenylephrine. In fact, sympathomimetics
should be avoided as they can lead to severe blood pressure
fluctuations. Since arginine vasopressin (AVP) does not affect
α- or β-adrenergic receptors, but acts on V1 receptors, AVP
may have an advantage over catecholamines or phenylephrine
in this form of neurogenic shock. It has not been studied in neurogenic shock, however, and it remains unclear whether AVP
may have adverse effects on neurologically ill patients. This
concern is based on animal studies indicating that vasopressin
may promote the development of vasospasm in SAH, and indirect experimental studies showing a reduction in brain edema
with vasopressin antagonists. No prospective human study has
been undertaken to confirm or dismiss this concern, and the
only retrospective study on the use of vasopressin in SAH did
not show any of these potentially adverse effects (48). In addition to vasopressors, a temporary demand pacemaker and/or
atropine may be required in cases of refractory bradycardia
and hypotension.
In cardiogenic neurogenic shock, some form of inotropic
support may be necessary, either in the form of a dobutamine,
milrinone, or norepinephrine infusion. Dopamine is generally
avoided because of its proarrhythmic properties. Dobutamine
and milrinone also have vasodilatory effects, frequently leading to more hypotension, requiring additional therapy with an
α-receptor agonist, such as phenylephrine or norepinephrine.
Afterload increases in the former, and tachycardia in the latter,
might be limiting factors and need careful monitoring. Cardiac
output monitoring may be undertaken with the guidance of
a PAC. Beta-blockade is usually not recommended. In neurogenic cardiogenic shock, coronary artery disease is typically not
present, and compensatory tachycardia is necessary to maintain cardiac output. Afterload reduction with cautious use of
angiotensin-converting enzyme (ACE) inhibitors should be attempted, but further hypotension must be avoided to maintain tenuous cerebral perfusion pressures. Short-acting agents
should be used whenever possible. Repeating an echocardiogram several days after the initial one is recommended to monitor the progression/resolution of cardiac dysfunction. The need
for an intra-aortic balloon pump to mechanically reduce afterload and improve coronary perfusion pressure may be considered, albeit rarely used.
Once diagnosed, neuroendocrine neurogenic shock from
primary, or more often secondary, adrenal insufficiency is
treated with steroid replacement therapy. We use the same dosing as in adrenal insufficiency in septic shock: hydrocortisone,
50 mg intravenously every 6 hours. As previously discussed,
a cortisol stimulation test is usually not helpful, and empiric
treatment after a random cortisol level should be initiated.
SUMMARY
Neurogenic shock is not a single entity, but rather is composed
of three subtypes and pathophysiologies: vasodilatory, cardiac,
and neuroendocrine. Other causes of hypotension should be
ruled out first, prior to making the diagnosis of neurogenic
shock. In most cases, neurogenic shock is transient and reversible, making this entity very treatable. Diagnosis and treatment should be tailored to the subtype of neurogenic shock.
Maintenance of cerebral perfusion pressures is the key prin-
ciple of management to prevent secondary brain injury and
improve outcome.
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CHAPTER 60 ■ ANAPHYLACTIC SHOCK
MEGHAVI S. KOSBOTH r ERIC S. SOBEL
Anaphylaxis is severe, has a rapid onset, and is potentially
fatal—a systemic allergic reaction that occurs after contact with
an allergy-causing substance (1,2). Activation of mast cell and
basophil populations by either IgE-dependent (i.e., anaphylactic reactions) or IgE-independent (i.e., anaphylactoid reactions)
mechanisms results in the release of multiple mediators capable
of altering vascular permeability and vascular and bronchial
smooth muscle tone, as well as recruiting and activating inflammatory cell cascades. Because the clinical presentations
of anaphylactic and anaphylactoid reactions are indistinguishable, they will be referred to as anaphylaxis for the purposes
of this chapter. Initial sequelae, which occur within minutes
to an hour after exposure to an inciting stimulus, include gen-
eralized hives, tachycardia, flushing, pruritus, faintness, and a
sensation of impending doom. Dermatologic (i.e., urticaria and
angioedema), respiratory (i.e., dyspnea, wheeze, stridor, bronchospasm, and hypoxemia), and gastrointestinal (i.e., abdominal distension, nausea, emesis, and diarrhea) manifestations
are common. Involvement of the cardiovascular and respiratory systems may result in potentially life-threatening manifestations, such as cardiovascular collapse caused by vasodilation
and capillary leak, myocardial depression, myocardial ischemia
and infarction, and atrial fibrillation (3). Prompt recognition and effective intervention are essential to prevent
the fatal manifestations of anaphylactic and anaphylactoid
reactions.
