Download Table 1. Fluid Therapy Definitions Crystalloid solution is water with

FLUID THERAPY
Todd Duffy, DVM, DACVECC
Aratana Therapeutics
Fluid therapy is a cornerstone of patient care, especially in the surgical and critically ill
patient. Animals are likely to be prescribed fluid therapy, whether it be intravenous (IV),
intraosseous (IO) or subcutaneous (SQ),
more than any other medication that you
have in your pharmacy. It is therefore very
evident that a thorough understanding of
Table 1. Fluid Therapy Definitions
Crystalloid solution is water with semi-permeable
ions (electrolytes) dissolved in it, both of which
pass readily through the capillary membrane
fluid therapy physiology, as well as the
pathophysiology of the pertinent disease
process that is being treated, helps
maximize the provision of this valuable
therapeutic modality. Fluids can be
administered with the intention of providing
therapy directed at one or more of the
following: 1) volume expansion
(intracellular, interstitial or intravascular);
2) correcting electrolyte disturbances;
3) normalizing acid-base imbalances;
4) provide oncotic support; 5) administer
medications; 6) provide nutritional support.
Sixty percent of an adult’s body
weight is water, this increases to as high as
80% in neonates. This water is distributed
Colloid is a water solution that high molecular
weight substances that do not pass readily
through the capillary membrane.
Isotonic solutions have a similar concentration of
impermeant solutes, when compared to plasma.
Hypotonic solutions have a concentration of
impermeant solute that is lower than plasma.
Hypertonic solutions have a concentration of an
impermeant solute that is higher than plasma.
Replacement solutions are generally isotonic,
with an electrolyte composition that has a similar
to that found in plasma. May be further
categorized and unbalanced or balanced
electrolyte solution.
Maintenance solutions usually contain lower
sodium and chloride, higher potassium +/dextrose when compared to maintenance
solutions and are generally hypotonic.
throughout the body in different
“compartments”. These compartments are
Alkalinizing solutions have a buffer that may be
metabolized to bicarbonate.
in a dynamic equilibrium with each other. In
a healthy patient, total body water is
Acidifying solutions generally do not have a
buffer, some contain higher chloride levels.
generally divided such that 2/3 of the body
water is in the intracellular fluid (ICF) compartment and the remaining 1/3 of the fluid is in the
extracellular compartment. The extracellular fluid (ECF) compartment is further divided into the
intravascular space (which makes up about ¼ of the extracellular compartment) and the
interstitium (which makes up the remaining ¾ of the extracellular compartment). There are other
components of the extracellular compartment, including the joint spaces, cerebral spinal fluid,
pleural and pericardial spaces, and dense connective tissues, which have negligible influence of
water distribution in health, but could become important during disease (ie. patient with ascites,
pleural effusion, etc). The fluid in the urinary bladder and GI tract are truly outside the body.
Fluid is generally gained through water ingested, water contained in food and water
produced by oxidation of carbohydrates, proteins and fats. Water is generally lost through
sensible (measurable) loss, which includes urine output, and insensible (difficult to quantify)
losses, which includes losses from the respiratory tract, skin, and feces.
Fluid therapy is an inexact science that relies on a thorough patient assessment in
addition to monitoring the patient’s response to the fluids administered. In general, intravascular
volume may be assessed by examination findings referred to as “perfusion parameters” and the
Table 2. Physical Exam Perfusion Parameters vs Hydration Parameters
Hydration parameters
Perfusion parameters
Mucous membrane moisture
Mucous membrane color
Skin turgor
Capillary refill time
Globe position
Heart rate
Serial body weights
Pulse character/quality
Mentation
Extremity temperature
interstitial volume is assessed by “hydration parameters” (see table 2). As a standard
recommendation, intravascular volume deficits (hypovolemia) are replaced rapidly (with the
possible exception of an uncontrolled hemorrhagic shock case), while interstitial volume deficits
(ie. dehydration) is replaced more slowly and typically depends on the rate of development of the
dehydration. There is no reliable, clinical method to assess intracellular volume status of a
patient but is primary influenced by changes in sodium levels. Large volumes of IV fluids are
more easily administered through short, large-bore IV catheters. However, the larger the IV
catheter is, the more rapid phlebitis develops making catheter life shorter.
