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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. Neuro-
genic shock refers to a neurologically mediated form of circu-
latory 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 pre-
sentation, and management strategies for this special form of
shock.
Contrary to common belief, neurogenic shock is not a sin-
gle 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 de-
veloping 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 as-
sociated 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 cate-
cholamine surge or ischemic stroke, especially those involv-
ing the right insula
■ Hypopituitarism/adrenal insufficiency.
Although some subtypes of neurogenic shock occur more
frequently with certain disease entities—for example, car-
diogenic neurogenic shock after SAH, vasodilatory neuro-
genic shock with spinal cord injury—significant overlap ex-
ists 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 oc-
curs. Interestingly, only some patients with neurologic injuries
experience true neurogenic shock, and it remains difficult to
predict in whom this will be seen.
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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 transtho-
racic 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 requir-
ing 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 insuffi-
ciency, 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). Al-
though 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 de-
myelinating peripheral neuropathy) but also with traumatic
brain injuries, large hemispheric ischemic strokes, and intra-
cerebral hemorrhages. The hallmark of vasodilatory neuro-
genic 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, giv-
ing rise to neurons projecting to autonomic centers in the
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926 Section VI: Shock States

Vasodilatory Shock Cardiogenic Shock

due to autonomic dysfunction due to stunned myocardium after
with unopposed vagal tone catecholamine surge
• Bradycardia, hypotension • Tachycardia, hypotension
• Seen in cervical and upper • ↓CO, ↑CVP, ↑PCWP,
thoracic spinal cord injury • 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, sub-
arachnoid hemorrhage; TBI, traumatic brain injury.

brainstem—the periaqueductal gray matter in the midbrain, the
parabrachial regions in the pons, and the intermediate reticu-
lar 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 paraver-
tebral sympathetic trunk ganglia next to the vertebral column.
The main ganglia within the sympathetic trunk are the cervi-
cal and stellate ganglia. The adrenal medulla receives pregan-
glionic fibers and thus is equivalent to a sympathetic ganglion.
Blood pressure control depends on tonic activation of the sym-
pathetic 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 sub-
division 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 or-
gans.
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 auto-
nomic hyperreflexia with associated hypertension or hypoten-
sion 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 adrenore-
ceptor 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 dys-
reflexia occurs in patients with lesions above T5 (15). This state
is characterized by sympathetically mediated vasoconstriction
in muscular, skin, renal, and presumably gastrointestinal vas-
cular 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 dysregu-
lation is likely caused by acute demyelination not only of sen-
sory 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 in-
fluence on the autonomic nervous system. Cortical asymme-
try is present and is reflected in a higher incidence of tachy-
cardia, ventricular arrhythmias, and hypertension with lesions
of the right insula—resulting in loss of parasympathetic in-
put and thus sympathetic predominance—and a higher inci-
dence 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 complica-
tion of ischemic and hemorrhagic stroke, first described over
50 years ago (19). It is most often recognized on the elec-
trocardiogram (ECG) as arrhythmias, QRS, ST-segment, and
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FIGURE 59.2. Example of a right ischemic stroke resulting in ventric-
ular arrhythmias and cardiogenic shock. A 61-year-old man presents
with sudden onset of left hemiparesis affecting his face and arm, left-
sided 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 car-
diac 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 ventricu-
lar 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. Echocar-
diogram showed global hypokinesis and no regional wall motion ab-
normalities. 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 suc-
cessfully. A repeat echocardiogram 2 weeks later showed resolution of
the abnormalities.
T-wave abnormalities (20,21). Studies of SAH and cardiac in-
jury have shown that the severity of SAH is an independent pre-
dictor of cardiac injury, supporting the hypothesis that cardiac
neurogenic shock is a neurally mediated process (22). Based
on the similarities observed between pheochromocytoma cri-
sis and SAH, the cardiovascular changes have been linked to a
catecholamine surge.
This hypothesis has been confirmed by many studies. Pa-
tients 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 experimen-
tal SAH causes specific lesions on electron microscopy within
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Chapter 59: Neurogenic Shock 927
FIGURE 59.3. Contraction band necrosis. Histologic examination of
the myocardium, showing contraction band necrosis, see arrow. (Cour-
tesy of Dr. James R. Stone, M.D., Ph.D., Department of Pathology,
Massachusetts General Hospital, Boston, MA.)
4 hours of SAH (24). Selective myocardial cell necrosis, also
known as contraction band necrosis, is the hallmark of cate-
cholamine exposure (25–27). The same lesions can be found in
patients with pheochromocytoma (28) and SAH (29), underlin-
ing 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 arter-
ies 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 myocar-
dial lesions consisting of foci of necrotic muscle fibers, hem-
orrhages, 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 my-
ocardial lesions. Pre-existing hypertensive heart disease led to
significantly fewer myocardial lesions, possibly reflecting a de-
creased 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 hemor-
rhages 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 cate-
cholamine 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 af-
terload 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 myocar-
dial compliance (stunning of the myocardium) is reflected by
a characteristic shape of the cardiac silhouette on a ventricu-
logram and on chest radiograph, which has given this disease
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928 Section VI: Shock States