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INCIDENCE
CLINICAL MANIFESTATIONS
The incidence of anaphylaxis is difficult to determine accurately
due to underdiagnosis and underreporting. In the United States,
fatal anaphylaxis causes 500 to 1,000 fatalities per year and
accounts for 1% of emergency department visits (1,4,5). The
anaphylaxis rate was found to be 21 per 100,000 person-years
in a study of nonhospitalized individuals in Olmsted County,
Minnesota, between 1983 and 1987 (6). A subsequent analysis
of the General Practice database in the United Kingdom noted
the incidence to be 8.4 per 100,000 person-years (7). An epidemiologic study involving 481,752 individuals suggested that
hospitalized patients are at increased risk of anaphylaxis, but
these reactions are rarely fatal (8).
The clinical syndromes associated with systemic anaphylactic and anaphylactoid reactions represent medical emergencies, as they are associated with a rapid, critical destabilization of vital organ systems. These syndromes, which are,
again, clinically indistinguishable, may become rapidly fatal
if appropriate therapy is not instituted immediately. Initial
symptoms can appear within seconds to minutes but may
be delayed by as much as 1 (or rarely more) hour after exposure to an inciting agent (30), and are often nonspecific
(31). These symptoms include tachycardia, faintness, cutaneous flushing, urticaria, diffuse or palmar pruritus, and a
sensation of impending doom (32). Of these, generalized urticaria is the most common, occurring in approximately 90%
of patients (Table 60.3) (33,34). Subsequent manifestations indicate involvement of the cutaneous, gastrointestinal, respiratory, and cardiovascular systems. Involvement of the cardiovascular and respiratory systems is responsible for the fatal
ETIOLOGY
The most common causes of anaphylaxis include insect stings,
foods, drugs, and physical factors/exercise. Idiopathic anaphylaxis (where no causative agent is identified) accounts for up
to two thirds of patients referred to allergy/immunology specialty clinics (9,10). Foods such as shellfish, eggs, nuts, and milk
account for one third of food-induced anaphylactic episodes
(10–13) (Tables 60.1 and 60.2). There is a syndrome of fooddependent, exercise-induced anaphylaxis (FDEIA) that develops only if food is ingested prior to exercise or exertion (14).
Seafood, nuts, celery, wheat, and grains have been implicated
as allergens in this syndrome. It is important to note that these
foods are tolerated by the patient in the absence of exertion
(14,15).
Anaphylactic reactions to stings or bites of various insects,
such as members of the order Hymenoptera (yellow jackets,
bees, wasps, hornets, and saw flies) are commonly reported.
A positive venom skin test along with a systemic reaction to
the insect sting predicts a 50% to 60% risk of reaction to
future stings (16). Medications can cause anaphylactic (IgEmediated) and anaphylactoid (non–IgE-mediated) reactions.
Previous exposure to drugs is required for IgE production and
anaphylactic reactions, but anaphylactoid reactions can occur
upon first administration. Penicillin is one of the most common causes of anaphylaxis, with 1 to 5 per 10,000 courses
with penicillin resulting in allergic reactions and 1 in 50,000
to 1 in 100,000 courses with a fatal outcome (17–19). Nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin are the
second most common class of drugs implicated in anaphylaxis
(20). Some hypersensitivity reactions will occur with different NSAID agents, while others are specific to a single drug
(21).
With widespread adoption of universal precautions against
infections, latex allergy has become a significant problem. The
development of low-protein, powder-free gloves has been associated with reduction in occupational-contact urticaria caused
by latex rubber gloves (22). Despite this, latex allergy is still
a concern since latex is found in gloves, catheters, and tubing
(23–25). Iodinated radiocontrast media can cause anaphylaxis;
however, life-threatening reactions are rare (26). A history of a
previous reaction to radiocontrast media, asthma or atopic disease, treatment with β-blockers, and cardiovascular disease are
risk factors for developing anaphylaxis to radiocontrast media
(27–29).
