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Midterm- Hthsci-3PA2A
Integrated pathophysiology for nurses (McMaster University)
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HTHSCI 3PA2A Midterm Pathophysiology Notes
Inflammation Module
Types of distributive shock:
 Sepsis shock
 Neurogenic shock
 Anaphylactic shock
Other Types of shock:
 Hypovolemic shock
 Cardiogenic shock
 Obstructive shock
Inflammation (non-specific) attempts to eliminate injurious stimuli (tissue damage,
infective organisms) in the body and promote healing
Sepsis
Dysregulation of defense processes (over-reaction or under-reaction of inflammation)
can be seen in sepsis
- Roughly 1 in 18 deaths in 2011 in Canada involved sepsis
- 12th leading cause of death in Canada in 2011
Costs related to sepsis hospitalizations are much higher than other illnesses
- Longer stays in hospital (average 12 days)
- Commonly admitted to ICUs
- Higher incidence of sepsis in the very young/very old
Co-morbidities lead to higher mortality in sepsis (greater the co-morbidities
higher the morality)
 Most common: HIV, cancer, and diabetes
 Mortality rates higher in men
 Nosocomial infections (hospital acquired) of sepsis have higher mortality rates
than those being admitted already with sepsis
Sepsis-3
The criteria indicate that the inflammatory response is systematic rather than localized.
 Higher or lower than normal body temp, increased HR, increased respiratory
rate, and high or low WBC count
 Another marker is a large proportion of bands (immature WBCs): >10% band
forms indicate body-wide inflammation (might be present instead of
increased/decreased WBCs)
 SIRS may occur without the presence of infection and some patients admitted to
critical care may present with new organ failure and infection, but lack the 2 SIRS
indications for the diagnosis of sepsis
 SIRS = Systemic Inflammatory Response Syndrome
 New sepsis guidelines deemed SIRS criteria unhelpful for assessing sepsis
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SIRS criteria may highlight inflammatory response, it does not necessarily denote
dysregulated or life-threatening response
New sepsis definition stresses the immune system dysregulation and points the
need for urgent attention
Sepsis is now described by organ dysfunction as assessed by a 2 point change
in the sepsis related sequential organ failure score (SOFA)
SOFA score in healthy individuals = 0
Score increases with presumed infection/organ dysfunction
Sepsis: "a life-threatening organ dysfunction caused by a dysregulated host response
to infection
Septic Shock: "a subset of sepsis in which particularly profound circulatory, cellular and
metabolic abnormalities are associated with a greater risk of mortality than with sepsis
alone"
Septic Shock
 Severe sepsis is no longer a term used
 It is not necessarily a continuum from sepsis to severe sepsis to septic shock
(term was found redundant)
 Septic shock mortality rate is 40% (associated with hypotension even with
adequate fluid resuscitation.
 Elevated serum lactate levels are associated with anaerobic energy generation
due to inadequate tissue perfusion
qSOFA
 Glasgow coma scale is used to evaluate mental status, a score of less than 13
on the scale indicates altered mentation in this context, but even scores less than
15 should prompt further evaluation
*comorbidities increase the risk for sepsis
Sepsis and PCI
 Persistent critical illness (PCI) is a condition where individuals continue to suffer
from organ dysfunction for weeks or months
 Surviving sepsis, septic shock and/or PCI tends to result in lasting disabilities
such as cognitive dysfunction, neuropathies or dysfunctional immune systems
 This leaves survivors at high risk for premature death, with 5 year mortality rates
up to 75%
Mitochondrial Dysfunction
 Effects of sepsis and septic shock are due to dysfunction at the cellular
level (Mitochondrial dysfunction) which occurs and creates an energy deficit for
the cells
 This is no thought to result in the failure of cell communication in and between
organs due to the use of the available energy for individual cell survival
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This leads to the barrier failure that is a hallmark of sepsis and results in the
inability to return to homeostasis
As metabolic impairment in cells continues, organ dysfunction occurs
As the number of failing organ systems increases, so does the risk for mortality
Hypoxia-induced Metabolic Changes
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This schematic describes the changes in cellular metabolism when there is
hypoxia, or lack of oxygen.
Without oxygen, glycolysis can proceed in the cytoplasm of the cell but its
product, pyruvate, cannot enter the citric acid cycle within the mitochondrion.
Pyruvate must then be converted to lactate to allow energy production to
continue.
Far fewer ATP molecules are produced this way and cellular processes such as
the sodium/potassium pump are negatively impacted.
Failure of this pump allows sodium to flow into the cell and potassium to leave
the cell, upsetting the electrochemical gradient.
This gradient is required for action potentials in cells such as neurons and
muscle cells so the effects will be evident in the nervous system and myocardium
fairly quickly.
In addition to interference with chemical and ionic gradients, water flows into the
cell leading to swelling, cellular membrane disruption, and release of lysosomal
contents.
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These events initiate positive feedback loops that cause greater deterioration of
the cell and impairment of perfusion.
Meanwhile, the ongoing anaerobic metabolism results in a drop in pH due to
lactic acid buildup and depletion of glycogen stores because of reduced nutrient
delivery and increased metabolic demands.
Protein synthesis is reduced and use of intracellular and plasma proteins for fuel
may ensue as nutrient stores run out.
The cellular response to this metabolic stress exacerbates the inflammatory
response.
Interacting Systems Promote Homeostasis
The latest hypotheses points to a failure of homeostasis as the cause of sepsis, rather
than an overwhelming pro-inflammatory response as previously thought.
Research suggests that the immune, neural and neuroendocrine systems cooperate to
resolve inflammation by removing threats and repairing damage while returning
metabolism and organ function to normal levels.
It is hypothesized that the body accomplishes these goals by engaging the following
mechanisms.
Organs: immune signals that arise in organs travel to the brain along the afferent vagus
nerve.
Muscle & Cells: independent of the immune system, sensory nerves surrounding cells
detect infection and/or injury and transmit afferent signals to the brain through the dorsal
root ganglia and the spinal cord
Brain & Efferent Pathways (Sympathetic and Vagus): the efferent signal travel
through both the sympathetic chain and vagus nerve. Vagal signals act on the adrenal
cortex and T-cells in the spleen to release hormones that decrease cytokine expression
and release. Sympathetic activation leads to norepinephrine release, increasing or
decreasing cytokine release depending on the type of adrenergic receptor stimulated.
Neuroendocrine System: the neuroendocrine system is affected by signals transmitted
through the afferent neuronal pathways. Cytokines that infiltrate the blood-brain barrier
as well as cytokines produced by cells of the CNS similarly affect neuroendocrine
function. Hormones are subsequently released and affect immune cells such as B-cells
and T-cells and macrophages.
Summary: altered signaling in these four pathways results in failure to restore
homeostasis, which is evident in sepsis, septic shock, and persistent critical illness.
Immune Cells and Sepsis
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Sepsis is the result of both pro and anti-inflammatory response.
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As sepsis continues, both the innate and adaptive arms of the immune response
begin to fail, resulting in T-cell "exhaustion" and the death of many different immune
cell types.
The hypoxia-induced metabolic changes associated with sepsis, that ultimately
result in decreased energy available to individual non-immune cells, drives these
cells to prioritize internal homeostasis, causing them to lose their specialization of
function and integration within organ systems.
This is hypothesized to be the reason for the inability to restore homeostasis.
Massive cell death and tissue necrosis is not generally observed on autopsy of
septic patients, although loss of immune cells is evident, consistent with the
increased apoptosis described here.
Sepsis and Shock
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It is now recognized that it is not only the microorganisms themselves, but also
the products of tissue damage that lead to the dysregulated host immune response
and the impairment of homeostasis associated with sepsis.
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Failure of the epithelial and endothelial barriers is a current hypothesis to explain
the increased vascular permeability and lack of perfusion observed in clients with
sepsis, and may also explain why cellular substrates such as liver enzymes and
renal creatinine are able to enter the blood.
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This is also thought to be the mechanism by which cytokines and other immune
mediators and even immune cells cross the blood-brain barrier I cases of sepsis.
Treatment for Sepsis
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Early recognition and treatment are most effective treatment
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Earlier the treatment, the better the chance of restoring homeostasis and halting
the progression to septic shock, organ failure, and death.
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A protocol was devised to administer treatments such as fluid resuscitation and
monitor the patient for results, treating until goals have been attained for central
venous pressure or CVP, mean arterial pressure or MAP, and central venous oxygen
saturation or ScvO2.
Mechanisms in Sepsis
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We still don’t fully understand the complex nature of sepsis
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Originally thought to be due to overreaction of the pro-inflammatory response
more recent research has shown that immunosuppression may occur
simultaneously
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The predominant new theory of sepsis points to dysfunctional immune and neural
systems that result in a failure of homeostasis
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They hope to develop specific treatments to augment the supportive measures
that are the only course of action at present
Types of Shock
4 Types of Shock: cardiogenic, obstructive, hypovolemic and distributive.
Cardiogenic Shock
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Cardiogenic shock comes about due to failure of the "pump"
Common causes of pump failure include MI, cardiac conduction problems
(arrhythmias or blocks) and diseases of the heart muscle collectively referred to as
cardiomyopathies
An inability of the heart to contract (or to contract in a coordinated manner) which
prevents it from functioning as an effective pump.
Leads to a reduction in stroke volume (or HR)
Obstructive Shock
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Obstruction to blood flow which either impedes the filling or emptying of the
heart
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Common causes include PE (obstructs blood flow through the pulmonary circuit),
cardiac tamponade (obstructs proper filling of the heart) and tension pneumothorax,
otherwise known as collapsed lung (which obstructs filling of the heart by causing
collapse of the vena cava and right atrium)
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Impaired blood flow
Hypovolemic Shock
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Reduction in total blood volume
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Can be related to bleeding (hemorrhage) or excessive loss of body fluids as
occurs during dehydration or with burns
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Reduced preload
Distributive Shock
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Profound vasodilation that increases the capacity of the vascular system, such
that ones normal blood volume may no longer be sufficient to fill this space and
maintain a blood pressure
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Often times the vasodilation is accompanied by an increase in capillary
permeability which makes the situation even worse as fluids begin to leak from the
blood vessels into the tissue
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Common causes of excessive vasodilation include systemic inflammation (as
may occur in sepsis), allergic reaction (anaphylaxis), and loss of sympathetic input to
blood vessels as in acute spinal cord injury
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Decreased systemic vascular resistance
Recognition of Shock
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Recognition of signs of sepsis or shock is essential so that interventions may be applied to
prevent progression to organ failure and death
Spectrum of symptoms that appear with shock
Low BP, decreased urine production, poor perfusion leading to acidosis are characteristic of all
types of shock, but some of the other symptoms are dependent on the cause of the physiological
disturbance
Body temp is decreased but may be increased at onset of shock (may be warm and flushed
rather than cool and clammy)
Skin is warm and dry in neurogenic shock and usually involves bradycardia rather than
tachycardia
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Anaphylactic shock presents as apprehension, abdominal cramping, coughing, wheezing, and
hives with quick onset
Cardiogenic Shock
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Failure of the heart to pump sufficient blood to adequately perfuse the tissues, despite ample
blood volume, can result in cardiogenic shock if not corrected
Consequence of MI or severe myocardial ischemia and can also be a late stage result of coronary
artery disease
The renin-aldosterone-angiotensin system (RAAS) attempts to compensate through fluid
retention and vasoconstriction
Anti-diuretic hormone (ADH) is released as well which gives rise to further increase in blood
volume
The adrenal glands react by releasing catecholamines that cause vasoconstriction and increased
HR. this can worsen the problem by making the heart work harder, increasing systemic vascular
resistance, or SVR and preload due to the inability to completely empty the ventricle in addition to
increased blood volume
Pulmonary and/or peripheral edema may occur due to fluid overload or mismatched ventricular
pumping
In addition, myocardial oxygen demands go up because of the increase in heart rate and
perfusion is impaired due to decreased oxygen delivery to the myocardium
Blood pressure falls because of reduced cardiac output and proper cellular metabolism cannot
continue with delivery of insufficient quantities of oxygen and nutrients
This leads to dysfunction not only in the heart but other organ systems as well
Hypovolemic Shock
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Loss of blood up to about 10%, which is the volume you would lose through blood donation is
not problematic
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Amounts above 10% begin to affect cardiac output and perfusion, and losses of between 35 and
45% of blood volume abolish cardiac output and arterial pressure
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Similar to compensatory mechanisms in cardiogenic shock, the body retains fluid via the RAAS
and release of ADH from the pituitary gland and the heart rate is increased
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Further to these mechanisms, cardiac contractility is increased and vasoconstriction occurs in
the extremities to keep vital organs perfused
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Blood stored in the liver is released into the circulatory system and the hypothalamus stimulates
thirst in an effort to increase fluid volume from external sources
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Blood pressure can be maintained by these mechanisms for a short time but if the vascular
volume is not restored adequate tissue perfusion cannot be maintained and organ dysfunction will
occur with possible progression to organ failure
Neurogenic Shock
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Neurogenic shock (vasogenic shock) occurs when the balance between parasympathetic and
sympathetic nervous systems is lost
in addition to spinal cord and brain trauma, this can be caused by depressant drugs and
anaesthetics and insufficient delivery of glucose to the brain, possibly due to the action of excess
insulin
Widespread vasodilation occurs and although there is sufficient fluid volume, the vascular
compartment has expanded so this volume is no longer adequate
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Due to the suppression of the sympathetic system, this is the one type of shock in which the
heart rate slows instead of escalating, and the skin remains warm and dry instead of cold and
clammy, as in other forms of shock
Neurogenic shock is categorized as a type of distributive shock along with septic shock and
anaphylactic shock since there is no loss of fluid rather a redistribution that impairs tissue perfusion
This is the rarest form of shock and tends to be transitory
Anaphylactic Shock
Anaphylactic shock results from an overwhelming systemic allergic response and
can vary in severity according to the amount of antigen the patient is exposed to as
well as their sensitivity to the antigen
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Vasodilatory substances such as histamine are released in large quantities and
increase the capillary permeability as well as dilating the vessels
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In addition to the circulatory effects, anaphylactic reactions can include laryngeal
and angio-edemas, gastrointestinal cramps, hives and bronchoconstriction that
causes difficulty breathing
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Common antigens that cause anaphylactic shock are nuts, shellfish, bee stings
and drugs such as penicillin
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This form of shock comes on very suddenly and treatment must be administered
immediately
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The rapid drop in blood pressure diminishes tissue perfusion and quickly leads to
altered mentation
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Epinephrine is administered quickly via IM injection or IV to cause vascular
constriction, reverse airway constriction, and curtail mast cell and basophil
degranulation, minimizing release of histamine and other vasodilatory substances
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Multiple doses may be required (due to short half-life of epinephrine)
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In addition to regular resuscitation, antihistamines, both short and long-acting
may also be required
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Metabolic Consequences of Shock
Shock is a condition that may be arrived at several different ways and may
manifest with different symptoms but the underlying impairment to cellular
metabolism caused by inadequate perfusion is the same
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This figure illustrates this common pathway and the mechanisms that occur and
lead to organ dysfunction
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The switch to anaerobic metabolism was mentioned previously along with the
reduction in efficiency of ATP production and the intracellular consequences of this
scarcity in energy
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the increase in lactate levels and ensuing metabolic acidosis dur to anaerobic
glycolysis was discussed as well
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The drop in pH in the blood due to lactic acidosis decreases hemoglobin's affinity
(ability to bind) for oxygen, further aggravating the hypoxic situation
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The effects of impaired glucose utilization has not yet been considered
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Delivery of glucose is decreased by hypoperfusion in the same way as delivery of
oxygen to the cells
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Uptake of glucose may also be reduced due to the release of hormones,
vasoactive substances and steroids into the blood
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This lack of glucose in the cells increases the use of other fuels so that lipolysis,
glycogenolysis and gluconeogenesis are all enlisted for energy production
Due to the extremely limited supply of glycogen in most cells other than liver and
muscle, energy stores are quickly reduced
Utilization of lipolysis for energy increases the quantity of free fatty acids and
triglycerides in serum; free fatty acids have been found to be cytotoxic, especially to
pancreatic beta cells (that produce insulin)
These dysregulations of cellular metabolism can lead to cell death but
gluconeogenesis is the process that can lead to organ failure
Use of protein for energy not only increases the amount of urea and toxic
ammonia produced, but also depletes plasma protein levels allowing the movement
of more fluid out of the vasculature in response to lower oncotic pressure
Alanine is also generated and once converted to pyruvate for energy production
worsens the state of lactic acidosis
Use of proteins from muscles can lead to wasting of both skeletal and cardiac
fibers and depletion of immunoglobulin proteins can impair immune function, which
is especially problematic in septic shock
Treatment for Shock
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Successful treatment of shock depends on prompt recognition and rapid
intervention
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Compensatory mechanisms, already examined, that the body enlists to restore
homeostasis are pictured and described in the figure
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In most cases these processes are ineffective in reinstating cardiac and vascular
balance so pharmacologic treatments must be administer as well
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The first step in treating shock is investigation and discovery od the cause and
correction or removal if possible (ex. Pt experiencing hypovolemic shock due to
hemorrhage, further loss of blood would be stopped first)
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Similarly neurogenic shock would first be treated by stabilization of the spine if
spinal cord trauma was the cause, and removal or neutralization of the antigen
would be attempted first in the case of anaphylactic shock
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Treatment with fluids such as crystalloids, colloids or whole blood, if indicated,
are used to enhance blood volume
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If vasopressors (to increase BP) or inotropes (to increase myocardial
contractility) are needed, they would be administered in the ICU
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Pt admitted to the ICU would undergo regular monitoring, usually hourly to
assess effectiveness of these treatments
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Correct Answer:
C) - Pancreatitis
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Wound infection, viral meningitis and urosepsis are all examples of pathologies
induced by infective agents
Answer E) ankle sprain involves inflammation with no infection but this would
produce a local rather than systemic response
SIRS can and does occur without infection, an example of this is the case of
pancreatitis
Pathophysiology of Pancreatitis
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Pancreatitis is an inflammation of the pancreas
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It is a potentially serious condition that may result in hospitalization, organ
dysfunction and even death
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It can be acute or chronic and may occur as a mild disease, although roughly
20% of patients experience a severe disease course
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In addition to its endocrine role releasing hormones insulin and glucagon into the
blood stream, the primary role of the pancreas is as an exocrine gland delivering
digestive enzymes produced in the acinar cells into the duodenum
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It is damage to these cells that is thought to be the cause of pancreatitis
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The acinar cells generate proteolytic enzymes as well as amylase and lipases in
nonactive forms that become activated once they reach the small intestines
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Because the enzyme trypsin activates the other proteolytic enzymes once
cleaved, the acinar cells also secrete trypsin inhibitor
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Acinar cell injury leads to activation of trypsin which prematurely activates other
enzymes and causes autodigestion of the pancreatic tissues
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The resulting tissue damage provokes inflammation with release of proinflammatory cytokines and complement system activation
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In the more severe cases of pancreatitis the damage is widespread enough to
incite systemic inflammation and the appearance of SIRS
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Shock or other forms of organ dysfunction such as acute respiratory distress
syndrome, ARDS, in the lungs or acute tubular necrosis, ATN, in the kidneys may
occur depending on the severity of the disease process
A large quantity of fluid may migrate to the abdominal cavity and cause a
reduction in blood volume with the accompanying hypoperfusion
In addition, the lining of the gut becomes dysfunctional due to damage and
allows translocation of intestinal bacteria into the bloodstream, resulting in sepsis
The most common symptom in pancreatitis is severe epigastric or midabdominal
pain, which can radiate to the back as well and may require narcotics to control
The preferred drug for pain relief is meperidine hydrochloride or Demerol rather
than morphine due to a reduced incidence of spasm in the pancreatic duct
sphincter
The most specific and sensitive diagnostic marker for pancreatitis in an elevated
serum lipase level
Serum amylase may be elevated as well but this marker is more transient,
disappearing upon late presentation
Other inflammatory markers may be assessed such as C-reactive protein or
CRP; this indicator is also used to evaluate disease severity
Common Causes of Pancreatitis
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The most common causes of pancreatitis are gallstones and alcohol abuse
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A procedure called endoscopic retrograde cholangiopancreatography or ERCP,
can also irritate the pancreas
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This can result in acute pancreatitis, either from mechanical injury of the tissue or
due to sensitivity or allergy to the dye
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Drug reactions and abdominal trauma can also trigger the condition, as can
hypertriglyceridemia
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Due to the worldwide increase in the incidence of obesity, this may become an
increasingly important factor in the prevalence of pancreatitis
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Recent research has shown that severity is increased in obesity and a greater
number of complications occur in these patients
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Finally there are about 15% of cases that are idiopathic (no known cause)
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Top pic is a healthy pancreas, lower picture is in acute hemorrhagic pancreatitis
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The white arrow denotes a pseudocyst filled with blood, while the white patches
highlight areas of fat necrosis
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This type of disease is often due to chronic pancreatitis, which may be alcohol
induced, or may be of genetic or autoimmune cause
Treatments for Pancreatitis
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The treatments for pancreatitis include pain relief as mentioned previously
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In addition to meperidine or morphine, fentanyl is also used for pain relief,
especially in mild cases of pancreatitis since it has less damaging effects on the
kidneys than other drugs
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Pt should receive no food or fluids by mouth, in order to allow the pancreas to
rest, and a nasogastric tube may be employed to remove gastric fluids that irritate
the condition
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Resuscitation fluids are given IV in an attempt to restore blood volume and
electrolyte balance may need to be re-established, especially in cases of stomach
acid removal
Another medication that has been used is somatostatin, also known as
octreotide, which is given IV or subcue as it limits pancreatic secretions, helping the
pancreas to rest and thus aiding healing
Ultrasound may be used to investigate the cause of condition when gallstones
are suspected and CT is often used to scan for the extent of tissue necrosis and
accumulation of fluid
Removal of gallstones and/or necrotic tissue may help resolve the illness
Cholecystectomy or gallbladder removal is indicated for all patients who have
had acute pancreatitis due to gallstones
When possible this should be done after recovery but before discharge from
hospital
In 25-30% of cases pancreatitis will reoccur within 6-18 weeks if the gallbladder
is not removed
Gallbladder or bile duct inflammation may occur as well is the gallbladder is not
removed, even in mild cases of pancreatitis
If the attack is alcohol induced, health teaching about the need to discontinue all
alcohol use must occur, as failure to eliminate alcohol consumption may lead to
chronic pancreatitis
Nutritional support is indicated for pt who will need to be fasted for 7 days or
longer
Enteral feeding of patients is preferred to parenteral because of lower risk of
infection due to maintenance of the gut barrier
TPN may need to be used if enteral feeding is not well tolerated
Those with mild pancreatitis that resolves in a few days don’t need nutritional
supplementation and can resume eating a soft food, low fat diet once pain has
subsided
A cause of pancreatitis in the critically ill receiving parenteral nutrition may be the
lipid suspension in the TPN
This may need to be removed and slowly reintroduced as the condition resolves
Summary
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In summary this module discussed the pathophysiology of sepsis and shock
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Remember that overall mortalities from sepsis are higher than those for
myocardial infarctions
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At present these are no good biomarkers or tests for detecting sepsis
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As such, it is important for the healthcare team to closely observe a client with a
suspected or confirmed infection. The quick SOFA tool is ideal for monitoring these
clients so they may be referred for further evaluation if they meet the criteria
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Early intervention in sepsis and shock result in better outcomes
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In both sepsis and shock it is important to identify and treat (if possible) the
underlying cause
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This module also discussed the pathophysiology of pancreatitis which can
quickly become systemic leading to SIRS and potentially shock
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Sepsis and shock can quickly lead to multiple organ dysfunction syndrome or
MODS, hence the importance of early detection and treatment. MODS is the focus
of your final culminating pathophysiology module entailed "multiple interacting
systems" and will be explained further there
Alterations in Reproduction Function Module
HPO axis: hypothalamic pituitary ovarian axis, the main hormonal feedback pathway
responsible for the reproductive system
Menarche: the first menstrual cycle achieved
Os: the opening from the uterus through the cervix into the vagina, can measure the
dilation of the os to monitor the progress of labour
Fundus: the top of the uterus, during pregnancy this can be used as one measurement
point for monitoring growth of the fetus (symphysis-fundal height), after delivery the
fundus is palpated to monitor the resolution phase
Infertility: failure to achieve pregnancy after one year of unprotected intercourse, noting
that if the female partner is over 35 years then the interval is shortened to 6 months
IUI: intra uterine insemination, where a small catheter is passed into the uterus via the
vagina and cervix so that semen may be instilled directly into the uterus
IVF: in virto fertilization, the process by which the ova and semen are collected from the
individuals and mixed together to permit fertilization to occur and after 3-5 days later 1-2
growing embryos are returned to the uterus, any remaining fertilized ova can be frozen
for future attempts
Prenatal: the period of time from conception to the birth of the infant, also known more
commonly within the healthcare community as the antenatal period
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Postnatal: the period of time from the delivery of the infant until complete resolution of
the body to the pre-pregnant state, usually 6-8 weeks
Parity: the number of deliveries that a woman has had over 20 weeks gestation, when
this number is over 5 this is considered to be a state of grand multiparity, or the woman
is referred to as grand multipara
GTPAL: a short hand for describing a woman's obstetrical history
G - Gravida: total number of pregnancies, including miscarriages, abortions and still
births
T - Term: the total number of deliveries over 37 weeks gestational age
P - Preterm: total number of deliveries between 20 and 37 weeks gestational age
A - Abortions: which can be spontaneous (occurring on their own) or therapeutic
(occurring by surgical intervention)
L - number of living children
Viability: the point at which should a fetus deliver there is a reasonable expectation of
survival, usually defined as 500 gm or more than 20 weeks gestation.
Fetal Presentations
Macrosomia: when the fetal head size has grown larger than can be passed vaginally
Polyhydramnios: the amount of amniotic fluid is more than 2 standard deviations
above the norm for gestational age
Normal Female Anatomy