A C

FIGURE 59.4. Takotsubo cardiomyopathy. A: Japanese octopus fishing pot. B: CT brain of a 47-year-
old 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, tako-
tsubo (35–37) (Fig. 59.4).
Pulmonary edema with concomitant hypoxia is frequently
encountered in this context and may result from cardiac con-
gestion but can occur independently from the cardiac dysfunc-
tion 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) re-
ported the rapid onset of acute pulmonary edema after severe
head injury. In addition, experimental models as well as mul-
tiple human case reports of TBI and SAH have shown massive
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Acute Brain Injury
TBI, SAH, ICH,
ischemic stroke
Catecholamine Surge
α α+β
Peripheral Pulmonary
venous Platelet
vasoconstriction
constriction aggregation
Microemboli
↑Pulmonary
capillary
pressure Damaged
endothelium
Neurogenic ↑Pulmonary
pulmonary permeability
edema
sympathetic discharges as the primary cause of neurogenic pul-
monary edema (39–41). Figure 59.5 summarizes the patho-
physiology of cardiogenic neurogenic shock.
Overall, cardiac neurogenic shock, with or without neuro-
genic 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. Inappropri-
ately reduced release of cortisol in stress situations can lead
to decreased systemic vascular resistance, reduced cardiac con-
tractility, 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 insuf-
ficiency using a low random serum cortisol value and highlight
the fact that an increase in the cortisol level after a stimula-
tion 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 af-
fected organs, and the adrenal glands might well be expected
to mount an appropriate response when stimulated. When rec-
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Chapter 59: Neurogenic Shock 929
β
Myocardial
contraction band
necrosis
LVEF ↓
FIGURE 59.5. Summary of the pathophysiology of
Shock the cardiogenic type of neurogenic shock. ICH, in-
tracerebral hemorrhage; LVEF, left ventricular ejection
fraction; SAH, subarachnoid hemorrhage; TBI, trau-
matic 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 re-
mains 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 op-
tions in SAH.
CLINICAL MANIFESTATIONS
Figure 59.6 illustrates the clinical manifestations and symp-
toms seen in neurogenic shock. Acutely, vasodilatory neuro-
genic 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 pres-
sure (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 in-
jury 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 extrem-
ities. Orthostatic hypotension without reflex tachycardia on
changing from a supine to an upright position—by standing
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930 Section VI: Shock States
Dry, warm skin
Bradycardia
Vasodilatory Hypotension
Neurogenic Shock SVR ↓
SV and CO ↓
CVP ↓ or normal
Dry, or wet, cold skin
Tachycardia (rarely bradycardia)
Hypotension
SVR ↑
SV and CO ↓
CVP ↑ or normal
Cardiogenic
PCWP ↑
Neurogenic Shock 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
Hypotension not
responsive to vasopressors
Neuroendocrine SVR ↓
Neurogenic Shock
SV and CO ↓
CVP ↓ or normal
or with reverse Trendelenburg position—is common. When
treating this form of neurogenic shock with a vasopressor infu-
sion (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 capil-
lary wedge pressure (PCWP), and end-diastolic volume index
(EDVI), is normal or high, with low stroke volumes and car-
diac 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 estab-
lish a cutoff value that differentiates stunned myocardium from
myocardial infarction with atherosclerotic coronary artery dis-
ease. 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 hypoten-
sion that does not respond well to vasopressor infusion. Hemo-
dynamic 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 neu-
rogenic shock, as the adrenal gland is usually not the primarily
affected organ (6). For this reason, we do not find any clini-
cal 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.
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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 bleed-
ing, because of the absence of sympathetic tone below the
level of injury. The usual pallor from vasoconstriction and re-
flex tachycardia might also be absent. The patient may even
be bradycardic while continuing to bleed. For the same rea-
son, 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 Dis-
charge 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 antithrom-
botic 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 con-
sidered 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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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 im-
portant diagnostic tools. In particular, one should look for pul-
monary vascular congestion and evaluate the size and shape of
the cardiac silhouette. Hemodynamic monitoring with continu-
ous blood pressure and central venous pressure (CVP) monitor-
ing 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 up-
per 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 ad-
dition, 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 exten-
sive hemodynamic monitoring may be necessary with either
noninvasive cardiac monitoring devices or a pulmonary artery
catheter (PAC). Echocardiography is very important to under-
standing 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 hy-
pothesis 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 set-
ting 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 sep-
sis 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 impor-
tant 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 dis-