TA B L E 6 0 . 1
ETIOLOGIC AGENTS FOR ANAPHYLAXIS (IGEMEDIATED)
HAPTENS
β-Lactam antibiotics
Sulfonamides
Nitrofurantoin
Demethylchlortetracycline
Streptomycin
Vancomycin
Local anesthetics
Others
SERUM PRODUCTS
γ -Globulin
Immunotherapy for
allergic diseases
Heterologous serum
FOODS
Nuts (peanuts, brazil
nuts, hazelnuts,
cashews, pistachios,
almonds, soy nuts)
Shellfish
Buckwheat
Egg white
Cottonseed
Cow’s milk
Corn
Potato
Rice
Legumes
Citrus fruits
Chocolate
Others
VENOM
Stinging insects, particularly
Hymenoptera, fire ants, deer
flies, jelly fish, kissing bugs
(triatoma), and rattlesnakes
HORMONES
Insulin
Adrenocorticotropic hormone
Thyroid-stimulating hormone
ENZYMES
Chymopapain
L-Asparaginase
MISCELLANEOUS
Seminal fluid
Others
Boldface: Relatively common causes
Modified from Austen KF. Systemic anaphylaxis in man. JAMA. 1965;
192:108; and Kaliner M. Anaphylaxis. NER Allergy Proc. 1984;5:
324.
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TA B L E 6 0 . 2
ETIOLOGIC AGENTS FOR ANAPHYLACTOID REACTIONS
COMPLEMENT-MEDIATED REACTIONS
Blood
Serum
Plasma
Plasmate (but not albumin)
Immunoglobins
ARACHIDONIC ACID MODULATORS
Nonsteroidal anti-inflammatory drugs
Tartrazine (possible)
NONIMMUNOLOGIC MAST CELL ACTIVATORS
Opiates and narcotics
Radiocontrast media
Dextrans
Neuromuscular blocking agents
UNKNOWN
Sulfites
Others
IDIOPATHIC
Most common conclusion after thorough evaluation
THERMOREGULATORY MECHANISM
Cold temperature, exercise
Boldface: Relatively common causes.
Adapted from Kaliner M. Anaphylaxis. NER Allergy Proc. 1984;5:324.
complications of anaphylactic/anaphylactoid reactions. An
unsettling sensation—including hoarseness, dysphonia, or
dyspnea—may precede acute upper airway obstruction secondary to laryngeal edema. Other pulmonary manifestations
include acute bronchospasm, intra-alveolar pulmonary hemorrhage, bronchorrhea, and a noncardiogenic, high permeability–
type pulmonary edema (17,35). Tachycardia and syncope may
precede the development of hypotension and frank cardiovascular collapse (36,37). Anaphylactic shock occurs as a consequence of diminished venous return secondary to systemic
vasodilation and intravascular volume contraction caused by
capillary leak. Although transient increases in cardiac output
may occur at the onset of anaphylaxis, hemodynamic parameters later reveal decreases in cardiac output, systemic vascular resistance, stroke volume, pulmonary artery occlusion, and
central venous pressures (38–44). In addition, the acute onset
of a lactic acidosis and diminished oxygen consumption have
been noticed after an anaphylactoid reaction (45). Other potentially serious cardiovascular manifestations are myocardial
ischemia and acute myocardial infarction, atrioventricular and
intraventricular conduction abnormalities such as prolonged
PR interval, transient left bundle branch block, and supraventricular arrhythmias such as atrial fibrillation. Severe, but reversible, myocardial depression also has been reported (37).
Hematologic manifestations, such as disseminated intravascular coagulation and hemoconcentration secondary to volume
contraction, also may complicate anaphylactic and anaphylactoid reactions (32). Gastrointestinal manifestations include
nausea, bloating, abdominal cramps, and diarrhea.
In 1% to 20% of patients, there is a recurrence of symptoms
after a period of recovery, termed biphasic anaphylaxis (46). In
most cases, the symptoms recurred 1 to 8 hours after the initial
TA B L E 6 0 . 3
CLINICAL MANIFESTATIONS OF ANAPHYLACTIC AND ANAPHYLACTOID REACTIONS
System
RESPIRATORY
Upper
Symptom
Frequency
Sign/clinical manifestation
60%–80%
Lower
Dyspnea, dysphonia, cough, “lump in
throat”
Dyspnea, cyanosis
CARDIOVASCULAR
Palpitations, faintness, weakness
CUTANEOUS
Flushing, pruritus, rash
GASTROINTESTINAL Abdominal pain, bloating, cramps,
nausea
NEUROLOGIC
Dizziness, disorientation, hallucinations,
headache, feeling of impending doom
NASAL
Pruritus, sneezing
OCULAR
Conjunctival pruritus, periorbital edema
HEMATOLOGIC
DIC, disseminated intravascular coagulation.