Sexual differentiation of embryo occurs around 7 weeks (XX female, XY male)

SRY protein on Y chromosome is teste determining factor. Without that protein
females develop the vagina, uterus, and fallopian tubes (known as Mullerian ducts)

Ovaries produce the secondary oocytes and hormones like estrogen,
progesterone, inhibin and relaxin

Newborn female ovaries contain all primary oocytes and secondary oocytes form
after puberty once a month at ovulation

Uterus (muscular organ) is the site of implantation for the fertilized ovum, the
fetus develops here and it contains 3 layers
o
Endometrium
o
Myometrium
o
Perimetrium

The vagina is the receptacle for sperm during intercourse and also the
passageway for childbirth

The position of the uterus in the pelvis is something females are born with and
this uterine position will remain the same throughout their lifetimes

During a routine pelvic examination, a clinician can palpate the uterus during a
bimanual examination to determine their uterine lie or position as per the diagram.
This does not affect fertility.
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Female Hormones

With the onset of puberty the hypothalamic neurosecretory cells release the
gonadotropin releasing hormone (GnRH) which subsequently binds to the anterior
pituitary's cells called the gonadotrophs and stimulates them to increase the
secretion of the follicular stimulating hormone (FSH) and luteinizing hormone (LH)

FSH stimulates the growth of follicles of the ovaries to produce estrogen,
progesterone and inhibin

LH is responsible for stimulating the ovulation, remembering the LH surge and
formation of the corpus luteum

Estrogen is responsible for the development and maintenance of the female
reproductive structures, secondary female characteristics such as adipose tissue
deposition, voice pitch, broad pelvis and pattern of hair growth. As estrogen can
work synergistically with the human growth hormone, it can increase protein
synthesis including bones. Lastly, estrogen lowers blood cholesterol, although the
exact mechanism for this is unknown.

Progestogen is secreted mainly by the cells of the corpus luteum in the last two
weeks of the menstrual cycle. It works with the estrogen to prepare and maintain the
endometrium and to prepare the mammary gland for lactation.

Relaxin is produced by the corpus luteum and it has a role to play with the
relaxation of the uterine smooth muscle.

Inhibin is secreted by the granulosa cells of the follicles and together with the
levels of estrogen and progesterone, these hormones provide feedback for the HPO
axis, either stimulating or inhibiting further release of FSH and LH.
Female Monthly Cycle Summary

The normal female reproductive cycle can range from 24 to 36 days, with the
biggest variation occurring during the pre-ovulatory phase.

Day 1-5 is the menstrual phase when the uterus sheds all but the deepest layers
of the endometrium; approx. 50-150 mL of blood, tissue, fluid, mucus and epithelial
cells. This discharge is due to the decreased amount of progesterone and
estrogen.

Clinically we can manipulate this with the exogenous hormones such as the oral
birth control pill. When the woman stops taking the active hormones, the level of
progesterone particularly decreases and this withdrawal promotes bleeding. At this
time the ovarian hormones are at the lowest levels and this stimulates the secretion
of the GnRH and subsequently FSH and LH

Day 6-14 is the variable pre-ovulatory phase and under the influence of FSH the
maturation of the dominant follicle occurs. This phase is the uterus as estrogen
promotes the endometrial growth.

At approx. day 14 ovulation occurs when the secondary oocyte is released into
the pelvic cavity, surround by the zona pelucida and corona radiata. The leftover
cells in the ovary become the corpus luteum under the influence of LH and this
structure then secretes estrogen, progesterone, inhibin and relaxin.