ease, after instrumentation of the head or spinal canal, or in
immunocompromised patients. Placement of intracranial pres-
sure measurement devices do not contribute to the diagnostic
workup of shock, but they are important tools in the manage-
ment of neurogenic shock, such as when the goal mean arterial
pressure (MAP) is being titrated to the cerebral perfusion pres-
sure. 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
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Chapter 59: Neurogenic Shock 931
injury, low random serum cortisol levels, and thus adrenal in-
sufficiency, may be encountered for several days after injury (6).
Many neurologically injured patients, especially those with
spinal cord injuries, receive steroids while in the neurointen-
sive 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 appro-
priately. 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 treat-
ment right after the blood draw. However, hypotension is fre-
quently severe enough that immediate treatment is warranted,
and withholding steroids often is not an option. Dexametha-
sone, 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 recom-
mended 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 hy-
potension
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, treat-
ment 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 impor-
tant 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 im-
proved 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 ), indi-
cate 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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932 Section VI: Shock States
patients frequently have peripheral α-adrenoceptor hyperre-
sponsiveness, 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 neu-
rogenic 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 indi-
rect 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 addi-
tion 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 lead-
ing 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 neuro-
genic cardiogenic shock, coronary artery disease is typically not
present, and compensatory tachycardia is necessary to main-
tain cardiac output. Afterload reduction with cautious use of
angiotensin-converting enzyme (ACE) inhibitors should be at-
tempted, but further hypotension must be avoided to main-
tain tenuous cerebral perfusion pressures. Short-acting agents
should be used whenever possible. Repeating an echocardio-
gram several days after the initial one is recommended to moni-
tor the progression/resolution of cardiac dysfunction. The need
for an intra-aortic balloon pump to mechanically reduce after-
load and improve coronary perfusion pressure may be consid-
ered, 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 dos-
ing 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 re-
versible, making this entity very treatable. Diagnosis and treat-
ment should be tailored to the subtype of neurogenic shock.
Maintenance of cerebral perfusion pressures is the key prin-
Printer: Yet to come
October 23, 2008 13:22
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., anaphylac-
tic 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 in-
flammatory cell cascades. Because the clinical presentations
of anaphylactic and anaphylactoid reactions are indistinguish-
able, 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-
Printer: Yet to come
October 23, 2008 13:22
Chapter 60: Anaphylactic Shock 933
derly patients with acute traumatic cerebral injury. Chinese J Traumatol.
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47. Barreca T, Gandolfo C, Corsini G, et al. Evaluation of the secretory pattern
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surgery and neurology patients: a review. Neurosurgery. 1994;34(2):280–
296; discussion 296.
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after internal jugular vein cannulation. Br J Anaesth. 1991;67(4):476–479.
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systolic dysfunction after subarachnoid hemorrhage: evidence for neurally
mediated cardiac injury. J Am Soc Echocardiogr. 2000;13(8):774–779.
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abnormal left ventricular wall motion in acute subarachnoid hemorrhage.
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control of elevated intracranial pressure in patients with severe head injury.
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tor or not to monitor? A review of our experience with severe head injury.
J Neurosurg. 1982;56(5):650–659.
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ment of severe head injury. Brain Trauma Foundation. Eur J Emerg Med.
1996;3(2):109–127.
61. Czosnyka M, Guazzo E, Iyer V, et al. Testing of cerebral autoregulation
in head injury by waveform analysis of blood flow velocity and cerebral
perfusion pressure. Acta Neurochirurgica. 1994;60:468–471.
eralized hives, tachycardia, flushing, pruritus, faintness, and a
sensation of impending doom. Dermatologic (i.e., urticaria and
angioedema), respiratory (i.e., dyspnea, wheeze, stridor, bron-
chospasm, and hypoxemia), and gastrointestinal (i.e., abdom-
inal distension, nausea, emesis, and diarrhea) manifestations
are common. Involvement of the cardiovascular and respira-
tory systems may result in potentially life-threatening manifes-
tations, such as cardiovascular collapse caused by vasodilation
and capillary leak, myocardial depression, myocardial ischemia
and infarction, and atrial fibrillation (3). Prompt recogni-
tion and effective intervention are essential to prevent
the fatal manifestations of anaphylactic and anaphylactoid
reactions.
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934 Section VI: Shock States