5%–10%
Upper airway obstruction caused by laryngeal
edema and spasm; bronchorrhea
Noncardiogenic pulmonary edema, bronchospasm,
acute hyperinflation, alveolar hemorrhage
Shock, tachycardia, capillary leak, syncope,
supraventricular arrhythmias, conduction
disturbances, myocardial ischemia and infarction
Urticaria, angioedema, diaphoresis
Emesis, diarrhea, hepatosplenic congestion; rarely
hematemesis and bloody diarrhea
Syncope, lethargy, seizures
16%–20%
10%–15%
Rhinorrhea, nasal congestion
Conjunctival suffusion, lacrimation
20%
90%
30%
Hemoconcentration, DIC
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presentation, although there have been reports of recurrence
up to 72 hours later. There were no features of the primary
response that predicted the occurrence of a secondary response
(47).
DIAGNOSIS
The diagnosis of anaphylaxis is established on the basis of clinical grounds alone because expedient institution of appropriate therapy is mandatory. These diagnoses should be considered when typical multisystem manifestations occur in a direct
temporal relationship with exposure to an inciting agent. Recently, the National Institute of Allergy and Infectious Diseases
(NIAID) and the Food Allergy and Anaphylaxis Network
(FAAN) proposed clinical criteria for the diagnosis of anaphylaxis (Fig. 60.1) (1). Because of the multisystem nature of anaphylactic and anaphylactoid reactions, the list of differential
diagnoses that must be considered is extensive. Diagnostic possibilities include cardiac dysrhythmias, myocardial infarction,
distributive or hypovolemic shock, vasovagal syncope, asthma,
pulmonary embolism, upper airway obstruction secondary to
ingestion of a foreign body, hypoglycemia, and the carcinoid
syndrome (Table 60.4).
Demonstration of acute elevations of markers specific to
mast cell activation such as histamine and tryptase have been
proposed to help confirm the diagnosis of anaphylaxis (48,49).
However, in a series of 97 patients presenting to an emergency
department and given the diagnosis of anaphylaxis, only 42%
were found to have elevated plasma histamine levels, and 24%
had increased plasma tryptase levels (50). Skin testing or serum
antibody tests can help demonstrate the presence of IgE against
a specific allergen. Skin testing should be delayed for up to 4
weeks to allow the dermal mast cells to replenish intracellular
mediators (51).
PATHOPHYSIOLOGY
The systemic manifestations of anaphylactic and anaphylactoid reactions represent sequelae that result from the release
of inflammatory mediators by mast cells and basophils. The
classic anaphylactic response occurs through allergen-induced
crosslinking of IgE tightly bound to the high-affinity FcR1 receptor constitutively expressed by mast cells (52). Release of
histamine from preformed mast cell granules seems to be the
primary pathophysiologic mediator, resulting in systemic vasodilation, increased vascular permeability, bronchoconstriction, pruritus, and increased mucus production. However,
a number of other preformed mediators are released, including heparin, serotonin, and mast cell proteases such as
chymase and tryptase (53). In addition, other important mediators of anaphylaxis are generated by the metabolism of membrane phospholipids. Activation of the 5-lipoxygenase pathway results in synthesis of leukotrienes, including leukotrienes
C4 , D4 , E4 (termed the slow-reacting substance of anaphylaxis), and B4 . Leukotrienes C4 , D4 , and E4 , along with the
intermediary products 5-hydroxyeicosatetraenoic acid and 5hydroperoxyeicosatetraenoic acid, elicit increases in vascular
permeability and bronchoconstriction, whereas leukotriene B4
possesses eosinophil and neutrophil chemotactic properties.
Activation of the cyclooxygenase pathway leads to the production of prostaglandin D2 , which produces bronchoconstriction.