Day 15-28 is the post-ovulatory phase during which the progesterone and
estrogen secreted by the corpus luteum causes further growth and coiling of the
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endometrial glands and thickening of the endometrium, all in preparation for a
fertilized ovum.
Without the fertilized ovum, the corpus luteum degenerates, leading to a
decreased amount of progesterone. With the withdrawal of progesterone,
menstruation occurs.
Implantation
Terminology

Zygote: the fertilized ovum

Blastocyst: collection of rapidly proliferating cells up to two weeks

Embryo: 2-8 weeks

Fetus: 2 weeks - birth

To achieve pregnancy the fertilized zygote must be able to penetrate into the
endometrial layer of the uterus. This process takes several days. At about day 10-12
post-fertilization you will start to see a rise in the beta subunit of the glycoprotein
called the human chorionic gonadotrope hormone (hCG). This marker is used to
detect pregnancy in both urine and blood.

Within a few hours after implantation the trophoblast or specialized cells around
the blastocyst will begin to produce this hormone. hCG is specifically produced
during pregnancy and the role of this hormone is to maintain the corpus luteum,
which produces the increasing amounts of progesterone needed to support and
thicken the uterine lining.

If the hCG levels are insufficient, the corpus luteum will regress, progesterone
levels will drop and the sloughing of the endometrial layer will occur.

Typically the beta-hCG value will double every two days in early pregnancy and
clinically this fact is used to support viability of the pregnancy or to rule out ectopic
pregnancy. A blood test is a more sensitive test that can detect a rise above 5 IU's
per litre and for a urine test to be positive, the hormone must be at the level of 25 IU
per litre.

When doing a home pregnancy test use first void of the morning (most
concentrated level of hCG)

Some woman experience spotting or light bleeding at the time their next menses
is due (much lighter than usual flow). This can signify a potential implantation bleed
caused by the burrowing of the zygote through the endometrial layers

It is usually not of consequence but can falsely date a pregnancy when a woman
feels that she did have her menses at her normal expected time.
Development

Embryogenesis a stage of rapid development of the ectodermal, endodermal,
and mesodermal layers for all the structures and systems in the human embryo and
fetus

By the end of the 13th week of gestation, all major structures and pathways are
formed and the remainder of the pregnancy is more about the growth and fine-tuning
of these. This is why the first trimester is the most important in trying to ensure that
the baby will be born healthy.
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however, due to the fact that most pregnancies are still unplanned, it is at this
time the developing fetus can be exposed to adverse substances and events such
as alcohol ingestion, tobacco smoking and used of recreational drugs
The chorion membrane is derived from two layers of tissue - the inner layer from
the ectoderm that becomes the trophoblast and the outer layer that us the
mesoderm. The trophoblast divides rapidly and creates small finger-like projections
to the uterine myometrium to begin to form the chorionic villi. The mesoderm fills in
these projections with branches of umbilical vessels so that they become
vascularized.
The chorion contributes to the development of the placenta, especially those
parts of the chorion that that are in contact with the uterine wall
Between 8-10 weeks the placenta will develop and take over the task of
producing progesterone and hCG, enabling the corpus luteum to degenerate
At 10-14 weeks the chorionic villi and intervillous spaces or maternal sinuses has
blood flowing and can facilitate nutrients and gas exchange. O2 plays a key role in
the regulation of villious vasculogenesis. At this time there is increased blood flow,
increased intra-placental oxygen demand and increased oxygen tension that may
contribute to excessive oxidative stress, which can be overwhelming in some
pregnancies and can lead to miscarriage.
Ultimately the arteries and veins increase in number and capacity and divide into
secondary then tertiary vessels before entering the mainstem villi or umbilical stalk.
Placental Development

The placenta provides all of the fetal nutrition during pregnancy

Formed by the 10th week of gestation, it filters nutrients, O2, and fetal waste
products by diffusion between the mother and fetus. It forms finger like projections or
interdigitation into the endometrium that perform these important functions.

After delivery a woman will experience lochia flow this is a sign that the location
of the placenta attachment is healing. Think of it as an open wound after the
separation of the placenta and heals like a scab would on your arm

The amnion is a membranous sac that surrounds the developing fetus and
provides protection as it grows.

It appears as a small sac that eventually enlarges and becomes fluid filled by the
4th or 5th week. The amniotic fluid accumulates to be a total of about 1-2 litres at
term.

When the water breaks, there is an opening in the amniotic sac that permits the
fluid to exit. When the membranes rupture, we note the quantity and colour of the
fluid to determine if the fetus has passed meconium prior to birth as this changes the
delivery protocol.

In certain conditions of pregnancy the amnion can produce too much or too little
amniotic fluid.

Polyhydramnious is associated with gestational diabetes and involves an
excessive amount of fluid which can over extend the uterine cavity and can lead to
poor decent of the presenting part into the pelvis. Should the membranes rupture
prior to adequate descent, then there is potentialfor the prolapse of the umbilical
cord which is an obstetrical emergency. Increased thirst and urination.
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Gestational hypertension can also be associated with oligohydramnious or too
little fluid around the baby. This can lead to intolerance of the stresses of labour,
such as fetal heart decelerations. Think of what happens with high BP, the vessels
are constricted and thus not as much blood passes between the placenta and the
fetus and results in lower volume of fluid.
Placenta

There are two umbilical arteries and one umbilical vein

The umbilical vein carries oxygenated blood to the fetus while the arteries
remove deoxygenated blood. (only other example is the pulmonary vasculature;
pulmonary arteries carry deoxygenated blood and pulmonary vein carries
oxygenated blood).

The delivery of the placenta is the third stage of labour.

The cord is always inspected after delivery for the presence of the three vessels.
Often on routine ultrasound of any pregnancy they will look for that.

The delivering midwife or physician will also examine the placenta following the
delivery to ensure the placenta is whole and there are not gross abnormalities.
There could be a velamentous or circumvalate cord insertion, vasa previa or
succenturiate or accessory lobe of the placenta.

If the baby is small for gestational dates, meaning less than 2500g at full term
birth, postdates, that is born after 41 completed weeks of gestation, or the placenta
does not appear normal on gross examination it can be sent to pathology for
histological studies.
Velamentous

The major umbilical vessels separate in the fetal membranes before reaching the
placental disk. Such a condition is of no major consequence in utero, but could lead
to a greater chance for cord trauma with bleeding during delivery.
Vasa Previa

Placenta after delivery showing vasa previa. Vessels are seen running
unprotected through the membranes.
Placenta Accerta

Results from a lack of formation of a normal decidual plate. Thus, the chorionic
villi extend into myometrium, and the placenta cannot separate normally following
delivery and severe hemorrhage results.
Placenta Positions

The location of where the placenta develops happens by chance, however there
are risk factors for the development of placenta previa which includes grand
multiparity, recurrent abortions or miscarriages or uterine surgery.

Placental previa is a condition whereby the placenta forms so that it is either
completely or partially covering the uterine os.

Position of the placenta is noted on ultrasound at 18-20 week of gestation

It findings of abnormal placentation, they will measure how close the leading
edge of the placenta is to the uterine os, which is the opening of the uterus to the
cervix. This provides a guide to the clinician for options for delivery.
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There is a potential that the placental position can change as the uterus
continues to grow and so repeat ultrasound exams will be undertaken.
Should the placenta completely cover the os, then delivery will be planned by csection.
With low lying or marginal previa, they may consider a vaginal delivery usually
with a double setup – that is being prepared to preform a c-section at a moments
notice.
The big risk with this condition is an antepartum hemorrhage, which can put both
mother and baby at risk; so with this diagnosis comes a recommendation for
complete pelvic rest.
Hormones in Pregnancy

Rise in estrogen and progesterone are the most important and the appearance of
hCG and placental proteins

The beta-hCG is one example of chorionic gonadotropins that we have
discussed, as this is initially created by the trophoblast and its main role is to
maintain the corpus luteum of pregnancy

Also hCG has the capacity, with its thyroid stimulating hormone-like activity
(TSH), to stimulate the maternal thyroid gland to increase circulating thyroid
hormones. Maternal thyroxin crosses the placenta and facilitates fetal development
and in some studies, maternal thyroid dysfunction can be associated with an
increased risk of preeclampsia, gestational hypertension, low birth weight, preterm
delivery, perinatal morbidity and mortality.

Other chorionic gonadotropins include hCS (human chorionic
somatomammotropin) and hCG (human chorionic corticotropin)

HCS is a protein hormone with immunological and biological similarities to the
pituitary growth hormone (also called the human placental lactogen)

HCS is referred to as the growth hormone of pregnancy with anti-insulin
characteristics – namely decreased glucose uptake and increased free fatty acids
being released (also had potent prolactin like or lactinogenic bioactivity

It is secreted by the placenta into the maternal circulation with very little reaching
the fetal circulation. The maternal plasma concentrations are linked to placental
mass. New research is looking at the functions of this hormone with fetal growth.

Human chorionic corticotropin (hCC) or Human chorionic adrenocorticotropin This role is unclear but interestingly the levels of hCC can be detected in both
maternal and fetal circulation but the maternal ATCH does not reach the fetus in the
thinking is that the parental hCC is not under the feedback regulations by maternal
glucocorticoids.

A number of pregnancy proteins have been identified such as pregnancy
associated plasma proteins; one example is PAPP-A, which is used for down
syndrome screening. There are also macroglobulins, placental proteins, placental
membrane proteins and although these have been isolated their functions have yet
to be fully detected

The corticotropin releasing factor or hormone is another placental synthesized
hormone, which is different than hCC.
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Placental CRH has similar characteristics of the hypothalamic CRH. CRH in a
non-pregnant woman is approximately 5 to 10 picomoles per litre but during
pregnancy this increases to 100 early in the third trimester and up to 500 per litre in
the last 5 to 6 weeks of gestation.
With the onset of labor, this level can rise another 2 to 3 times. Much of its role in
regulation is unknown but it has been thought that it plays a major role in the timing
of parturition, with the increased levels of CRH near the end of pregnancy, the
smooth muscles are relaxing, and there is increased formation of the
prostaglandins.
The other role that is associated with this is the fetal lung maturation and
development of fetal surfactants. Cortisol signals the lungs to start producing
surfactant so that the lungs may in turn, turn into functioning tissue upon delivery.
In the fetal state the lungs do not function in the manner that they do once in
extra-uterine life. While the organ develops and it grows, it does not function in-utero
to provide oxygenated blood to the tissues.
If threatened with premature labor, and it ensues, then a medication called
celestone or betamethasone (a corticosteroid) will be given into doses 12 to 24
hours apart by IM injection. This is to mimic the effects of the natural Cortisol and to
promote maturation of the fetal lungs.
Hormones in Pregnancy

HCG has two major subunits – alpha and beta

Remember its this glycoprotein that is responsible for maintaining the corpus
luteum of pregnancy. It’s the beta subunit that’s measured with pregnancy tests of
blood and urine

Alpha-hCG is used in fertility treatments to promote ovulation

During pregnancy, the levels of estrogen and progesterone continue to rise. This
is to support the changes in the breast tissue to permit breast feeding and to keeo
the endometrial lining thick and plentiful to support the utero-placental unit.
Changes in Pregnancy

At 12 weeks gestation you will just begin to palpate the uterus above the pelvic
bone while doing a pelvic exam.

It is at this time you may be able to auscultate the fetal heartbeat with using an
ultrasound doppler using the appropriate transmission gel. The uterus wil The uterus
will be about the shape of a large avocado or the size of a softball.

At 16 weeks the fundus will be about halfway between the pubic bone and the
umbilicus

At 20 weeks the fundus should be around the umbilicus. At this time you would
start to measure the symphysis-fundal height (SFH), which is a quick clinical
measure of fetal growth. With a singleton pregnancy, you would expect the SFH to
be within 1-2 cm of the number of weeks pregnant
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Note that an infant born before 37 weeks is considered a pre-term infant, if born
between 37-42 weeks the infant is term, and born after 42 weeks is considered postterm
Weight Gain
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Remember that in the early stages of pregnancy, the second individual is smaller
than a pea; so while the nutrient need increases, the caloric needs are not
significantly greater

Excessive weight gain during pregnancy pit the woman and fetus at risk.
Conditions such as gestational diabetes, gestational hypertension, fetal macrosomia
and dystocic labour can occur. Dystocic labour is where the uterus cant get into a
concerted, rhythmic pattern of contractions to affect delivery. Usually the labour can
be augmented if this occurs
Uterine size

Refer to the slide for a chart describing uterine sizes and changes during
pregnancy.
Dating for EDC

When calculating the due date or expected date of confinement (EDC) it is
imperative to use and determine the first day of the LMP. Be aware that the interval
from the last menses to ovulation is included in the EDC calculation.

Many people date in their minds from intercourse date. This is incorrect and can
lead to confusion and upset when a date is given may not jive when a partner was
"in town"

Once an EDC has been established and confirmed with an ultrasound, it is very
important that you do not change it – be consistent.

A pregnancy wheel is an easy way to determine the date or use a pregnancy
calculator

Least frequent used is naegele's rile (subs=tract 3 months and add 7 days to the
first day of the LMP date)

Full Term Pregnancy

At time of delivery evaluation of the presenting position of fetus done by palpating
for the anterior and posterior fontanelles for the infant during a vaginal exam.

The anterior fontanelle is a diamond shaped soft spot created where the skull
bones come together. The posterior fontanelle is triangle shaped.

The purpose of determining the fontanelles is to determine which way the occiput
(back of skull) is pointing. Occiput anterior presents the fetus in the best position to
effect vaginal delivery, as the widest part of the head goes into the widest part of the
pelvis, conversely occiput transverse and posterior presentations put the wide part of
the head into the narrow part of the pelvis which can result in failure to progress.
Uterus

During the pregnancy the uterus enlarges from a 50 gm size to 1100 gms and the
volume increases from 10 mL to hold an average of 5000 mL or 5L and in some
extreme cases up to 20L

The uterus is initially the shape if a pear but becomes more spherical by 12
weeks and then an ovoid shape with an increased length compared to width for the
rest of the pregnancy. The uterus starts in the pelvic cavity but after 12 weeks rises
towards the anterior abdominal wall and ultimately the liver starts to displace the
intestines laterally and superiorly.

As the pregnancy progresses hypertrophic uterus becomes more elastic and
fibrous in response to estrogen and progesterone levels. The position of the
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placenta influences where the uterus becomes more hypertrophic because the area
of the placenta site enlarges more rapidly than the rest. Also the uterine isthmus
becomes soft and compressible known as Hegar's sign.
Breast

Nipple enlargement and increased pigmentation occurs during pregnancy. Within
an increased blood supply the veins become more visible and in the second and
third trimester the proliferation of mammary glands occur related to pregnancy
hormones. More pronounced elevations noted on the areola are hypertrophic
sebaceous glands called the glands of Montgomery or Montgomery's tubercles

The mammary glands are ready for lactation during the pregnancy however this
is prevented with high levels of estrogen – so after delivery when the estrogen levels
drop lactation can occur.
Cardiovascular

As the uterus enlarges and pushes against the diaphragm, the heart becomes
laterally displaced to the left which directly impacts the PMI landmark.