INCIDENCE CLINICAL MANIFESTATIONS

The incidence of anaphylaxis is difficult to determine accurately The clinical syndromes associated with systemic anaphylac-
due to underdiagnosis and underreporting. In the United States, tic and anaphylactoid reactions represent medical emergen-
fatal anaphylaxis causes 500 to 1,000 fatalities per year and cies, as they are associated with a rapid, critical destabi-
accounts for 1% of emergency department visits (1,4,5). The lization of vital organ systems. These syndromes, which are,
anaphylaxis rate was found to be 21 per 100,000 person-years again, clinically indistinguishable, may become rapidly fatal
in a study of nonhospitalized individuals in Olmsted County, if appropriate therapy is not instituted immediately. Initial
Minnesota, between 1983 and 1987 (6). A subsequent analysis symptoms can appear within seconds to minutes but may
of the General Practice database in the United Kingdom noted be delayed by as much as 1 (or rarely more) hour after ex-
the incidence to be 8.4 per 100,000 person-years (7). An epi- posure to an inciting agent (30), and are often nonspecific
demiologic study involving 481,752 individuals suggested that (31). These symptoms include tachycardia, faintness, cuta-
hospitalized patients are at increased risk of anaphylaxis, but neous flushing, urticaria, diffuse or palmar pruritus, and a
these reactions are rarely fatal (8). sensation of impending doom (32). Of these, generalized ur-
ticaria is the most common, occurring in approximately 90%
of patients (Table 60.3) (33,34). Subsequent manifestations in-
dicate involvement of the cutaneous, gastrointestinal, respira-
ETIOLOGY tory, and cardiovascular systems. Involvement of the cardio-
vascular and respiratory systems is responsible for the fatal
The most common causes of anaphylaxis include insect stings,
foods, drugs, and physical factors/exercise. Idiopathic anaphy-
laxis (where no causative agent is identified) accounts for up
to two thirds of patients referred to allergy/immunology spe- TA B L E 6 0 . 1
cialty clinics (9,10). Foods such as shellfish, eggs, nuts, and milk
account for one third of food-induced anaphylactic episodes ETIOLOGIC AGENTS FOR ANAPHYLAXIS (IGE-
(10–13) (Tables 60.1 and 60.2). There is a syndrome of food- MEDIATED)
dependent, exercise-induced anaphylaxis (FDEIA) that devel-
ops only if food is ingested prior to exercise or exertion (14). HAPTENS VENOM
β-Lactam antibiotics Stinging insects, particularly
Seafood, nuts, celery, wheat, and grains have been implicated
Sulfonamides Hymenoptera, fire ants, deer
as allergens in this syndrome. It is important to note that these Nitrofurantoin flies, jelly fish, kissing bugs
foods are tolerated by the patient in the absence of exertion Demethylchlortetracycline (triatoma), and rattlesnakes
(14,15). Streptomycin
Anaphylactic reactions to stings or bites of various insects, Vancomycin HORMONES
such as members of the order Hymenoptera (yellow jackets, Local anesthetics Insulin
bees, wasps, hornets, and saw flies) are commonly reported. Others Adrenocorticotropic hormone
A positive venom skin test along with a systemic reaction to Thyroid-stimulating hormone
the insect sting predicts a 50% to 60% risk of reaction to SERUM PRODUCTS
future stings (16). Medications can cause anaphylactic (IgE- γ -Globulin ENZYMES
Immunotherapy for Chymopapain
mediated) and anaphylactoid (non–IgE-mediated) reactions.
allergic diseases L-Asparaginase
Previous exposure to drugs is required for IgE production and Heterologous serum
anaphylactic reactions, but anaphylactoid reactions can occur MISCELLANEOUS
upon first administration. Penicillin is one of the most com- FOODS Seminal fluid
mon causes of anaphylaxis, with 1 to 5 per 10,000 courses Nuts (peanuts, brazil Others
with penicillin resulting in allergic reactions and 1 in 50,000 nuts, hazelnuts,
to 1 in 100,000 courses with a fatal outcome (17–19). Non- cashews, pistachios,
steroidal anti-inflammatory drugs (NSAIDs) and aspirin are the almonds, soy nuts)
second most common class of drugs implicated in anaphylaxis Shellfish
(20). Some hypersensitivity reactions will occur with differ- Buckwheat
Egg white
ent NSAID agents, while others are specific to a single drug
Cottonseed
(21). Cow’s milk
With widespread adoption of universal precautions against Corn
infections, latex allergy has become a significant problem. The Potato
development of low-protein, powder-free gloves has been asso- Rice
ciated with reduction in occupational-contact urticaria caused Legumes
by latex rubber gloves (22). Despite this, latex allergy is still Citrus fruits
a concern since latex is found in gloves, catheters, and tubing Chocolate
(23–25). Iodinated radiocontrast media can cause anaphylaxis; Others
however, life-threatening reactions are rare (26). A history of a
previous reaction to radiocontrast media, asthma or atopic dis- Boldface: Relatively common causes
ease, treatment with β-blockers, and cardiovascular disease are Modified from Austen KF. Systemic anaphylaxis in man. JAMA. 1965;
192:108; and Kaliner M. Anaphylaxis. NER Allergy Proc. 1984;5:
risk factors for developing anaphylaxis to radiocontrast media 324.
(27–29).
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Chapter 60: Anaphylactic Shock 935