Platelet-activating factor is also newly synthesized by activated
mast cells and can result in bronchoconstriction, increased vascular permeability, platelet aggregation, and neutrophil chemotaxis. It also leads to further production of platelet-activating
factor through stimulation of nuclear factor (NF)-κB, a positive feedback mechanism involving the cytokines interleukin-1
(IL-1) and tumor necrosis factor (TNF)-α, and contributes
to a biphasic pattern seen in some patients (54). Combined,
these primary mediators then facilitate the production of a diverse number of secondary mediators by platelets, neutrophils,
eosinophils, and other cells, resulting in activation of the complement, coagulation, and fibrinolytic pathways (55).
Many of these mediators have complicated effects, and their
relative roles in mediating anaphylaxis in vivo have been difficult to evaluate. Mouse models of anaphylaxis using strains
with targeted deletions of specific mediators have been useful
in elucidating the importance of different effector molecules,
such as the leukotrienes (56–58), and in identifying regulatory
Acute onset of illness (minutes
to few hours)
No known exposure to allergen
Exposure to likely allergen for
that patient
Exposure to known allergen for
that patient
Skin or mucosal involvement and
either:
At least two of the following:
Reduced BP or associated signs
Respiratory compromise
Skin and/or mucosal involvement
or
Reduced BP or associated signs
Respiratory compromise
or both
Reduced BP or associated signs
Persistent gastrointestinal symptoms
FIGURE 60.1. Clinical criteria for diagnosing anaphylaxis. Fewer signs are
required for diagnosis as the history
of allergen exposure becomes more
certain. Signs or symptoms of skin
involvement: Generalized hives, pruritus, or flushing. Signs of mucosal
involvement: Swollen lips, tongue,
and/or uvula. Signs of respiratory
compromise: Dyspnea, wheeze, bronchospasm, stridor, reduced peak expiratory flow, and/or hypoxemia. Definition of reduced blood pressure
(BP): Adults—systolic BP less than
90 mm Hg or greater than 30% decrease from that person’s baseline;
children—systolic BP less than 70 mm
Hg from 1 month to 1 year, less than
(70 mm Hg + [2 × age]) from 1
to 10 years, and less than 90 mm
Hg from 11 to 17 years or associated signs: Hypotonia, syncope, incontinence. Persistent gastrointestinal symptoms: Crampy abdominal
pain and vomiting.
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937
TA B L E 6 0 . 4
DIFFERENTIAL DIAGNOSIS OF ANAPHYLAXIS
FLUSH SYNDROME
Carcinoid
Pheochromocytoma
Peri-postmenopausal hot flushes
Medullary carcinoma of thyroid
Red man syndrome (vancomycin)
HYPOTENSION
Septic shock
Hemorrhagic shock
Cardiogenic shock
Hypovolemic shock
Vasovagal reaction
POSTPRANDIAL COLLAPSE
Airway foreign body
Monosodium glutamate ingestion
Sulfite
Scombroid fish poisoning
MISCELLANEOUS
Panic attacks
Systemic mastocytosis
Basophilic leukemia
Hereditary angioedema
Hyper-IgE syndrome
RESPIRATORY DISTRESS
Status asthmaticus
Airway foreign body
Epiglottitis
Pulmonary embolism
Asthma and COPD exacerbation
Vocal cord dysfunction
IgE, immunoglobulin E; COPD, chronic obstructive pulmonary disorder.
pathways, such as IL-10 (59), but have also provided some
surprises that may lead to clinically useful information. For example, mice with targeted deletions of either the high-affinity
FcR1 receptor or IgE, not surprisingly, had a markedly decreased susceptibility to IgE-mediated anaphylaxis (53,60).
This pathway can also be blocked with targeted deletion of
histamine receptor 1 and, to a lesser extent, platelet-activating
factor (52,53). However, such mice also revealed the presence
of an alternate IgE-independent pathway of anaphylaxis (61).
This pathway was mediated largely through platelet-activating
factor, which was triggered by the binding of IgG to Fcγ RIII
receptors present on macrophages (52,62). Like the classic IgEmediated pathway, this alternative pathway required prior exposure to antigen, but differed in that much higher concentrations of antigen were required. The importance of this pathway
in humans is as yet unclear (52). However, the administration
of biologic agents, such as the anti-TNF antibody infliximab,
has been reported to cause an IgE-independent anaphylactic
response (63), and may be an example of this alternative pathway. The use of these biologic agents is expected to continue
to increase.