Overall the heart size increases both in intracardiac volume and myocardial mass
by approx. 12% to accommodate the demands. The mothers cardiac output
increases 30-40% and peaks around 24 weeks.

Blood volume increases by 40-50% during pregnancy and this hypervolemia
helps meet the metabolic demands of the placenta and enlarging uterus. While the
bloods volume increases, there is a disproportional increase in plasma compares to
erythrocytes that can lead to a physiological anemia of pregnancy.

The higher blood volume is precipitated by an increase in circulating aldosterone
(promotes water retention in the kidneys), and increased bone marrow RBC
production and reticulocytes being released due to higher maternal erythropoietin
levels.

Due to all these increases it is not uncommon to hear a systolic ejection murmur.

Although both systolic and diastolic BP levels decline slightly during the
pregnancy they reach their pre-pregnancy levels by approx. 36 weeks. Venous
pressure increases in the later part of pregnancy in the lower extremities leading to
venous congestion in the form of varicose veins, hemorrhoids and dependent
edema.
Respiratory

Although resp rate remains unchanged, tidal volume and resting minute
ventilation increases whereas the functional residual capacity and the residual
volume are decreased as the uterus elevates the diaphragm.
GI

Heartburn due to lower esophageal sphincter tone

Decreased motility (can lead to constipation)

Enlarged gallbladder with potential for cholestasis (due to bile stasis increasing
risk for gallstones)
Renal

Increase in length, weight and volume

Predisposition for UTIs
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Increase renal blood flow and GFR
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Antenatal monitoring
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Skin

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Striae (stretch marks in 50% of woman)
Hyperpigmentation with linea nigra and/or chloasma due to increased stimulation
of the melanocytes to produce melanin.
Infertility

Infertility: the failure of a couple to conceive after one year of unprotected
intercourse.

If the woman is over 35, it is a 6 month period of time.

8.5% in 2001

Causes attributed to females 40% and males 30-40%, unknown in 10-20% of
cases

Female issues can be hormonal, such as ovulation disorders, PCOS where there
is an excess of male hormones in the woman causing ovulatory issues, and some
imbalances that can cause recurrent miscarriages.

Endometriosis and pelvic inflammatory disease can lead to fallopian tube
occlusion. Congenital anomalies in the female genital tract may also be at issue.

Modifiable risk factors are age, weight and exercise.

Male factors can be due to poor sperm quality, quantity, mot quantity, motility or
shape due to sexual dysfunction

Part of the workup of the infertile couple is to do a semen analysis which looks at
the shape, movement and number of sperm in a recently collected ejaculate sample
after 3 days of abstinence.

Stressors, smoking, alcohol, tobacco and substance use and abuse may also
affect either partner.

For the unexplained causes, newer research is focused on link between immune
and reproduction systems
Ovulatory Disorders

Ovulation requires many factors to be working together in a normal fashion

When a young woman achieves menarche it can take several years before the
HPO axis is mature and ready to ovulate regularly. In some instances irregular
cycles persist due to alterations in the pathway. This would by cycle lengths less
than 24 days or more than 36 days.

Most woman will experience an occasional anovulatory cycle for reasons such as
stress, weight changes or idiopathically. The most common reason for anovulation is
pregnancy.

When evaluating amenorrhea it helps to follow a stepwise approach to diagnostic
tests and procedures. You can divide the possible disorders into groups based on
the ovarian hormone secretion profile and then further subgroups by the
gonadotropin levels.

When the ovarian hormone secretion is normal, think about uterine function as a
main cause of the issue. Is there even a uterus present? Has there been surgery
which might affect the ability of the uterus to permit implantation? Pregnancy can
also cause loss of menses with normally functioning ovaries.
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With increased ovarian hormone secretion one should think about reasons why
there is an increased amount. Are the ovaries enlarged due to tumours or PCOS?
With decreased ovarian hormones secretion we then look higher in the HOO axis
to see how the hypothalamic derived gonadotropins fit into the picture. If the
gonadotropin levels are high then the hypothalamus is working very hard to try to get
the ovaries to respond. Think about conditions such as menopause, ovarian failure,
previous chemotherapy that has affected the ovaries.
With low or normal gonadotropin levels consider other hormones that may be
impacting on the system, such as the adrenals or other steroid hormones.
With low gonadotropin levels think again about the higher structures of the
hypothalamus and pituitary glands. Increased levels of the hormone prolactin, which
is required for lactation, can suppress the appropriate response of the pituitary
gland. These elevated hormone levels can be due to a prolactinoma (tumour of the
pituitary). Also, chronic starvation, such as in anorexia, can result in this normal
hormone pattern.
Alterations in thyroid gland functioning may also impact the menstrual cycle
including changes in cycle length and blood flow which can lead to oligomenorrhea
(or cycles longer than 36 days) and potential ovarian failure.
Hypothyroidism can interfere with the normal GnRH secretion which is essential
for follicular development and ovulation. A decrease in the release of LH can lead to
a wide range of menstrual dysfunctions and the gonadal dysfunction of FSH/LH may
decrease the amount if thyroid hormone availability for the necessary ovarian
function.
Studies have identified that thyroid hormone receptors have been found on the
oocytes and surrounding granulosa cells. It seems that both the hCG and maternal
thyroxine are required to achieve fertilization, blastocyst development and fetal brain
development
However there are few actual studies linking infertility and hypothyroidism, rather
this seems to impact some but not all woman suggesting this multifactorial as well.
Ovarian cysts may also impact ovulation as they are sending altered feedback
signals to the HPO axis that may result in irregularities in the cycle.
PCOS – polycystic ovarian syndrome is an extreme form of cystic ovary that can
result in chronic anovulation, endometrial hyperplasia and other pathologic
conditions.
Polycystic Ovary Syndrome (PCOS)

The picture on the left denotes a very common "string of pearls" appearance on
the u/s of a polycystic ovary.

The volume of the ovary can become significantly enlarged and the normal
ovarian volume is less than 9mL.

PCOS is a common endocrine disorder in woman and is associated with
primarily hyperandrogenemia +/- anovulation and its associated with infertility and
with the clinical manifestations of oligomenorrhea (less frequent menses), hirsutism
(excess hair growth which can occur in a more male pattern distribution) and acne.
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The exact prevalence of this condition us unknown however it is felt that with
increasing obesity rates we will see higher rates of PCOS as these seem to be
linked.
While the exact etiology of the condition is not yet known a genetic basis is
suspected and our understanding is improving with research into this condition
From a reproductive view point we need to look at the follicles in the ovaries. The
key defining and morphological feature of this syndrome is the increased number of
follicles as compared to a normal ovary. These increased follicles then over produce
androgens, which lead to androgenemia.
The following criteria may be used to differentiate a normal from polycystic ovary:
increased volume (>9mL), 10 or more follicles of 2-18 mm diameter, an increase in
the amount and density of the ovarian stroma and thickening of the tunica.
Pathophysiology of PCOS

PCOS is also associated with a metabolic defect which presents as insulin
resistance and hyperinsulinemia.

Both muscle and adipose tissue demonstrate altered glucose uptake. However,
the gonadotropic effect of insulin on the ovarian tissue is unaffected and this further
increases the androgen production and premature cessation of follicular growth.

As insulin also reduces serum sex hormone – binding globulin (SHBG) - s
glycoprotein that binds testosterone and estradiol in the circulation to make the
inactive, thus there will be more biologically active steroids available.

Together with the excessive ovarian androgen production and less SHBG the net
effect is an increase in free testosterone and estrogen.

As FSH is typically lower, it is the elevated LH that leads to the androgens –
particularly DHEA-S (dehydroepiandrosterone sulfate) levels from the adrenal cortex
to be secreted in up to 50% of PCOS patients. It is this blunted FSH/LH feedback
that leads to stimulation for new follicles but not to full maturation or ovulation thus
accounting for anovulatory cycles. As you can see this is a very cyclic problem

Usually the treatment for PCOS is to reestablish normal hormonal levels using
the oral birth control pill but for infertility sometimes metformin (oral
antihyperglycemic drug in the biguanide class) is used to decrease the ovarian
steroidogenesis.

Pregnant woman with PCOS have increased risk of GDM, G-HTN), preterm birth
and perinatal mortality.

It should be noted that potential later sequelae of PCOS include dyslipidemia,
cardiovascular disease, DM or metabolic syndrome.
Late Maternal Age

Remember woman are born with all the oocytes or ova they will have in their
lifetime and many woman today are choosing to delay childbearing until after they
have established their careers.
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Unfortunately as they age, this results in declining quality of the ova as they have
continued to be exposed to potential lifestyle choices of alcohol, tobacco, and poor
diet quality. Thus achieving pregnancy may become more difficult.
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If a woman does achieve a pregnancy there is also a higher spontaneous
miscarriage rate that may also impact her ability to carry a fetus to term. As well, as
woman age the risk of gestational HTN and GDM, two of the main complications of
pregnancy increase.
It is well known that fertility begins to decline after the age of 35 for most woman
and this is multifactorial. The graph of the likelihood of infertility versus the likelihood
of getting pregnant demonstrates that infertility shows an exponential rise after 35
while there is a more linear decline in the likelihood of getting pregnant.
Recent trends in Canada show more woman are having their first child after the
age of 30.
As you can see from the slide on the rates of pregnancy with own versus donor
eggs that certainly an older woman can get pregnant, but at the cost of genetic
connection to the child.
Many woman are willing to forgo this connection to be able to experience
pregnancy and motherhood, as many men with medical conditions such as CF, or
azoospermia have been willing to select a semen donor and forgo a genetic
connection to a child to become a parent.
Tubal Disorders

Untreated STIs in woman can cause blocked fallopian tubes which can lead to
infertility + higher risk of ectopic pregnancy

Chlamydia and gonorrhea are common causes of pelvic inflammatory disease,
woman often have no S+S of STI due to the site of infection

Increased # and severity of infections can significantly decrease chances for
getting pregnant due to permanent injury to fallopian tubes with loss of cilia function,
fibrosis and even complete occlusion

Surgery can alleviate blockage but does not decrease chances of ectopic
pregnancy and isn't commonly done.

Endometriosis can also cause blockages

Other causes can be embryological in origin
Hysterosalpingography (HSG)

HSG is done to evaluate the patency of the fallopian tubes.

It is a fluoroscopic examination preformed in radiology.

A speculum is inserted into the vagina and dye is injected through a catheter in
the uterine cavity and into both tubes.

A surgical evaluation may also be done of the pelvis and uterus called a
hysteroscopy and due transit. Dye is injected often methylene blue to see if it will
free spill from the tubes into the peritoneal cavity.

It is rare to have bilateral blockages and usually only one tube is affected.
Endometriosis

Endometriosis is the appearance of plaques of endometrial tissue on other
structures in the body.

These plaques can form on any structure in the pelvis or peritoneal cavity such
as bowel, bladder, ovary or fallopian tube.
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Endometrial tissue affected swells and slough in a similar manner to the uterine
lining due to hormonal changes monthly
There is no egress or exit point (unlike uterine os) for the products of endometrial
tissue which causes significant pain and scarring
Cause is unknown but some evidence supports a retrograde menstruation as the
cause
Effects on infertility is unknown; did infertility cause endometriosis or did
endometriosis cause infertility?
A definitive diagnosis is done with a laparoscopy
# of plaques do not correlate with symptomology
Check out website for more information
Uterine Anomalies

The female genital tract is known as the mullerian system.

During embryogenesis there can be small changes in the usual development
process of this system that result in major anatomical anomalies at maturation.

Should pregnancy be achieved and carried past the point of viability with one of
these uterine anomalies there is a higher risk of preterm delivery and
malpresentation at the time of delivery, that is breach or transverse.

There also may be fibroid tumors that exist on, in or in the muscle layers of the
uterus. These can alter the shape of the uterine cavity and can also result in preterm
delivery or malpresentation.
Treatments for Infertility

Treatments for infertility can range from medical to surgical or include both
approaches.

Intrauterine Insemination (IUI) is the least invasive and involves instilling the
semen directly into the uterus.

The Dr. May choose to add ovarian stimulation to this procedure using
medications like clomiphene (ovulatory agent) which is taken orally or injectable
medications such as follitropin (or Gonal-F which is a gonatropin with the active
ingredient of FSH).

These meds are used to increase the # of mature ova in the given cycle to
increase the chances if achieving a pregnancy. (if this fails woman may use IVF)

In Virtro Fertilization is a process whereby the ova and sperm are combined
outside the body, permitted to develop for 3-5 days and then the resultant zygotes
are transferred into the woman's uterus. The ova are collected through transvaginal
aspiration of the ovary under ultrasound guidance. Excess zygotes may be frozen
for future attempts.

With transfer of multiple zygotes comes the risk of a multiple gestation
pregnancy. Due to the higher potential for maternal and fetal complications in a
multiple gestation pregnancy there is much ethical debate in the fertility literature
about the optimal number of transfer per cycle.
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The current trend is to transfer fewer zygotes to hopefully reduce the risks of
multiple gestations.
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Hypertensive Disorders of Pregnancy (HDP)
Pre-Existing HTN

Is when the systolic is >140 mmHg or diastolic >90 and this is diagnosed before
20 weeks gestational age.

Accounts for 1% of pregnancies requiring ongoing medical monitoring.

Older literature may refer to it as "chronic HTN".
Gestational Hypertension (GHTN)

Defined as a diastolic >90 mm Hg or the systolic > 140 mm Hg occurs after 20
weeks gestation

The diastolic # is a better predictor of adverse pregnancy outcomes compared to
systolic but both are important to monitor during the antenatal period during each
visit

Leading cause of maternal morbidity and mortality in Canada with approx. 15%
of maternal deaths attributed to GHTN.
Severe GHTN

Defined as systolic is >160 mmHg or the diastolic >110 mmHg.

Is based on the fact that a systolic # of >160 us associated with increased risk of
stroke in pregnancy.
Pre-eclampsia

Condition of hypertension and increasing proteinuria.

Woman with pre-existing HTN have a 10-20% risk or if they develop GHTN
before 34 weeks they have up to 35% risk of developing pre-eclampsia.

If HTN before 20 weeks = pre-existing but then if pt develops proteinuria or
clinical S&S she would have pre-existing HTN with pre-eclampsia.

GHTN if developed after 20 weeks gestations and if she had proteinuria or
clinical S&S it would be GHTN with pre-eclampsia.