TA B L E 6 0 . 2
ETIOLOGIC AGENTS FOR ANAPHYLACTOID REACTIONS

COMPLEMENT-MEDIATED REACTIONS ARACHIDONIC ACID MODULATORS

Blood Nonsteroidal anti-inflammatory drugs
Serum Tartrazine (possible)
Plasma
Plasmate (but not albumin) IDIOPATHIC
Immunoglobins Most common conclusion after thorough evaluation

NONIMMUNOLOGIC MAST CELL ACTIVATORS UNKNOWN

Opiates and narcotics Sulfites
Radiocontrast media Others
Dextrans
Neuromuscular blocking agents 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 sec-
ondary to laryngeal edema. Other pulmonary manifestations
include acute bronchospasm, intra-alveolar pulmonary hemor-
rhage, bronchorrhea, and a noncardiogenic, high permeability–
type pulmonary edema (17,35). Tachycardia and syncope may
precede the development of hypotension and frank cardiovas-
cular collapse (36,37). Anaphylactic shock occurs as a con-
sequence 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 param-
eters later reveal decreases in cardiac output, systemic vascu-
lar 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 po-
tentially 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 supraven-
tricular arrhythmias such as atrial fibrillation. Severe, but re-
versible, myocardial depression also has been reported (37).
Hematologic manifestations, such as disseminated intravascu-
lar coagulation and hemoconcentration secondary to volume
contraction, also may complicate anaphylactic and anaphy-
lactoid 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 Symptom Frequency Sign/clinical manifestation