Intravenous fluids should be considered as “drugs” and as such, there are different types
of fluids available (see table 1) that can be used to provide support to the different fluid
compartments. These different types of fluids can be divided into several different classifications
that allow one to understand how a fluid will “function” when it is administered to a patient. The
functions of these fluids are due to a combination of their electrolyte and non-electrolyte
composition (ie. ratio of solute to water), their acid-base status and the size of the particles in the
sterile water solution.
Crystalloids
Crystalloids are fluids containing electrolytes and non-electrolyte solutes that will
eventually enter all fluid compartments. Crystalloids come in many different forms (ie. isotonic,
hypotonic, etc). In general isotonic (examples are LRS, 0.9% NaCl, Plasmalyte, Normosol-R)
crystalloids may be referred to as balanced (ie. LRS, Normosol-R, Plasmalyte) or unbalanced
(0.9% NaCl) electrolyte solutions. Alternatively, crystalloids may also be referred to as
replacement (sodium concentration similar to plasma) or maintenance solutions (sodium levels
lower than plasma). Replacement solutions are generally isotonic to hypertonic, on the contrary,
maintenance solutions are generally hypotonic. Isotonic crystalloids are interstitial hydrating
agents. That is, even when they are administered IV, 75-80% of the volume infused is found in
the interstitial space after the first hour. Although crystalloids may expand the intravascular
volume, they are not as efficient as colloids (ie. traditional teachings are that general
requirements for crystalloids are 2-4 times that of a colloid for intravascular volume expansion,
but more recent evidence suggests it is closer to 1.4 to 1.6 times) are for this and may predispose
to interstitial edema if given rapidly and in large quantities. Hypertonic crystalloids act much like
colloids, such that they cause interstitial fluids to enter the intravascular space, but their effect is
shorter in duration than colloids. The shortened duration is because the sodium is rapidly
redistributed to the interstitial compartment. Hypertonic solutions are typically given as short term
therapy, as they will predispose the patient to becoming hyperosmolar if administered repeatedly
or in large volumes. As such, hypertonic saline should not be used in patients with hypernatremia
or severe dehydration. Hypotonic solutions (ie. ½ strength or 0.45% saline, D-5-W, etc) generally
cause intracellular hydration. Hypotonic solutions should never be administered in large volumes
rapidly in order to avoid cellular swelling.
Additional differences in crystalloids are the absence or presence of buffers - buffers are
metabolized into bicarbonate. If a buffer is present, the quantity and type of buffer varies between
different products. Isotonic saline does not have a buffer present, this in addition to its high
chloride level, make isotonic saline an acidifying solution. This solution is therefore administered
to patients that have an alkalemia, due to a metabolic alkalosis. Lactate Ringers solution (LRS)
has lactate as a buffer. Lactate is metabolized by the liver and therefore may not be ideal in
patients with hepatic insufficiency or failure. Plasma-lyte and Normosol solutions utilize acetate
and gluconate as buffers, which are metabolized by muscle. Their higher molar concentration of
buffer gives these crystalloids a greater alkalinizing ability than LRS.
Not all products are compatible with all IV fluids. Most of these concerns involve the
calcium present in lactated Ringer’s solution. Such incompatibilities include blood products
(recently questioned), sodium bicarbonate, thiopental, amphotericin and many others.
General recommendations are to limit the osmolarity of a peripherally administered IV
solution to 600 mOsm/kg, in an attempt to avoid injury to the intimal layer of the cannulated
vessel. Short term administration of a hypertonic solution may be tolerated, but chronic
administration predisposes to phlebitis. A central line is recommended if hypertonic fluid therapy
is required. It is important to understand that supplementing IV fluids (ie. KCl, dextrose, etc.)
increases the osmolarity of that solution. The osmolarity of the final solution is dependent on the
starting osmolarity, as well as the type and quantity of the supplement provided.
Isotonic fluids that do not contain dextrose (replacement solutions) may be administering
subcutaneously or intraperitoneally. They should also not be used intra-operatively, unless
hypoglycemia is a concern. Recent evidence also supports that we are overhydrating patients
intra-operatively, with current intra-operative maintenance fluid rate recommended is 3-5 ml/kg/hr.