Increased BP increases mothers risk of MI, stroke, heart failure and renal failure.
It increases fetus's risk of placental complications; poor oxygen transfer, placental
abruption, fetal growth restriction, preterm birth, and even death.
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Treatment in pregnancy for pre-existing and gestational HTN is similar with betablockers such as labetalol, metoprolol, CCB such as nefedipine, methyldopa – a
centrally acting alpha 2 adrenergic agonist, or in severe cases hydralazine a direct
vasodilator
For call cases of hypertension in pregnancy both ACEIs and ARBs are
contradicted due to their teratogenic and/or fetotoxic effects
Pre-eclampsia

Affects 1-2% of pregnancies & is a progression of hypertension with clinically
significant proteinuria (a dipstick of > 2+ or > 30mg/mmol urinary creatinine in a
random urine sample, or >0.3g/day in a 24 hour urine) with adverse conditions such
as new/unusual headache, visual disturbances, persistent epigastric pain, chest
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pain, dyspnea, changing liver enzymes, decreasing platelets, are only some of
these.
Routine nursing evaluation includes dipstick urinalysis as a common screening
test for the presence of protein and blood pressure measurement at every antenatal
visit.
Changes in amount of protein should be noted and examination of deep tendon
reflexes + testing for the presence of clonus (sign of CNS irritability – may serve as
predictor of seizure activity).
Risk factors – advanced maternal age (over 40), first continuing pregnancy,
obesity/excessive weight gain in pregnancy, family Hx of pre-eclampsia, an
interpregnancy (less than 2 years or greater than 10 years), use of reproductive
technologies, multiple gestation or elevated BP at initial prenatal visit.
Treatment - (pre-conception) counselling about heathy lifestyle (diet, exercise),
depends on gestational age + disease severity because the only cure is delivery of
the fetus. Bed rest is commonly recommended.
Treatment goals in the early phases of GHTN includes control of BP, which can
be done with the use of beta blockers and/or methyldopa. With the addition of preeclampsia especially if before 34 week gestation antenatal corticosteroid therapy
should be given to all woman, namely betamethasone IM x2 to facilitate fetal lung
maturation.
If after 37 weeks the woman presents with pre-eclampsia often she proceeds to
inductio and delivery to be safe.
Hypertensive Disorders

Maternal, placental and fetal factors involved in the pathophysiology of
eclampsia.

Incomplete trophoblastic invasion and placental implantation (leads to shallow
vessel development).

Immunological maladaptation between maternal/paternal and fetal tissue
(suggestive of acute graft rejection) - leads to overall poor placentation.

High numbers of leukocytes, inflammatory cytokines (such as TNF-alpha, ILs),
prostaglandins, and free radicals contribute to oxidative stress.

Endothelial activation which promotes a prothrombotic and pro-inflammatory
state leading to the maternal syndrome.
Anti-ang factors: anti-angiogenic factors (e.g. s-Fil-1: PIGF ratio)
ARDS: acute respiratory distress syndrome
ATN: acute tubular necrosis
DIC: disseminated intravascular coagulation
PBLs: peripheral blood leukocytes
PGs: eicosanoids (prostaglandins, prostacyclins, thromboxanes, leukotrienes)
ROS: reactive oxygen species
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Low doses of aspirin (60-150mg) can reduce the incidence of pre-eclampsia by
at least 10% in woman who are at elevated risk.
Potential Sequelae
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Untreated pre-eclampsia can lead to eclampsia or HELLP (hemolysis, elevated
liver enzymes, low platelets) syndrome.
Eclampsia occurs in 1-3 out of 1000 pre-eclamptic pt and includes all features of
pre-eclampsia with the addition of seizure activity.
It is an obstetrical emergency.
Goals of treatment: stop seizures and deliver the baby; maternal seizures cause
the uterus to seize – results in placental abruption, prolonged seizures can have
neurological impact on mother.
Prevention of seizures is the next goal; using magnesium sulfate (acts as muscle
relaxant).
Delivery is ultimate goal but gestation age of fetus needs to be considered for
risk/benefit ratio.
Seizures can occur post-partum for 3-6 days.
HELLP syndrome includes Hemolysis or the breakdown of the blood cells, the
elevated liver enzymes signify inflammation of the liver and condition is
characterized by pain under the right ribcage due to inflamed liver, lastly low
platelets can signal an impending disorder of clotting status that if left unchecked
can progress to disseminated intravascular coagulopathy (DIC)
Delivery of fetus vaginally or c-section is done as soon as possible (as this can
progress quickly to DIC).
Maternal corticosteroids are given for both fetal and maternal benefits, and blood
products such as platelets are given especially if values are under 50 x 10^9/L
Disseminated Intravascular Coagulation

DIC is a major medical complication that can occur with pregnancy as well as
other conditions such as sepsis and major trauma. To simplify this is an imbalance
between coagulation being overactivated.

Overactivated coagulation promotes thrombin generation, and the body then
consumes the clotting factors and platelets leading to abnormal bleeding even
severe hemorrhage.

In cases of DIC with pre-eclampsia or other obstetrical complications, the main
initiating factor is the over expression of tissue factor.
1.
& 2. TF along with other pro-inflammatory mediators such as IL-1, IL-6, IL-8 or
adhesion modules continue to facilitate the secretion of TF from endothelial cells or
monocytes.
3.
TF is responsible for activating the coagulation cascade especially with the
activation of thrombin.
4.
Normally plasmin works in conjunction with the thrombin limiting the fibrin clot –
as with any injury. You expect the clot to be contained to the local area while still
permitting perfusion to the other tissues surrounding the injured area to promote
healing.
5.
One of the mediators, tumor necrosis factor – alpha (TNF-a) stimulates
plasminogen activator inhibitor (PAI), thus limiting plasmin from breaking up any
fibrin clots.
6.
Continuing with this spiraling process any inflammation continues to activate
more monocytes by a variety of cytokines further expressing TF leading to more
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fibrin deposition. It is here that the current research is looking at the deficiencies of
protein C (another mediator when activated that helps to limit clots but with
excessive stimulation the body cannot make enough of this liver protein).
7.
& 8. there is a direct link with inflammation to the kinin and complement systems.
Together they can lead to increased vascular permeability, decreased BP, shock,
and further platelet activation inducing more TF and cytokines.
9.
Overall there is an overwhelming consumption of platelets and clotting factors so
that the body can no longer clot and this can lead to hemorrhage. Identified by small
petechiae or large hematomas to bleeding from every orifice. In this case this
population is at risk for placental abruption or PP hemorrhage that becomes
uncontrollable is high. Unlike the general population with trauma or sepsis, if the
mom delivers the baby and if supportive care is available the outcome can be
favorable.
10.
In this sage there are microvascular clots in the organs and small vessels leading
to ischemia or necrosis which will further activate inflammatory cytokines. If the clot
persist, organ failure can result.
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Supportive care; frequent BP/vital signs, blood work, IV access, oxygenation,
blood products (PRBC, FFP, platelet and cryopreciptate), fluids (N/S or R/L), ensure
mom stays warm.
Postpartum Hemorrhage

Can be caused by many factors, abnormal tone with uterine atony – including
over distension of the uterus, as with multiple gestation, polyhydramnios, fetal
macrosomia or even bladder distension preventing uterine contraction, prolonged
labor; retained placental tissue; obstetrical lacerations or trauma; and maternal
intrinsic bleeding defects (Von Willebrand's disease, ITP).

Active management of stage 3 is recommended (delivery of placenta); administer
dose of oxytocin with the delivery of anterior shoulder (given IM, IV or IV Bolus).

Should excess bleeding occur; monitor amount by # of pads/towels saturated by
weight or by volume suctioned.

Treatment as in any hemorrhagic shock is to get help and start resuscitation
quickly ensuring adequate perfusion of oxygen to tissues. Thus assessing
circulation, airway and breathing, adding oxygen, ensuring patent IVs, equipment to
frequently monitor vital signs plus recording values and interventions are all
important.

Uterine massage may be done by experienced health care providers to promote
the production of prostaglandins and lead to uterine contractions. Common meds
given are uterotonics; oxytocin, ergotamine or misoprostol (a prostaglandin).
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This table outlines the different levels of hemorrhagic shock and potentially what to
expect clinically.
Gestational Diabetes (GDM)
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DM that only occurs in pregnant state.

Untreated GDM leads to increased maternal and perinatal morbidity while
intensive treatment is associated with outcomes similar to those of the general
population.

Risk factors; previous GDM, previous delivery of a macrosomic infant (>4000 gm
at birth), ethnicity (Aboriginal, Hispanic, Southeast Asian or African), age >35 years,
obesity or PCOS.

Urine dip at each antenatal visit.

Universal screening of all pregnant women between 24-28 weeks gestational age
with a 50 gm oral glucose challenge (BG <7.8 mmol/L following 50 g OGTT is
normal).

BG between 7.8-11 mmol/L would require a confirmatory or diagnostic test.

If BG is = or > than 11.1 mmol/L no need for further testing a diagnosis of GDM.

Treatment; medical Nutrional management, client education, frequent BG
monitoring. If lifestyle/diet don’t manage GDM insulin therapy is implemented.
Studies show god results of glyburide and metformin.
Pregnancy and Blood Sugar

GDM is mostly a disease of insulin resistance. Glucose will cross the placenta
but insulin does not.

Elevated maternal glucose will lead to elevated fetal glucose and increased
secretion of insulin from the fetal pancreas. Insulin acts like a growth hormone and
can result in increased birth weight and incidence of macrosomia (increases risk of
should dystocia during vaginal delivery = injury of newborns brachial plexus).
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Fetal effects: greater risk of stillbirths and pre-term labor. Hypoglycemia,
hypocalcemia, hyperbilirubinemia and polycythemia (risk decreases if good BG
control).
Increased risk of pre-eclampsia.
Increased risk of obesity in child.
Key strategy; return to ideal body weight after delivery thus less chance to
develop T2DM.
If development of T2DM potential long-term risks are CV disease, HTN, renal
disease, etc.
Schizophrenia Module
Epidemiology

Schizophrenia has been described as a disconnection between thought and
language. There is an interference with the filtering of stimuli from the environment
which affects a person's thoughts, feelings, perceptions and overall behaviors.

Schizophrenia is a complex disorder that occurs in about 1.3% of the population
in Canada.

It occurs in all countries and cultures, and is equally distributed amongst men
and women, although there is a later onset in women because estrogen is believed
to be a protective factor and delays onset of symptoms.
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10% of persons with schizophrenia will commit suicide.
DSM-5
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The Diagnostic and Statistical Manual of Mental Disorders of the American
Psychiatric Association states that schizophrenia is a mixture of positive and
negative symptoms that present for a significant portion of a 1-month period but with
continuous signs of disturbance persisting for at least 6 months.
Positive Symptoms

Positive symptoms can be remembered as symptoms that exist but should not,
and are an excess or distortion of normal functions. The positive symptoms of
schizophrenia include delusions and hallucinations.

Delusions are false fixed beliefs that usually involve a misinterpretation of an
experience.

The various types of delusions include:
o
Grandiose where the person believes that they have exceptional powers,
wealth, skill, influence or destiny.
o
Nihilistic where the person believes that they are dead or that a calamity
is pending.
o
Persecutory where the person believes that they are being watched,
ridiculed, harmed, or plotted against.
o
Somatic where the person believes they have abnormalities in their bodily
functions or structures.

Hallucinations are perceptual experiences that occur without actual external
sensory stimuli.

Hallucinations involve any of the 5 senses, but are usually visual or auditory. The
persons may see or hear things that are not in the external world but nevertheless
are very real to the person experiencing them.

Auditory hallucinations range from simple repetitive sounds, to many voices
speaking at once and can be interpreted as pleasant to distressing by the person
experiencing them.

When visual hallucinations occur, they often occur in conjunction with auditory
hallucinations.
Negative Symptoms

Negative symptoms can be remembered as symptoms that don’t exist but
should. They reflect the lessoning or absence of normal social and interpersonal
behaviors.

Alogia – a reduced fluency and productivity of thought and speech.

Avolition – withdrawal and inability to initiate and persist in goal-directed
activity.

Apathy – a decreased reaction to stimuli along with diminished interest and
desire.

Affective – a flattening or blunting in range of emotion expressed, or an
inappropriate affect.
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Anhedonia – an inability to experience pleasure in things that ordinarily are
pleasurable.
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Ambivalence – the concurrent experience of equally opposing feelings making it
impossible to make a decision.
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It is also important to note that a person with schizophrenia may have an
increased tolerance to pain.
Neurocognitive Impairment

There are several areas of cognitive function which may be impaired in
schizophrenia and this dysfunction can occur even if the positive symptoms of
schizophrenia are in remission.

These areas of dysfunction include: short and long-term memory
o
Vigilance or sustained attention
o
Verbal fluency or the ability to generate new words
o
Executive functioning including volition, planning, purposive action, and
self-monitoring behaviors
Disorganized Symptoms

Disturbances in thought processes include various types of delusions.

Other examples include depersonalization or the belief that one's self and one's
body is strange or unreal and magical thinking which is a belief that one's own
thoughts, words or actions have the power to cause or prevent things from
happening.

Examples of disturbances in thought processes include loosening of association
where there is a lack of logical relationship between thoughts and ideas and
conversation shifts from one topic to another in a completely unrelated manner.

Another example is thought blocking where there is an abrupt pause or
interruption in one's train of thought, after which the individual cannot recall what
they were saying.

Ancillary symptoms that may accompany schizophrenia but are by no means the
main symptoms include anxiety, depression, and hostility.

Disorganized behaviors of schizophrenia are coupled with disorganized speech
and may for example include a slow, rhythmic and ritualistic movement coupled with
disorganized speech.

Other examples include aggression which often occurs if the person believes
someone is trying to harm them, agitation involving an inability to sit still or attend to
other which is accompanied by heightened emotions and tension, catatonic
excitement which involves a hyperactivity characterized by purposeless activities,
abnormal movement such as grimacing and posturing, echopraxia which involves
involuntary imitation of another person's movements and gestures, regressed
behavior involving childlike and immature behavior, stereotype involving repetitive
purposeless movements that are idiosyncratic to the individual and somewhat out of
their control, hypervigilance involving sustained attention to external stimuli as if
expecting something important or frightening to happen, and waxy flexibility involving
holding a posture in an off to unusual fixed position for an extended period of time.
Risk Factors for Schizophrenia
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The precise neurobiological mechanism in relation to maternal infections is not
known, but it is believed that cytokines and an abnormal immune response to these
infections interfere with normal fetal brain development during this period.
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Obstetrical complications may cause fetal hypoxic or ischemic damage to the
developing brain, where premature cortical synaptic pruning may occur (this means
that connections between brain cells or neurons become disconnected or pruned
prematurely).
Older parental age including both the mother and the fathers age has been found
to double the risk for developing schizophrenia in offspring, and this is thought to be
related to impaired formation of sperm cells leading to an increased risk of genetic
mutation.
Urban settings are thought to be more stressful environments
Infants who have been affected by the previously stated maternal stressors have
conditions that include their own risk such as low birth weight, short gestation, early
developmental difficulties and in childhood central nervous system infections.
First degree relatives of persons with schizophrenia have been found to be at
great risk.
Risk for Schizophrenia: Cannabis Use

The video explores the increased risk for schizophrenia related to marijuana use;
describes that the active ingredient in marijuana delta 9-tetrahydrocannabinol or
THC has been shown to quadruple a teens chance of developing this disorder.