MANAGEMENT
The clinician must have a high index of suspicion for anaphylactic and anaphylactoid reactions because they require a
prompt clinical diagnosis and a rapid therapeutic response. Because anaphylactic and anaphylactoid reactions both represent
sequelae of mast cell and basophil degranulation, the therapeutic approaches to these disorders are identical. Initial attention should be given to assessment and stabilization of the
pulmonary and cardiovascular manifestations of anaphylaxis,
because these are the major causes of death.
Epinephrine is the mainstay of initial management and
should be administered immediately. It decreases mediator synthesis and release by increasing intracellular concentrations
of cyclic adenosine monophosphate (cAMP) and antagonizes
many of the adverse actions of the mediators of anaphylaxis
(41). Aqueous epinephrine, 0.01 mg/kg (maximum dose 0.5
mg) administered intramuscularly every 5 to 15 minutes as
necessary to control symptoms and maintain blood pressure, is
recommended (41,64). The participants of the NIAID/FAAN
symposium concluded that the intramuscular administration of
epinephrine in the anterior lateral thigh is preferred over subcutaneous injection (1,2). In cases of severe laryngospasm or
frank cardiovascular collapse, or when there is an inadequate
response to subcutaneous epinephrine administration and fluid
resuscitation, intravenous epinephrine is an option. There is
no established dosage regimen for intravenous epinephrine in
anaphylaxis, but suggested dosages are 5 to 10 μg bolus (0.2
μg/kg) for hypotension and 0.1 to 0.5 mg in the setting of
cardiovascular collapse (1,2,65). When epinephrine is administered IV, the clinician should be aware of the potential adverse consequences of severe tachycardia, myocardial ischemia,
hypertension, severe vasospasm, and gangrene—the latter
when infused by peripheral venous access (66).
Blood pressure measurements should be obtained frequently, and an indwelling arterial catheter should be inserted
in cases of moderate to severe anaphylaxis. High-flow oxygen
given via endotracheal tube or a nonrebreather mask should
be administered to patients experiencing hypoxemia, respiratory distress, or hemodynamic instability (1,2). Orotracheal
intubation may be attempted if the airway obstruction compromises effective ventilation despite pharmacologic intervention; however, attempts may be unsuccessful if laryngeal edema
is severe. If endotracheal intubation is unsuccessful, then either needle-catheter cricothyroid ventilation, cricothyrotomy,
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or surgical tracheostomy is required to maintain an adequate
airway. Clinicians must be familiar with at least one of these
techniques in the event that endotracheal intubation cannot be
accomplished. It has been suggested that inhaled β 2 -agonists
such as albuterol may be useful for bronchospasm refractory to epinephrine (1,2,67). Patients should be placed in the
recumbent position, with lower extremities elevated to increase fluid return centrally, thereby increasing cardiac output (68). Airway protection should be ensured in the event of
vomiting.
Antihistamines (H1 and H2 antagonists) are considered
second-line treatment for anaphylaxis (1,2). They are useful in
the treatment of symptomatic urticaria-angioedema and pruritus. Recent studies suggest that treatment with a combination
of H1 and H2 antagonists is more effective in attenuating the
cutaneous manifestations of anaphylaxis than H1 antagonists
alone (50,69). Diphenhydramine hydrochloride (25 to 50 mg
IV or IM for adults and 1 mg/kg, up to 50 mg, for children)
and ranitidine (50 mg IV over 5 minutes) are commonly used
in this setting. If hypotension persists despite administration of
epinephrine and H1 and H2 blockers, aggressive volume resuscitation should be instituted. Up to 35% of the blood volume
may extravasated in the first 10 minutes of a severe reaction,
with subsequent reduction in blood volume due to vasodilatation, causing distributive shock (70). Persistent hypotension
may require multiple fluid boluses (10 to 20 mL/kg under pressure) as well as colloid and crystalloid infusions (1,2). Vasopressors such as norepinephrine, vasopressin, Neo-Synephrine,
or even metaraminol may be useful in persistent hypotension
(31).