RESPIRATORY 60%–80%
Upper Dyspnea, dysphonia, cough, “lump in Upper airway obstruction caused by laryngeal
throat” edema and spasm; bronchorrhea
Lower Dyspnea, cyanosis Noncardiogenic pulmonary edema, bronchospasm,
acute hyperinflation, alveolar hemorrhage
CARDIOVASCULAR Palpitations, faintness, weakness 20% Shock, tachycardia, capillary leak, syncope,
supraventricular arrhythmias, conduction
disturbances, myocardial ischemia and infarction
CUTANEOUS Flushing, pruritus, rash 90% Urticaria, angioedema, diaphoresis
GASTROINTESTINAL Abdominal pain, bloating, cramps, 30% Emesis, diarrhea, hepatosplenic congestion; rarely
nausea hematemesis and bloody diarrhea
NEUROLOGIC Dizziness, disorientation, hallucinations, 5%–10% Syncope, lethargy, seizures
headache, feeling of impending doom
NASAL Pruritus, sneezing 16%–20% Rhinorrhea, nasal congestion
OCULAR Conjunctival pruritus, periorbital edema 10%–15% Conjunctival suffusion, lacrimation

HEMATOLOGIC Hemoconcentration, DIC

DIC, disseminated intravascular coagulation.

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936 Section VI: Shock States

presentation, although there have been reports of recurrence of inflammatory mediators by mast cells and basophils. The
up to 72 hours later. There were no features of the primary classic anaphylactic response occurs through allergen-induced
response that predicted the occurrence of a secondary response crosslinking of IgE tightly bound to the high-affinity FcR1 re-
(47). ceptor constitutively expressed by mast cells (52). Release of
histamine from preformed mast cell granules seems to be the
primary pathophysiologic mediator, resulting in systemic va-
DIAGNOSIS sodilation, increased vascular permeability, bronchoconstric-
tion, pruritus, and increased mucus production. However,
The diagnosis of anaphylaxis is established on the basis of clin-
a number of other preformed mediators are released, in-
ical grounds alone because expedient institution of appropri-
cluding heparin, serotonin, and mast cell proteases such as
ate therapy is mandatory. These diagnoses should be consid-
chymase and tryptase (53). In addition, other important medi-
ered when typical multisystem manifestations occur in a direct
ators of anaphylaxis are generated by the metabolism of mem-
temporal relationship with exposure to an inciting agent. Re-
brane phospholipids. Activation of the 5-lipoxygenase path-
cently, the National Institute of Allergy and Infectious Diseases
way results in synthesis of leukotrienes, including leukotrienes
(NIAID) and the Food Allergy and Anaphylaxis Network
C4 , D4 , E4 (termed the slow-reacting substance of anaphy-
(FAAN) proposed clinical criteria for the diagnosis of anaphy-
laxis), and B4 . Leukotrienes C4 , D4 , and E4 , along with the
laxis (Fig. 60.1) (1). Because of the multisystem nature of ana-
intermediary products 5-hydroxyeicosatetraenoic acid and 5-
phylactic and anaphylactoid reactions, the list of differential
hydroperoxyeicosatetraenoic acid, elicit increases in vascular
diagnoses that must be considered is extensive. Diagnostic pos-
permeability and bronchoconstriction, whereas leukotriene B4
sibilities include cardiac dysrhythmias, myocardial infarction,
possesses eosinophil and neutrophil chemotactic properties.
distributive or hypovolemic shock, vasovagal syncope, asthma,
Activation of the cyclooxygenase pathway leads to the produc-
pulmonary embolism, upper airway obstruction secondary to
tion of prostaglandin D2 , which produces bronchoconstriction.
ingestion of a foreign body, hypoglycemia, and the carcinoid
Platelet-activating factor is also newly synthesized by activated
syndrome (Table 60.4).
mast cells and can result in bronchoconstriction, increased vas-
Demonstration of acute elevations of markers specific to
cular permeability, platelet aggregation, and neutrophil chemo-
mast cell activation such as histamine and tryptase have been
taxis. It also leads to further production of platelet-activating
proposed to help confirm the diagnosis of anaphylaxis (48,49).
factor through stimulation of nuclear factor (NF)-κB, a posi-
However, in a series of 97 patients presenting to an emergency
tive feedback mechanism involving the cytokines interleukin-1
department and given the diagnosis of anaphylaxis, only 42%
(IL-1) and tumor necrosis factor (TNF)-α, and contributes
were found to have elevated plasma histamine levels, and 24%
to a biphasic pattern seen in some patients (54). Combined,
had increased plasma tryptase levels (50). Skin testing or serum
these primary mediators then facilitate the production of a di-
antibody tests can help demonstrate the presence of IgE against
verse number of secondary mediators by platelets, neutrophils,
a specific allergen. Skin testing should be delayed for up to 4
eosinophils, and other cells, resulting in activation of the com-
weeks to allow the dermal mast cells to replenish intracellular
plement, coagulation, and fibrinolytic pathways (55).
mediators (51).
Many of these mediators have complicated effects, and their
relative roles in mediating anaphylaxis in vivo have been dif-
PATHOPHYSIOLOGY ficult to evaluate. Mouse models of anaphylaxis using strains
with targeted deletions of specific mediators have been useful
The systemic manifestations of anaphylactic and anaphylac- in elucidating the importance of different effector molecules,
toid reactions represent sequelae that result from the release such as the leukotrienes (56–58), and in identifying regulatory