THC interacts with the cannabinoid system and dysregulates it.

This system serves a regulatory function in controlling the release of glutamate
and GABA has an effect on neuronal synaptic connections and on the dopamine
system.

Neuropruning or untangling of brain cells happens to teenagers in their normal
brain development, and THC is believed to interfere with the normal
developmental neuropruning process.

Prodromal symptoms are early symptoms of schizophrenia which often appear in
adolescence, and marijuana use has been seen to trigger and exacerbate these
early symptoms.

The video also explores a genetic component of schizophrenia related to
chromosome 22 where a person can have the met or val alllele.

If a person has one met and one val allele and smokes cannabis it doubles your
risk and if a person has two val alleles and smokes cannabis it increases their risk of
developing schizophrenia five times.

Brain imaging studies have also shown that the hippocampus and amygdala are
smaller in cannabis users.
Etiology of Schizophrenia: Neurodevelopment Model

Patients with schizophrenia have a biologic predisposition or vulnerability that is
exacerbated by environmental stressors.

Environmental factors include prenatal stressors, adolescent brain changes, and
neurobiological challenges.

Neurobiological changes involve some type of a lesion which causes anatomical
and functional changes in the brain which are believed to begin in the prenatal
period, continue to deteriorate during growth and development particularly in the
adolescent period but remain silent, and begin to be recognizable in late
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adolescence to early adulthood as behavioural changes and symptoms of
schizophrenia.
Gene-Environment Interaction

First degree relatives including siblings and children are 10x more likely to
experience schizophrenia than those in the general population.

Dizygotic twins share 50% of their genetic material and if one twin has
schizophrenia the risk of the other having the illness is 10-15%.

Monozygotic twins share 100% of their genetic material and if one twin has it the
risk of schizophrenia in the other is about 40-50%.

If both parents have schizophrenia, the risk of their children developing
schizophrenia is also about 40%.

Genetic factors are thought to contribute to about 80% of the liability to develop
schizophrenia in the population, and environmental factors are thought to contribute
to 20% of liability.

Certain variations in genes called polymorphisms, may increase the risk for
schizophrenia (polymorphism – alteration in gene sequence of DNA).

It is thought multiple genes are involved in the development of schizophrenia,
each appearing to have different regional brain expressions at different
developmental stages.

Research suggests that genes affecting brain development related to cognitive
ability are operating more strongly in late adolescence which correlates with the
onset of schizophrenia.
Neuroregulin

The short arm of chromosome 8 contains the gene neuroregulin which is
involved in neuronal migration and connectivity, cell signaling and myelination.

This gene is also related to a decreased activation of the temporal and frontal
lobe regions.

Research suggests that alterations in neuroregulin can also lead to altered
neuronal signaling of dopamine during development, possibly leading to
hyperdopaminergic states as an adult, and to impact GABA and glutaminergic
signaling.
Calcineurin

Located on chromosome 2 is implicated in schizophrenia and in studies with
mice it has been shown to be involved in the anti-social or isolative aspects of
schizophrenia.
DISC1 and DISC2 (Disrupted in Schizophrenia)

Located on chromosome 1 and this gene leads to neuronal migration problems
involved in the development of schizophrenia and may play an important role in
hippocampal development.

May be linked with cognitive impairment and social anhedonia as well as reduced
gray matter in hippocampus and cortex (seen in schizophrenia).

DISC1 signaling during development could contribute to the alterations of
dopaminergic signaling in the prefrontal cortex.
Dysbindin
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Chromosome 6 and is related to visual processing deficits, cognitive functioning,
and reductions in volume in the prefrontal and occipital cortex in persons with
schizophrenia.

Plays a major role in neuroplasticity and mutations lead to deficits in social
interaction, and poor performance in memory tasks has been observed.

Also a link between dysbindin and NMDA which is a glutamate receptor has been
observed.
AKT1

Located on chromosome 14, found in reduced levels in the hippocampus, frontal
cortex, gray matter volume in the caudate and right prefrontal cortex in
schizophrenia and reduced cognitive performance.

AKT1 has also been found to be implicated in proper dopaminergic
neurotransmission.
BDNF (Brain-Derived Neurotrophic Factor)

Located on chromosome 11

BDNF is involved in the birth, survival and maturation of brain cells during
development and is also involved in the production of "met" and "val" alleles

Plays a role in GABAergic transmission , regulation of glutamatergic
transmission, intracellular signalling and transmission
NMDA-R

A risk gene for schizophrenia has been found with NMDA receptor

Neuroplasticity

Neurobiological changes in the brain occur as a result of genetic and
environmental factors.

Some type of lesion in the brain occurs, which causes anatomical and functional
changes in the brain which are believed to begin in the prenatal period, continue to
deteriorate during growth and development particularly in the adolescent period but
remain silent, and begin to be recognized in late adolescence to early adulthood.

We are talking about the concept of neuroplasticity which can be defined as the
ability of the brain to change its structure and function in response to internal and
external pressures.

In neuroplasticity, nerve signals may be rerouted, nerve cells may learn new
functions, the sensitivity of or number of nerve cells may increase or decrease or
nerve tissue may be regenerated.

What happens in the brain of schizophrenics is that when the person has their
first psychotic break if they do not receive treatment first and for most medication
(D2 blockers) and regulate levels of dopamine, they can develop further neuroplastic
changes and even neurotoxicological changes that can further and permanently
affect the brain anatomically and functionally.
Neuroanatomical Changes

Brain anatomical changes associated with schizophrenia are not the result of
progressive brain deterioration or the effects of psychiatric medications, but are
caused by abnormalities in neurodevelopment that occur in prenatal or early
postnatal life.
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

These anatomical changes continue to deteriorate through the lifespan,
particularly In late adolescence to early adulthood when the positive symptoms
begin to occur and negative symptoms become enhanced.
The anatomical changes include an enlargement of the lateral and third
ventricles, a reduction on the frontal lobe, a reduction in the temporal lobe
particularly in the medial aspect, a whole-brain volume reduction, and diminished
neuronal content in both the thalamus and hippocapmus, prominent sulci an
increased activity in the limbic system and globus pallidus, and an increased
generally in D3 receptors.
Ventricular System

Total brain volume is reduced and lateral and third ventricle spaces are found to
be larger as can be seen with the MRI images of these monozygotic twins.

Well twins are on the left and the twins with schizophrenia are on the right

Remember that ventricular system is the part of the brain that houses the
cerebral spinal fluid, and that increases in the size of the ventricular system is a
result of a reduced overall brain volume reduction, so as the brain shrinks as
a result of abnormal pruning and neuroplasticity, the ventricle enlarges.
Hypofrontality

The prefrontal cortex is the part of the cerebral cortex which is the most evolved
portion of our brain (the chief administrator)

It is responsibe for planning, problem solving, intellectual insight, judgment, and
expression of emotion.

The prefrontal cortex is part of the frontal lobe which contains most of the
dopamine-sensitive neurons.

The dopmaine system is associated with reward, attention, short-term memory
tasks, planning and drive.

Dopamine tends to limit and select sensory information arriving from the
thalamus to the forebrain.

A positron emission tomography (PET) scan of the frontal lobe in this slid
shows hypofrontality or reduced blood flow and glucose metabolism in the prefrontal
cortex.

of people with schizophrenia (MRI show reduced neuronal volume in the frontal
lobes).

This hypofrontality of the frontal lobe perhaps relates to negative symptoms and
neurocognitive impairment in schizophrenia as has been previously described, for
example there is a poverty of thought and speech and the person has trouble
functioning and may have unusal movements and postures including when a person
becomes locked in a posture in a catatonic state.

It has been suggested that this cognitive impairment may be related to a D1
receptor deficit in the prefrontal cortex.
Medial Aspect of Temporal Lobe

Temporal lobe is responsible for processing auidtory info and language, visual
and spatial information, emotion and memory.
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

Limbic system structures buried within the temporal lobe are responsible for our
emotional responses.
Temporal lobe volume reduction results in formal thought disorders in this part of
the brain.
Damage to temporal lobe causes disconnect between thinking and language
which is expressed as a "word salad"
Damage to Broca's & Wernicke's area cause hallucinations, Broca'a is
responsible for production/expression of speech, Wernicke's area is
responsible fro comprehension of written and spoken language.
Temporal lobe – stores auditory, verbal, and visual information or memory
Amygdala – invloved in emotional memory
Hippocampus – takes short term memory and stores them as long term memory
The hippocampus interacts with the amygdala and stores the emotional attributes
of the memories; these memories are then the basis for dreams and hallucinations.
The most severe form of hallucinations is when a person experiences both
voices and visual hallucinations which come from the external environment.
Hippocampus and Thalamus

Cellular disarray or a disorganization in nerve cells also occurs and can be seen
in this slide, and this disorganization in neuronal content can also be seen
throughout the cortical or outermost layer or gray matter of the brain containing the
neurons and their connections and the limbic system In persons with
schizophrenia.

Volume decreases have been evident on MRI findings of both the hippocampus
and thalamus.

Thalamus function includes relaying sensation, spatial sense, and motor signals
to the cerebral cortex, along with regulation of the consciousness, sleep and
alertness.
Limbic System
The limbic system – primitive area in the temporal lobe that regulates our
emotional behaviour (area where positive symptoms of hallucinations and delusions
originate).

Includes the hippocampus, parahypocampus gyrus, cingulate gyrus, amygdala,
and fornix (connects hippocampus with hypothalamus).

The amygdala is constantly scanning the environment and assigns emotional
significance to everything you see, hear and feel. Helps us recognize emotional,
social, and sexual behaviour and to determine if someone is happy or sad.

The amygdala receives tactile, auditory, visual and olfactory stimuli and
overstimulation of the amygdala and the limbic system is thought to be the source of
sensory based hallucinations in the person with schizophrenia, who hears things,
sees things, can smell and taste things and feel tactile sensations which are not
present.
Left Globus Pallidus
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Globus pallidus – portion of basal ganglia next to putamen and connected to the
substantia nigra in an area of the brain involved with motor control and richly dense with
dopaminergic neurons.

This portion of the brain on PET scan has shown an abnormal function of
excessive neuronal activity as the schizophrenia progresses and an increased
neuronal volume.

The left globus pallidus has been correlated with the negative symptoms of
schizophrenia including poor cognitive, planning, and social capabilities.
Prominent Sulci
Sulci – the folds in the brain on the surface of the cortex.

There is a widening of the sucli in certain areas in the brain in individuals with
schizophrenia.

Studies have shown an impaired performance on tests of working memory and
executive functioning.
Overall reduction in Gray/White Matter

Volume reductions are not associated with reduction in nerve cell numbers, but
rather to changes in nerve cell density, to a decrease in the number of connections
between nerve cells, to a decrease in the number of synapses between nerve cells.

Complexity of dendritic branching, total dendritic length and dendritic spine
sensitivity is decreased in the prefrontal cortex of people with schizophrenia.
Dopamine Receptors

In schizophrenia there is elevated presynaptic levels of dopamine, increased D2
receptors, and a modest elevation in receptor density.

Increased levels of dopamine have been associated with the positive symptoms
of schizophrenia.

Dopamine in the prefrontal cortex is mainly mediated by D1 receptors, and D1
dysfunction in this region of the brain and hypofrontality has been associated with
cognitive impairment and negative symptoms of schizophrenia.
Changes in Dopamine Pathways

Several types of dopamine receptors including D1 through 6 receptors and
dopamine are found in four pathways in the brain and these pathways innervate
different parts of the brain.

Neurobiological changes in the dopaminergic system can be related to the
symptoms of schizophrenia and will be described in the following 4 slides.
Mesolimbic Tract

The mesolimbic pathway is one of the dopaminergic pathways in the brain.

It begins at the ventral tegmental area of the midbrain an connects to the limbic
system via the nucleus accumbens, the amygdala, and the hippocampus as well as
to the medial prefrontal cortex.
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
Positive symptoms of schizophrenia (hallucinations and delusions) are thought to
be caused by dopamine hyperactivity in the mesolimbic tract, which regulates
memory and emotion.
It is hypothesized that this hyperactivity could result from an overactive
modulation of neurotransmission from the nucleus accumbens.
Another explanation for dopaminergic hyperactivity in the mesolimbic tract is
hypoactivity of the mesocortical tract, which normally inhibits dopamine actively in
the mesolimbic tract by some feedback systems.
In schizophrenia the primary defect may be in the mesocortical tract, where
dopaminergic function is diminished, thereby decreasing the inhibitory effects on the
mesolimbic tract.
The disinhibition may be responsible for the overactivity of dopamine in the
mesolimbic tract, resulting in the positive symptom cluster.
Mesocortical Tract

Mesocortical pathway is a neural pathway that connects the ventral tegmentum
to the cerebral cortex, particularly in the frontal lobes.

It is essential to the functioning of the prefrontal cortex involved in motivation and
emotional response.

Dopamine hypoactivity in this region of the brain is thought to be associated with
the negative symptoms of schizophrenia, for example alogia which refers to a
reduced fluency and productivity of thought/speech, and avolition the withdrawal and
inability to initiate and persist in goal-directed activity as well as cognitive
impairment.

By its association with the prefrontal neocortex, the mesocortical tract contributes
to motivation, planning, sequencing of behaviors in time, attention, and social
behavior - all of which are disrupted in schizophrenia.
Tuberoinfundibular Tract

The tuberoinfundibular tract is active in the area of the hypothalamus of the
brain.

Dopamine released in the tuberoinfundibular tract regulates the secretion of
prolactin from the anterior pituitary gland.

Some antipsychotic drugs block the action of dopamine in this path, causing an
increase in blood prolactin levels and disruptions in women's menstrual cycles,
visual problems, headache and sexual dysfunction.

However this tract is not heavily implicated in schizophrenia.
Nigrostriatal Dopaminergic Tract

The nigrostriatal dopaminergic tract is the pathway connecting the
substantia nigra with the striatum.

This modulates motor activity and is believed to be the site if
the extrapyramindal side effects of antipsychotic drugs used to treat schizophrenia,
such as pseudoparkinsonism and tardive dyskinesia, because antipsychotic drugs
are not selective and block dopamine in all four pathways.
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
The nigrostriatal dopaminergic tract is also believed to be the site of some motor
symptoms of schizophrenia such as stereotypic behavior.
Biogenic Amine Hypothesis

The biogenic amine hypothesis suggests that changes in the levels of
neurotransmitters in the synaptic cleft, due either to increased or decreased
presynaptic release or increased or decreased postsynpatic sensitivity, is the
underlying pathologic process in mental illness.