There have been no placebo-controlled trials evaluating the
efficacy of corticosteroids in anaphylaxis, but their contribution in other allergic diseases has led to their inclusion in anaphylactic management. Due to their slow onset of action, they
are not useful in acute management. However, it has been suggested that they may prevent protracted or biphasic reactions
(67,71). The usual dose is 100 to 250 mg of hydrocortisone IV
every 6 hours (39).
The management of anaphylaxis in a patient receiving βantagonist medications, such as β blockers, represents a special circumstance in which the manifestations of anaphylaxis
may be exceptionally severe (72). β Blockade increases mediator synthesis and release, as well as end-organ sensitivity. In
addition, β-blockade antagonizes the beneficial β-mediated effects of epinephrine therapy, thereby resulting in unopposed
α-adrenergic and reflex vagotonic effects: vasoconstriction,
bronchoconstriction, and bradycardia. Therapy of anaphylaxis
occurring in patients receiving β-antagonist drugs, however, is
similar to that of other patients. In addition, atropine may be
useful for heart block and refractory bronchospasm, whereas
glucagons—which increase cAMP levels through a β-receptor–
independent mechanism—have been reported to reverse the
cardiovascular manifestations of anaphylaxis in patients receiving β-antagonists (72). Glucagon can be administered as
a 1- to 5-mg (20–30 μg/kg with maximum dose of 1 mg in
children) intravenous infusion over 5 minutes, followed by an
infusion of 5 to 15 μg/minute titrated to a clinical response
(1,2). Furthermore, these patients may require extended periods of observation because of the long duration of action of
many β-antagonist medications.
An emergent evaluation for the inciting etiologic agent must
accompany initial therapeutic interventions. After the etiologic
agent is identified, the clinician should attempt to prevent further access to the circulation or limit further absorption. Infusions of possible etiologic agents should be stopped and the
contents saved for analysis. If a Hymenoptera sting is responsible, the stinger should be removed. Small amounts of local
epinephrine—0.1 to 0.2 mL of a 1:1,000 solution—should be
injected next to a subcutaneous or intramuscular injection site
that is dispersing the inciting agent. A tourniquet also should
be placed proximal to the injection site and pressure applied to
occlude venous return. After successful pharmacologic therapy,
the tourniquet may be cautiously removed and the patient carefully observed for recurrent adverse sequelae. In cases where
the offending agent was ingested, consideration may be given
to insertion of a nasogastric tube to perform gastric lavage and
gastric instillation of activated charcoal.
THERAPEUTIC PEARLS
1. Rapidly assess and maintain the airway, breathing, and
circulation. If airway obstruction is imminent, perform
endotracheal intubation; if unsuccessful, consider needlecatheter cricothyroid ventilation, cricothyrotomy, or tracheostomy. Patients in anaphylactic shock should be placed
in a recumbent position with the lower extremities elevated, unless precluded by shortness of breath or vomiting.
2. Remove the inciting agent (i.e., remove Hymenoptera
stinger) and follow with an intramuscular epinephrine injection in the anterior lateral thigh. Consider gastric lavage
and administration of activated charcoal if the inciting
agent was ingested.
3. Administer aqueous epinephrine, 0.01 mg/kg (maximum
dose, 0.5 mg) intramuscularly every 5 to 15 minutes as
necessary for controlling symptoms and maintaining blood
pressure.
4. Establish intravenous access for hydration and provide
supplemental oxygen.
5. Administer histamine antagonists to block vasodilation,
capillary leak, and shock (H1 blockade, 25–50 mg of
diphenhydramine IV or IM for adults, and 1 mg/kg—up
to 50 mg—for children; H2 blockade, 50 mg of ranitidine
IV).
6. Administer vasopressors for persistent hypotension and
titrate to a mean arterial pressure of 60 mm Hg.
7. Consider aggressive fluid resuscitation with multiple fluid
boluses (10–20 mL/kg under pressure), including colloid
as well as crystalloid, in patients who remain hypotensive
despite epinephrine.
8. Administer inhaled β 2 -agonists such as albuterol for bronchospasm refractory to epinephrine (73).
9. Consider corticosteroid therapy for protracted anaphylaxis or to prevent biphasic anaphylaxis (1.0–2.0 mg/kg
methylprednisolone IV every 6 hours). Oral prednisone at
1.0 mg/kg, up to 50 mg, may be used for milder attacks.
Corticosteroids are not effective therapy for the acute manifestations of anaphylaxis.