FIGURE 60.1. Clinical criteria for di-

Acute onset of illness (minutes agnosing anaphylaxis. Fewer signs are
to few hours) required for diagnosis as the history
of allergen exposure becomes more
certain. Signs or symptoms of skin
involvement: Generalized hives, pru-
Exposure to likely allergen for Exposure to known allergen for ritus, or flushing. Signs of mucosal
No known exposure to allergen involvement: Swollen lips, tongue,
that patient that patient
and/or uvula. Signs of respiratory
compromise: Dyspnea, wheeze, bron-
Skin or mucosal involvement and
At least two of the following: Reduced BP or associated signs chospasm, stridor, reduced peak expi-
either:
ratory flow, and/or hypoxemia. Def-
inition of reduced blood pressure
Respiratory compromise Skin and/or mucosal involvement (BP): Adults—systolic BP less than
90 mm Hg or greater than 30% de-
or crease from that person’s baseline;
children—systolic BP less than 70 mm
Reduced BP or associated signs Respiratory compromise
Hg from 1 month to 1 year, less than
or both (70 mm Hg + [2 × age]) from 1
to 10 years, and less than 90 mm
Reduced BP or associated signs Hg from 11 to 17 years or associ-
ated signs: Hypotonia, syncope, in-
continence. Persistent gastrointesti-
Persistent gastrointestinal symptoms nal symptoms: Crampy abdominal
pain and vomiting.
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Chapter 60: Anaphylactic Shock 937

TA B L E 6 0 . 4
DIFFERENTIAL DIAGNOSIS OF ANAPHYLAXIS

FLUSH SYNDROME POSTPRANDIAL COLLAPSE

Carcinoid Airway foreign body
Pheochromocytoma Monosodium glutamate ingestion
Peri-postmenopausal hot flushes Sulfite
Medullary carcinoma of thyroid Scombroid fish poisoning
Red man syndrome (vancomycin)
MISCELLANEOUS
HYPOTENSION Panic attacks
Septic shock Systemic mastocytosis
Hemorrhagic shock Basophilic leukemia
Cardiogenic shock Hereditary angioedema
Hypovolemic shock Hyper-IgE syndrome
Vasovagal reaction