Neurotransmitter believed to be involved in the development of schizophrenia
include dopamine, glutamate, GABA, and the NMDA receptor and serotonin.
Dopamine Hypothesis

The dopamine hypothesis that supports that it is likely an excess of the amount,
sensitivity to and receptor number and affinity for dopamine that causes psychosis.
Glutamate and GABA

Glutamate, an excitatory neurotransmitter is also thought to be associated with
schizophrenia, and when phencyclidine (PCP or angel dust) and ketamine are used
to block glutamate (NMDA) receptors, this causes a psychosis resembling
schizophrenia.

NMDA is a receptor that is implicated in learning and memory.

If decrease in NMDA receptor than we have less glutamate transmission.

There is an anatomical and functional interrelationship between the dopamine
and glutamate systems such that inhibition of the NMDA receptor enhances the firing
rate of dopamine neurons, and in turn there would be more psychosis.

In post-mortem studies there has been shown to be a reduction in the brain of
glutamate receptors in people with schizophrenia.

Glutamate is also a precursor to GABA production.

GABA is the most widespread inhibitory neurotransmitter in the brain.

GABA has an inverse relationship with dopamine, so the less GABA there is, the
more dopamine and more psychosis.
Serotonin

Glutamate, an excitatory neurotransmitter is also thought to be associated with
schizophrenia, and when phencyclidine (PCP or angel dust) and ketamine are used
to block glutamate (NMDA) receptors, this causes a psychosis resembling
schizophrenia.

NMDA is a receptor that is implicated in learning and memory.

If decrease in NMDA receptor than we have less glutamate transmission.

There is an anatomical and functional interrelationship between the dopamine
and glutamate systems such that inhibition of the NMDA receptor enhances the firing
rate of dopamine neurons, and in turn there would be more psychosis.

In post-mortem studies there has been shown to be a reduction in the brain of
glutamate receptors in people with schizophrenia.

Glutamate is also a precursor to GABA production.
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

GABA is the most widespread inhibitory neurotransmitter in the brain.
GABA has an inverse relationship with dopamine, so the less GABA there is, the
more dopamine and more psychosis.
Cocaine and Psychosis

Both amphetamine and cocaine use can mimic the symptoms of schizophrenia.

These drugs can be seen here to block the reuptake of dopamine and foster
symptoms of schizophrenia.
Other Theories of Causation

The psychosocial theory used to explain the etiology of schizophrenia is no
longer held valid today.

This theory blamed dysfunctional parenting in early childhood as the cause.

Social theories used to explain the etiology of schizophrenia focus on theories of
family interaction.

The theory of expressed emotion or (EE) correlates family communication
patterns of negative comments about family members, when there are aspects of
speech that connote criticism, hostility and negativity, and when families are
emotionally "overly involved", overprotective and self-sacrificing with an increase in
symptoms and relapse in patients with schizophrenia.
Antipsychotic Medications

Conventional or first generation antipsychotics medications have been around for
50 years and are most affective for treating the positive symptoms of schizophrenia.
They are sub-classified as phenothiazines and non-phenothiazines.

Phenothiazines were used the first effective drugs used to treat schizophrenia.
These meds revolutionized the treatment of mental illness, but they exhibit
numerous adverse effects that can limit their pharmacotherapy.

Non-phenothiazines were introduced shortly after the phenothiazines and were
initially expected to produce fewer side effects although unfortunately this proved not
to be the case.

Atypical antipsychotic meds followed the discovery of the conventional meds and
have a broader spectrum of action, controlling both positive and negative symptoms
of psychosis and schizophrenia. They produce fewer EPS type side effects but do
produce troubling side effects of their own.
Mechanism of Action of Antipsychotics

Antipsychotic drugs have the general effect of blocking dopamine transmission in
the brain by blocking D2 receptors in the postsynaptic neurons, preventing
dopamine from stimulating the receptors.

Symptoms of schizophrenia seem to be mostly associated with the D2 receptor,
although some of the drugs block other dopamine receptors and travel to all
dopamine receptor sights in the brain resulting in unpleasant and undesirable side
effects.

The basal nuclei or ganglia are particularly rich in D2 receptors. Schizophrenia is
thought to involve dysfunction of the behavioral neuron circuits between the basal
ganglia and limbic system.
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All antipsychotic drugs act by entering the dopaminergic synapses and
competing for D2-receptors, by blocking about 65% of D2-Receptors, antipsychotic
drugs reduce the symptoms of schizophrenia. If 80% are blocked, motor
abnormalities begin to occur.

The major action of atypical antipsychotic meds is to act by blocking several
different receptor types in the brain including the D2 receptors, and the alphaadrenergic receptors. These second generation meds act as a serotonin agonist
which is a compound that activates serotonin receptors, mimicking the effects of the
neurotransmitter serotonin, increasing levels of serotonin and therefore decreasing
levels of dopamine.
·
Atypical antipsychotics are used to treat both positive and negative symptoms of
schizophrenia.

Non-Pharmacological Treatments

Show some promise for treatment but pharmacological treatments are
essential.

Electroconvulsive therapy

Transcranial magnetic stimulation helps with auditory hallucinations

Glycine (amino acid) used as dietary supplement that helps improve NMDA
receptor function

Antioxidant helps with negative symptoms

Omega-3 helps with negative and positive symptoms

Personal and cognitive therapy helps with recognition and responding
appropriately to arousing stimuli
·
Family therapy helps with coping
Diabetes Module
Complications
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
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Acute and chronic complications:
o
Acute complications include hypoglycemia and hyperglycemia states of
diabetic ketoacidosis and hyperosmolar hyperglycemia nonketotic syndrome.
o
Chronic complications can be further broken down into the microvascular
complications of retinopathy, neuropathy AND microvascular complications of
cerebrovascular disease, peripheral vascular disease and coronary artery
disease.
Triggers or underlying etiology of acute complications often include concurrent
illness and factors related to the management of plasma glucose levels including
noncompliance with diet or pharmacology therapy or side effects of pharmacological
therapy.
Chronic hyperglycemia and the resultant metabolic events have been associated
with the underlying etiology of chronic complications of diabetes.
Hyperglycemia affects cells that do not effectively reduce the transport of glucose
into the cell in a hyperglycemic state resulting in intracellular hyperglycemia.
Examples of cells that are vulnerable to chronic hyperglycemia include: capillary
endothelial cells in the retina, mesangial cells in the renal glomerulus and neurons
and Shwann cells in the peripheral nerves.
There are several theories that are well documented and describe the metabolic
mechanisms that are associated with the tissue damaging effects of chronic
hyperglycemia and the resultant diabetic complications that will be described later.
Answers:
1.
Plasma glucose varies based on the last meal. That being said the homeostatic
mechanisms of the body generally maintain glucose at a level <6.0 mmol/L.
2.
Glucose.
Hypoglycemia
Hypoglycemia is defined by:

The development of neurogenic/autonomic and/or neuroglycopenic symptoms.
Activation of the sympathetic nervous system results in the neurogenic or autonomic
symptoms of trembling, palpations, sweating, anxiety, hunger, nausea and tingling.
Abrupt cessation of glucose delivery to the brain results in neuroglycopenic
symptoms of difficulty concentrating, confusion, weakness, drowsiness, vision
changes, difficulty speaking, headache, and dizziness. Symptoms are variable
among individuals especially in children and the elderly; however, are usually
consistent for each person.

Below than normal blood glucose (BG) levels. Generally hypoglycemia occurs
when BG levels are between 2.5-3.3 mmol/L. In diabetic patients treated with insulin
or an insulin secretagogue BG levels <4 mmol/L are considered hypoglycemia.

Symptoms respond to the administration of a carbohydrate.

Hypoglycemia may be caused by exogenous, endogenous or functional
mechanisms.

In diabetic patients the exogenous mechanism of drug induced hypoglycemia is
most common. The negative social and emotional impact may make patients
reluctant to intensify pharmacological therapy. Furthermore there are short and long
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term risks of hypoglycemia. Short-term risks are safety related. For example, it
would be unsafe if an individual experienced hypoglycemia while driving or operating
machinery. Prolonged coma can be associated with transient neurological symptoms
like paresis, convulsions and encephalopathy. Long-term risks of severe
hypoglycemia are mild intellectual impairment and very rarely permanent neurologic
sequelae like hemiparesis and pontine dysfunction.

Severity of hypoglycemia is divided into mild, moderate, and severe.
o
Mild: autonomic symptoms, able to self-treat.
o
Moderate: autonomic and neuroglycopenic symptoms, able to self-treat.
o
Severe: unable to self-treat, requires assistance, unconsciousness may
occur. BG usually <2.8 mmol/L.
The cause of hypoglycemia in diabetes is two-fold:
1.
First, relative excess of insulin in the blood which can be the result of too much
exogenous insulin or when insulin secretagogues like sulfonylureas are used.
Hypoglycemia is more common in type 1 diabetes and occurs in more than 90% of
T1DM and often limits the management of the disease. Hypoglycemia can also
occur in type 2 diabetics particularly in those taking insulin secretagogues or using
exogenous insulin.
2.
Second, the cause of hypoglycemia can also be linked to deficits in glucose
counter-regulation. This second point is particularly important in type 1 diabetes.
Specifically, glucagon and epinephrine release during hypoglycemia become
defective, which blunts the otherwise autonomic symptoms associated with mild or
moderate hypoglycemia and puts these patients at greater risk of developing severe
hypoglycemia.

Some risk factors for hypoglycemia include: exercise, alcohol, older age, renal
dysfunction, infection, error in insulin dose, medication changes, cognitive
dysfunction, mental health issues.

Specific risk factors for severe hypoglycemia in T1DM include prior episode of
severe hypoglycemia, current low A1C of <6%, hypoglycemia unawareness, long
duration of diabetes, autonomic neuropathy, low economic status, adolescence, preschool children unable to detect and/or treat mild hypoglycemia on their own.

The pathophysiology is triggered by the relative excess of insulin causing a
decrease in blood sugar. A decrease in endogenous insulin secretion is the first line
of defense against hypoglycemia. This is critical in patients who have residual insulin
secretion. Normally beta cells suppress insulin secretion at a plasma glucose level of
about 4.6 mmol/L.

Hypoglycemia activates the SNS via the hypothalamus resulting in the
stimulation of adrenal gland to release counterregulatory hormones. Think about the
stress response specifically the hypothalamic-pituitary-adrenal axis.

The role of the liver in sympathoadrenal response to hypoglycemia is twofold.
First, the portal vein may play a role in sensing hypoglycemia and activating the
counterregulatory response. Secondly, as you already know, glucagon stimulates
glycogenolysis and gluconeogenesis in the liver.

Counterregulatory hormones including norepinephrine, epinephrine, growth
hormone and cortisol cause an increase in glucose production and decrease
glucose uptake in the periphery specifically adipose and muscle tissue.
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
Neuroglycopenic symptoms occur due to an abrupt cessation of glucose delivery
to the brain.
Hypoglycemia – Treatment

Treatment in conscious person with mild to moderate hypoglycemia:
o
15g carbohydrate – 2.1 mmol/L increase within 20 mins

Treatment in conscious person with Severe hypoglycemia:
o
20g carbohydrate – 3.6 mmol/L increase at 45 minutes

In both cases patient should re-test BG in 15 mins and retreat with another 15 or
20g of carbohydrate if BG <4.0 mmol/L.

Treatment in unconscious person with severe hypoglycemia > equal to 5 years of
age:
A) 1 mg glucagon SC or IM
B) IV glucose 10-25 g (20-50 cc D5OW) over 1-3 mins

Examples of 15 g includes 15 g of glucose in the form of glucose tablets, 3
teaspoons or 3 packets of table sugar dissolved in water, 175mL of juice or regular
soft drink, 6 lifesavers, 1 tablespoon of honey. Monosaccharides like glucose are
preferred as they are absorbed directly into the blood stream.

Some clinical PEARLS to remember are that if a patient is taking an alphaglucosidase inhibitor, dextrose not sucrose should be used to treat hypoglycemia.

Secondly, glucagon will be ineffective in pt whose glycogen stores are depleted.
Glucagon will not be as effective in individuals who have consumed more than 2
standard alcoholic drinks within the previous few hours or those who have advanced
liver disease.
Hyperglycemic Emergencies

Hyperglycemic emergencies are life threatening associated with significant
morbidity and even mortality.

The two hyperglycemia conditions associated with diabetes are:
1.
Diabetic ketoacidosis (DKA)
2.
Hyperglycemic hyperosmolar nonketotic syndrome (HHNKS)

Both conditions can overlap however there are some distinct differences.
o
Both conditions arise from either a relative or absolute insulin deficiency.
o
And some form of trigger that causes an increase in counterregulatory
hormones and resultant hyperglycemia.
o
Osmotic diuresis and extracellular fluid volume depletion or hypovolemia
is more impressive with HHNKS and..
o
Acid-base imbalance specifically metabolic acidosis due to ketoacidosis is
less likely to occur in HHNKS but always present in DKA.
o
Electrolyte imbalances occur due to metabolic acidosis and osmotic
diuresis. The most serious electrolyte imbalance is hypo and hyperkalemia due
to the associated risk for cardiac arrhythmias.
o
And adverse neurological sequelae including cerebral edema, coma and
death are reported in both conditions.
DKA/HHNKS Pathophysiology
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First there is an insulin deficiency and some precipitating factor that increases
counterregulatory hormones including glucagon.

Glucagon directly stimulates glycogenolysis in the liver. Counterregulatory
hormones including glucagon cause decreased glucose uptake in the peripheral
tissues.

Protein breaks down to provide amino acids to the liver for gluconeogenesis.

Adipose tissue also breaks down to form glycerol for gluconeogenesis if there is
a relative insulin deficiency and free fatty acids to form ketones in the liver in the
case of absolute insulin deficiency. Specific ketones formed are called betahydroxybutyric and acetoacetic acids which result in metabolic acidosis.

The result of glycogenolysis and gluconeogenesis is hyperglycemia.

Hyperglycemia causes osmotic diuresis and large losses of electrolytes in the
urine. The total body deficit of water in adults is usually about 7-12 L in HHNKS
which represents a loss between 10-15% of body weight. If left untreated circulatory
failure ensues.

Hyperosmolality and metabolic acidosis can both cause CNS depression and if
left untreated coma.

As you can visually appreciate whether the hyperglycemia condition is classified
as DKA or HHNKS depends upon whether or not there is a relative or absolute
insulin deficiency.
Let's briefly compare DKA and HHNKS.

Remember that DKA usually affects T1DM and HHNKS usually affects T2DM.

DKA is more common and it is estimated that between 5,000-10,000 patients are
admitted to hospital in Canada every year because of DKA. HHNKS is less common
and it is estimated that between 500-1,000 pt are admitted to hospital in Canada
every year because of HHNKS.