10. Consider glucagon administration (1–5 mg IV over 1
minute, then 1–5 mg/hour in a continuous infusion) in
the setting of prior β-blockade because of its positive inotropic and chronotropic effects mediated by a β-receptor–
independent mechanism.
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11. Prevent recurrent episodes by avoidance of the inciting agent, desensitization, or premedication with corticosteroids and H1 and H2 blockade.
12. Admission to the intensive care unit is warranted for
invasive monitoring with arterial and pulmonary artery
catheters, electrocardiography, pulse oximetry, and frequent arterial blood gas measurements.
OBSERVATION
An observation period should be considered for all patients following treatment of an anaphylactic reaction. On the basis of
clinical data available to date, the NIAID/FAAN symposium
recommends that observation periods be individualized on the
basis of severity of initial reaction, reliability of the patient,
and access to care. A reasonable time would be 4 to 6 hours
for most patients, with prolonged observation or hospital admission for severe or refractory symptoms and patients with
reactive airway disease (1,2).
FOLLOW-UP, MANAGEMENT,
AND PREVENTION
The ideal method for managing severe systemic anaphylactic
and anaphylactoid reactions is by preventing their occurrence.
Persons with a known sensitivity should avoid re-exposure to
the inciting etiologic agents. Patients who have experienced
respiratory or cardiovascular symptoms of anaphylaxis should
receive self-injectable epinephrine for use if anaphylaxis develops. These patients should also have an emergency action plan
detailing its use and follow-up management (1,2). If a precipitating allergen is known or identified, patients should receive
information about avoiding it in the future, prior to their discharge from the emergency facility. They should be encouraged
to obtain prompt follow-up with their primary care physician
as well as an allergist (1,2).
IMPLICATIONS AND OUTCOME
Anaphylactic/anaphylactoid reactions represent important, potentially reversible, acute respiratory and cardiovascular emergencies. Although the optimal management method is that of
prevention, prompt diagnosis and institution of therapy are
crucial after these reactions have been initiated in order to prevent the fatal cardiovascular and pulmonary manifestations.
Factors associated with improved survival include the sensitivity of the person to the inciting agent, the duration between
the exposure and the onset of symptoms (short latency periods
are associated with more severe manifestations), the route and
dose of the offending agent (larger doses and parenteral administration are associated with more severe manifestations),
and the interval between onset of symptoms and subsequent
diagnosis and institution of appropriate therapy (74). Optimal
management of acute systemic reactions includes appropriate
pharmacologic intervention, support of pulmonary and cardiovascular function, and removal of the offending agent. Expeditious institution of these measures helps to reduce the morbidity
and mortality associated with these potentially life-threatening
syndromes.
939
SUMMARY
1. Anaphylactic reactions represent type I immune responses
mediated by IgE bound to mast cells or basophils. Common inciting agents include β-lactam antibiotics and Hymenoptera stings. Other common causes include foods, local anesthetics, and serum products.
2. Anaphylactoid reactions represent IgE-independent activation of mast cells or basophils, with resultant degranulation and mediator release. Common inciting agents include
iodinated radiocontrast media, neuromuscular depolarizing agents, and opiates, all of which induce direct mast
cell activation; nonsteroidal anti-inflammatory agents acting through cyclooxygenase inhibition; and blood products
acting through complement activation.
3. A history of a previous reaction to radiocontrast media,
asthma or atopic disease, treatment with β-blockers, and
cardiovascular disease are risk factors for developing anaphylaxis to radiocontrast media (27–29).
4. The differential diagnosis of anaphylactic and anaphylactoid reactions includes cardiac arrhythmias, myocardial infarction and cardiogenic shock, distributive or hypovolemic
shock, vasovagal syncope, asthma, pulmonary embolism,
upper airway obstruction secondary to a foreign body, vocal
chord dysfunction, hypoglycemia, carcinoid syndrome, systemic mastocytosis, hereditary angioedema, and leukemia
with excess histamine production.
5. Epinephrine is the initial drug of choice for the management of anaphylactic or anaphylactoid reactions. H1 and H2 -blocking agents also should be administered. Corticosteroids are not effective for the acute management
of anaphylactic or anaphylactoid reactions, but may prevent biphasic anaphylaxis or attenuate prolonged reactions.
Glucagon may be used for persistent hypotension in patients
taking β-blockers.
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