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 ex-
ample, mice with targeted deletions of either the high-affinity
FcR1 receptor or IgE, not surprisingly, had a markedly de-
creased 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 IgE-
mediated pathway, this alternative pathway required prior ex-
posure to antigen, but differed in that much higher concentra-
tions 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 path-
way. The use of these biologic agents is expected to continue
to increase.
MANAGEMENT
The clinician must have a high index of suspicion for ana-
phylactic and anaphylactoid reactions because they require a
prompt clinical diagnosis and a rapid therapeutic response. Be-
cause anaphylactic and anaphylactoid reactions both represent
sequelae of mast cell and basophil degranulation, the thera-
peutic approaches to these disorders are identical. Initial at-
tention 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 syn-
thesis 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 sub-
cutaneous 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 admin-
istered IV, the clinician should be aware of the potential ad-
verse 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 fre-
quently, 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, respira-
tory distress, or hemodynamic instability (1,2). Orotracheal
intubation may be attempted if the airway obstruction com-
promises effective ventilation despite pharmacologic interven-
tion; however, attempts may be unsuccessful if laryngeal edema
is severe. If endotracheal intubation is unsuccessful, then ei-
ther needle-catheter cricothyroid ventilation, cricothyrotomy,
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938 Section VI: Shock States
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 refrac-
tory to epinephrine (1,2,67). Patients should be placed in the
recumbent position, with lower extremities elevated to in-
crease fluid return centrally, thereby increasing cardiac out-
put (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 pruri-
tus. 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 resus-
citation 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 vasodilata-
tion, causing distributive shock (70). Persistent hypotension
may require multiple fluid boluses (10 to 20 mL/kg under pres-
sure) as well as colloid and crystalloid infusions (1,2). Vaso-
pressors 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 contribu-
tion in other allergic diseases has led to their inclusion in ana-
phylactic management. Due to their slow onset of action, they
are not useful in acute management. However, it has been sug-
gested 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 β-
antagonist medications, such as β blockers, represents a spe-
cial circumstance in which the manifestations of anaphylaxis
may be exceptionally severe (72). β Blockade increases medi-
ator synthesis and release, as well as end-organ sensitivity. In
addition, β-blockade antagonizes the beneficial β-mediated ef-
fects 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 re-
ceiving 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 peri-
ods 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
Printer: Yet to come
October 23, 2008 13:22
agent is identified, the clinician should attempt to prevent fur-
ther access to the circulation or limit further absorption. In-
fusions of possible etiologic agents should be stopped and the
contents saved for analysis. If a Hymenoptera sting is respon-
sible, 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 care-
fully 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 needle-
catheter cricothyroid ventilation, cricothyrotomy, or tra-
cheostomy. Patients in anaphylactic shock should be placed
in a recumbent position with the lower extremities ele-
vated, unless precluded by shortness of breath or vomiting.
2. Remove the inciting agent (i.e., remove Hymenoptera
stinger) and follow with an intramuscular epinephrine in-
jection 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 bron-
chospasm refractory to epinephrine (73).
9. Consider corticosteroid therapy for protracted anaphy-
laxis 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 man-
ifestations 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 in-
otropic and chronotropic effects mediated by a β-receptor–
independent mechanism.
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11. Prevent recurrent episodes by avoidance of the incit-
ing agent, desensitization, or premedication with cortico-
steroids 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 fre-
quent arterial blood gas measurements.
OBSERVATION
An observation period should be considered for all patients fol-
lowing 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 ad-
mission 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 devel-
ops. These patients should also have an emergency action plan
detailing its use and follow-up management (1,2). If a precip-
itating allergen is known or identified, patients should receive
information about avoiding it in the future, prior to their dis-
charge 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, po-
tentially reversible, acute respiratory and cardiovascular emer-
gencies. 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 pre-
vent the fatal cardiovascular and pulmonary manifestations.
Factors associated with improved survival include the sensitiv-
ity 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 ad-
ministration 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 cardio-
vascular function, and removal of the offending agent. Expedi-
tious institution of these measures helps to reduce the morbidity
and mortality associated with these potentially life-threatening
syndromes.
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October 23, 2008 13:22
Chapter 60: Anaphylactic Shock 939
SUMMARY
1. Anaphylactic reactions represent type I immune responses
mediated by IgE bound to mast cells or basophils. Com-
mon inciting agents include β-lactam antibiotics and Hy-
menoptera stings. Other common causes include foods, lo-
cal anesthetics, and serum products.
2. Anaphylactoid reactions represent IgE-independent activa-
tion of mast cells or basophils, with resultant degranula-
tion and mediator release. Common inciting agents include
iodinated radiocontrast media, neuromuscular depolariz-
ing agents, and opiates, all of which induce direct mast
cell activation; nonsteroidal anti-inflammatory agents act-
ing 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 ana-
phylaxis to radiocontrast media (27–29).
4. The differential diagnosis of anaphylactic and anaphylac-
toid reactions includes cardiac arrhythmias, myocardial in-
farction 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, sys-
temic mastocytosis, hereditary angioedema, and leukemia
with excess histamine production.
5. Epinephrine is the initial drug of choice for the man-
agement of anaphylactic or anaphylactoid reactions. H1 -
and H2 -blocking agents also should be administered. Cor-
ticosteroids are not effective for the acute management
of anaphylactic or anaphylactoid reactions, but may pre-
vent biphasic anaphylaxis or attenuate prolonged reactions.
Glucagon may be used for persistent hypotension in patients
taking β-blockers.
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