Mortality is lower in DKA ranging from 4-10% and even reported as less than 5%
in porth textbook. The mortality rate for HHNKS is higher ranging from 10-50%. The
range is likely due to underlying illnesses.

Hyperglycemia is characteristic of both conditions however plasma glucose
levels are much higher in HHNKS.

Extracellular fluid volume depletion and the resultant electrolyte imbalances are
common in both conditions however ECFV depletion is greater in HHNKS. This
makes sense as plasma glucose levels are higher in HHNKS resulting in greater
osmotic diuresis. A diagnostic marker for HHNKS is a plasma osmolarity of greater
than or equal to 320 mOsm/L.

In DKA, metabolic acidosis is present with a pH of less than or equal to 7.3 and
associated with decreased bicarbonate. Bicarbonate levels are usually 15 mmol/L or
less. In HHNKS pH is usually normal.

Since there is ketones production in DKA the presence of the typical acetone
breath which is sometimes described as a fruity odor is usually noticed at time of
presentation. Also, Kussmaul-Kien respiration due to metabolic acidosis can also be
present especially with severe metabolic acidosis. These clinical features are not
present in HHNKS.

DKA and HHNKS are complex hyperglycemic disorders that have overlapping
features and some distinct differences.

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You should be able to relate the clinical manifestations to the pathophysiology.
For example hypotension and tachycardia may be present in either DKA or HHNKS
due to ECFV depletion.
Management of DKA/HHNKS
Key principles of the management of DKA and HHNKS involves the following:
o
Fluid rehydration to restore normal ECFV and tissue perfusion.
o
Correction of hyperglycemia by addressing absolute or relative insulin
deficiency.
o
Resolution of ketoacidosis usually occurs with insulin therapy and fluid
rehydration.
o
For severe acidosis sodium bicarbonate may be used in the adult population. It is
not used in pediatrics.
o
Monitor and correct electrolytes specifically potassium.
o
Diagnosis and treatment of coexisting illness which may have been precipitating
factors.
o
Monitor for and prevent complications specifically adverse neurological sequelae
like cerebral edema.

This is a very simplified summary of the management of DKA and HHNKS. There
are specific clinical algorithms used to manage DKA in both adults and children.

It is not necessary to memorize either algorithm but as you go through it, you
should be able to make sense and provide rationale for each step.

Another important point is that potassium is added to maintain fluid even if
potassium levels are not abnormally low because when metabolic acidosis begins to
correct potassium shifts back into the cell. Since there is already an overall depletion
of potassium due to potassium having moved out of the cell during metabolic
acidosis and loss of potassium via osmotic diuresis it is imperative to anticipate this
to avoid life threatening arrhythmias.

Lastly, a sudden change in extracellular fluid osmolality can occur if
hyperglycemia is corrected to quickly which can result in cerebral edema.

Cerebral edema is more common in DKA and in children. It can be deadly or
have devastating neurological consequences.
Chronic/Long-Term Complications

Chronic and more long-term complications of diabetes can cause disease in
several body systems as illustrated in this figure.

Good diabetes care and management which includes health teaching can
prevent or delay onset of complications.

Two landmark studies, one called the Diabetes Control and Complications Trial
which looked at T1DM and the united kingdom prospective Diabetes Study which
looked at T2DM found that intensive diabetic treatment fan reduce the incidence of
complications.
o
80% of diabetics die of heart attack or stroke,
o
50% if diabetics have chronic kidney disease and chronic kidney disease
with diabetes is the leading cause of kidney failure in Canada.
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Blindness caused by diabetes is the most common cause of blindness in
people aged 65 years and younger.
o
Neuropathy can cause minor injuries to go unnoticed which if untreated
can lead to infection and gangrene. 7/10 non traumatic limb amputations are due
to diabetes.
Highlighted are some of the most common complications although the others are
not really all that uncommon. For example erectile dysfunction was the first clinical
sign of diabetes in up to 12% of males with diabetes.
o

Polyol Pathway

The polyol pathway is an alternative metabolic pathway for tissues not requiring
insulin for glucose transport.

These include the kidney, red blood cells, blood vessels, eye lens, and nerves.

Aldose reductase normally converts toxic aldehydes to inactive alcohols however
in the presence of hyperglycemia glucose is shunted to this pathway and aldose
reductase converts glucose to sorbitol.

In the process a cofactor called NADPH (nicotinamide adenine dinucleotide
phosphate) is consumed. NADPH normally an essential cofactor for regenerating
glutathione which is a critical intracellular antioxidant. This increases the
susceptibility of the cell to intracellular oxidative stress.

Sorbitol is then slowly converted to fructose by sorbitol dehydrogenase.

The accumulation of sorbitol and fructose causes increases in intracellular
osmotic pressure which attracts water and leads to cell injury.

This is a key part of the pathophysiological process of visual changes and
cataracts in diabetic patients.

Also, in nerves sorbitol interferes with ion pumps, damages schwann cells and
disrupts nerve conduction.

Swollen red blood cells can become stiff and perfusion can be compromised.
AGE Formation

Glycoproteins also known as advanced glycation end products or AGEs are
basement membrane components in the microcirculation.

Recurrent or persistent hyperglycemia increases the formation of AGEs to be
formed through the non-reversible binding of glucose to proteins, lipids and nucleic
acids.

Specifically hyperglycemia increases AGEs in collagen and other proteins in red
blood cells, blood vessel walls and interstitial tissues.

AGEs & their receptor (RAGE) have properties that can cause tissue injury or
pathologic conditions a/w diabetes.

Some of these effects include modifications of intracellular proteins specifically
those involved in gene transcription; cross linking and trapping of proteins;
thickening of the basement membrane; increased permeability in blood vessels and
nerves; stimulation of cellular proliferation; inducing lipid oxidation, oxidative stress
and inflammation; inactivation of NO and loss of vasodilation and diminished
endothelial function; and promotion of platelet adhesion and reduced fibrinolysis.
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Tissue Oxygenation/Oxidative Stress

Tissue oxygenation theories suggest that many of the chronic complications arise
from a decrease in oxygen delivery in small vessels.

One described pathway is a defect in RBCs which impairs the release of oxygen
from hemoglobin.

Chronic hyperglycemia increases production of reactive oxygen species and
subsequent damaging effects of oxidative stress.

Advanced glycation end products (AGEs), nitric oxide dysfunction and NADPH
discussed in the context of the polyol pathway are some of the contributors to
increased reactive oxygen species in the setting of chronic hyperglycemia.

Reactive oxygen species damage large and small vessels contributing to
atherogenesis, cardiovascular disease, nephropathy, and neuropathy.
Protein Kinase C

Intracellular hyperglycemia increases the synthesis of diacylglycerol (DAG) which
activates protein kinase C.

These are critical intracellular signaling molecules that regulate many vascular
functions including permeability, vasodilator release, endothelial activation and
growth factor signaling.

The consequences of elevated DAG and PKC are:
o
Blood flow abnormalities due to decreased endothelial NO synthase which
is a vasodilator and increased endothelin-1 which is a vasoconstrictor.
o
Increased vascular permeability to increased vascular endothelial growth
factor.
o
Capillary & vascular occlusion due to increased collagen and fibronectin
and decreased fibrinolysis respectively.
o
Pro-inflammatory gene expression.
o
Increased ROS & disordered mitochondrial fxn in response to chronic
hyperglycemia.

Clinically, vascular damage and associated disease of the retina, kidney and
nerves can be caused by activation of PKC in these blood vessels.
Hexosamine Pathway

The increased hexosamine pathway activity is a newer piece of the diabetes
pathogenesis puzzle.

Chronic hyperglycemia causes shunting of excess intracellular glucose into the
hexosamine pathway and O-linked glycosylation of proteins causes alteration in
signal transduction pathways & oxidative stress.

Specifically, O-linked attachment of N-acetylglucosamine on serine and threonine
residues of transcription factors often results in pathologic changes in gene
expression that are a/w insulin resistance & CV complications.
Microvascular Disease

Microvascular diabetic complications are the leading cause of blindness, endstage renal disease and various neuropathies.
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



It is characterized by thickening of the basement membrane, endothelial cell
hyperplasia, thrombosis and pericyte degeneration.
These microvascular changes occur in a hyperglycemic state. Specifically
accumulation of AGEs and resultant tissue injury and pathologic conditions
contributes to microvascular complications in diabetes.
Frequency of these complications seems to be proportionally r/t duration of
diabetes & blood glucose levels.
The Diabetes Control and Complication trial demonstrated that diabetics with
tightly controlled glucose were half as likely to have renal and eye complications as
those diabetics receiving standard therapy.
Microvascular complications in diabetes involves mainly the retina, nerves,
kidneys, and gastrointestinal system
Microvascular Disease – Neuropathy

In the western world, diabetic neuropathy is the most common cause of
neuropathy. Within 10 years of the onset of diabetes, detectable sensorimotor
polyneuropathy will develop in 40-50% of people with both T1DM and T2DM.

There are two main pathologic changes seen in diabetic neuropathies.

First, vessel ischemia due to thickening of the walls of the nutrient vessels that
supply the nerve. Secondly, the segmental demyelinization process affecting the
Schwann cell. Slowed nerve conduction accompanies this demyelinization process.

The underlying pathophysiology is multifactorial and includes microangiopathy,
oxidative stress, growth factor deficiency, abnormal signaling from AGE-RAGE
interaction, increased polyol pathway and inflammation.

Neuropathies can be subclinical and peripheral nerve dysfunctions can only be
detected with electromyographic (EMG) testing before progressing to the clinical
stage in which symptoms or clinically detectable neurologic deficits are present.

Somatic neuropathy may involve spinal cord posterior root ganglia or the
peripheral nerves.

Degeneration of the nerves begins in the periphery and sensory nerve
involvement usually precedes motor nerve involvement.
o
Distal symmetric polyneuropathy is the most common form of neuropathy
and involves the smaller unmyelinated peripheral C fibers and the larger
myelinated A-delta fibers. Sensory dysfunction usually occurs first and is distal,
bilateral and symmetric.
o
Loss of large nerve function results in sensory loss of proprioception and
vibration, ataxia, and loss of coordination.

Autonomic neuropathy involves sympathetic and parasympathetic nervous
system dysfunction.
o
In the bladder there may be loss of bladder sensation, urine retention and
recurrent infections.
o
In the GI system there may be dysfunction of GI enteric nerves which may
lead to nausea, bloating, gastroparesis, diarrhea, and constipation.
o
In men, sensory and autonomic dysfunction may lead to erectile
dysfunction (34-45% of diabetic men).
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Autonomic neuropathy can lead to dysfunction of sweating and body temp
regulation.
o
CV autonomic neuropathy specifically in T1DM is associated with heart
rate variability, changes in baroreceptor reflexes, postural hypotension,
arrhythmias, exercise intolerance, and painless MI.
Rapid screening for neuropathy is described in the CDA guidelines.
Comprehensive neurological exam is warranted in pt with S&S of neuropathy.
Asking pt about falls and foot injuries can provide valuable info when assessing for
diabetic neuropathy. EMG testing can provide info on subclinical neuropathy.
Management and prevention of neuropathy involves good glycemic control.
Neuropathic pain may be managed with tricyclic antidepressants, anticonvulsants
like gabapentin and opioid analgesia.
Autonomic neuropathies are managed by first ruling out any specific CV, GI or
GU pathology through assessment by a specialist and then treated primarily by
expert opinion of the specialists.
o

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

Microvascular Disease – Nephropathy
Diabetic nephropathy generally occurs due to lesions of the glomeruli in the kidney.

Glomerular changes include:
o
Capillary basement membrane thickening.
o
Diffuse glomerular sclerosis.
o
Nodular glomerulosclerosis. Nodular glomerulosclerosis is also
called Kimmelstiel-Wilson syndrome and specific to people with diabetes.

Chronic kidney disease is usually a clinical diagnosis that relies on S&S and lab
findings that assess kidney function. If there are any doubt about the diagnosis a
kidney biopsy may be preformed.

Genetics play a role in which individuals w/ diabetes develop kidney disease.

Risk factors for development of this diabetic complication include genetic and
familial predisposition, hypertension, poor glycemic control, smoking, hyperlipidemia
and microalbuminuria.

Microalbuminuria or albumin in the urine is one of the 1 st clinical manifestations of
kidney dysfunction. Once microalbuminuria is detected urine should be sent for
albumin/creatinine ratio (A/Cr).

Some of the chronic kidney disease S&S include fluid and electrolyte
imbalances, hypoproteinemia, edema due to decreased plasma oncotic pressure,
fluid overload and hypertension.

Prevention and management include good glycemic control, maintaining normal
BP, prevention of reduction in proteinuria using pharmacologic agents like ACE
inhibitors or angiotensin receptor blockers or through restricting protein in diet,
treatment of hyperlipidemia and smoking cessation.
Microvascular Disease – Retinopathy

Unfortunately almost 100% of people with T1DM and 60% of those with T2DM
have some form of retinopathy within 20 years of diabetes diagnosis.

Diabetes is the leading cause of acquired blindness.
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

Abnormal retinal vascular permeability, microaneurysms, neovascularization lead
to hemorrhage, scarring and retinal detachment.
Both prevention & management include achievement of glycemic control,
preventing and treating hypertension and hyperlipidemia.
Regular dilated eye exams should be a part of the plan of care for all individuals
w/ diabetes.
Treatment for retinopathy includes: laser, surgery specifically vitrectomy in more
severe forms of retinopathy and specific pharmacologic agents like antagonists to
growth factors.
Macrovascular Disease

The prevalence of macrovascular disease is increased 2-4 times in people with
diabetes.

50-75% if all people with T2DM will die from macrovascular disease.

Risk factors include: obesity, HTN, hyperglycemia, hyperinsulinemia,
hyperlipidemia, altered platelet fxn, endothelial dysfunction, systemic inflammation
evidenced by increased C reactive protein and increased fibrinogen.

The underlying patho if macrovascular complications is atherogenesis or
atherosclerosis.

Hyperglycemia triggers advanced glycation end products (AGE's) and protein
kinase C (PKC) activation causing endothelial dysfunction. Oxidative stress also
causes endothelial dysfunction.

Risk factors contribute to endothelial dysfunction and formation of foam cell and
fibrous plaque and eventual complicated atherosclerotic lesion.
Macrovascular complications:

CAD
o
Coronary artery disease is the most common cause of death in people
with T2DM and is common in T1DM as well.
o
The risk for CAD is higher in diabetes than general public even when HTN
& hyperlipidemia considered.

PVD
o
Peripheral vascular disease in compounded by microvascular disease of
neuropathy.
o
Often the atherosclerotic process in the peripheral vessels along with
neuropathy can lead to gangrene & amputation. Remember 70% of nontraumatic limb amputations are due to diabetes.

Cerebrovascular Disease
o
Lastly, cerebrovascular disease or stroke is twice as common in people
with diabetes.
o
Ischemic stroke is more common than hemorrhagic stroke.
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