Total potassium supplementation should remain below 30 mEq/L.
Colloids
A colloid refers to a solution with high molecular weight particles that are not freely
permeable across the intact capillary membrane. Therefore, colloids are effective intravascular
volume expanding solutions. The potency of colloid fluids as volume expanders will differ
amongst the individual fluids. Colloids may be further divided into a natural colloid and a
synthetic colloid. A natural colloid includes whole blood, plasma products, and human or canine
albumin.
The most commonly utilized synthetic colloid solutions are hydroxyethyl starch (HES)
solutions. HES is a hydrolyzed synthetic polymer of amylopectin and therefore is highly branched
polysaccharide that resembles glycogen. The amylopectin molecules vary in size ranging from a
few hundred daltons to over a million daltons. Several different HES products are now available,
with varying physicochemical characteristics. The latter is determined by their concentration (6%
or 10% solution), mean molecular weight, degree of substitution, C2/C6 ratio (hydroxyethylation
site at the carbon atoms of the glucose subunit) and solvent (isotonic saline or Lactated Ringers
solution).
The classification of HES solutions as rapidly or slowly degradable, is based on their
physicochemical characteristics. Smaller molecules are freely filtered and excreted by the
kidneys, and the larger molecules are hydrolyzed by amylase (hence, amylase levels will be
elevated in patients that are receiving HES and may remain elevated for up to 5-7 days) to
smaller molecules that can be excreted by the kidneys (contributing to urine specific gravity
measurements). The new generation HES products are of lower molecular weights and
substitution ratios, designed to limit side effects of the earlier generations (less coagulopathy,
etc), but also decreasing the half-life (duration of oncotic effects are up to 24 hours). There is a
very low incidence of anaphylactic reactions
with the starches when compared to some
of the other synthetic colloids. They cause
inhibition of Factor VIII and vonWillebrand
factor (vWf), therefore there is a variable risk
of coagulopathy.
Table 3. Physiologic Properties of Albumin
1. Provides oncotic support
2. Carries hormones
3. Oxygen free radical scavenger
4. Anticoagulant
5. Helps maintain intravascular integrity
6. Acts as a buffer
Species specific albumin products are considered a natural colloid, but are synthetically
produced. There are different sized bottles and concentrations of human albumin available.
Lyophylized canine albumin product allows flexibility when reconstituting, but has been
inconsistently available. Albumin is a monodispersed colloid, which is different when compared
to HES products, which are polydispersed. Albumin has many physiologic properties (see Table
3). Roughly 60% of the total body albumin level is located in the interstitial space, leaving only
40% in the intravascular space. This is why large volumes of plasma are needed to replenish
albumin in patients that are hypoalbuminemic – 45 mls/kg body weight is required to increase
serum albumin levels by 1.0 g/dL. Because albumin is smaller in size compared to HES, its
duration of action is shorter. There is a greater risk of allergic reaction with administration,
compared to synthetic colloid use. Patients receiving albumin products should be monitored
closely as though they are receiving an allogenic blood transfusion. Human albumin products
have been associated with severe hypersensitivity reactions.
Colloid-Crystalloid Conundrum
Although there is little debate about the benefit of IV fluid therapy for dehydrated patients
and those requiring diuresis, there remains a considerable disagreement about the most
appropriate fluid for volume resuscitation in critically ill patients. Although there is little doubt
about whether colloids are more efficient volume expanders than crystalloids, the degree of
difference between the two has been recently called into question, especially in critically ill
patients who have increased vascular permeability. The common argument against the use of
colloids, describing that they have not been shown to improve survival amongst critically ill
patients has now grown into a concern that HES products may increase mortality by contributing
to renal impairment. The latter has been based on studies concluding that septic patients
receiving HES had increased risk of renal failure and increased requirements for renal
replacement therapy.
REFERENCES AVAILABLE UPON REQUEST
TRIAGE & INITIAL TREATMENT OF THE EMERGENT PATIENT
Todd Duffy, DVM, DACVECC
Aratana Therapeutics
Survival of the emergency patient involves a collaborative effort between the reception staff,
nursing staff and the veterinarian(s). By practicing organized teamwork and hospital readiness,
the veterinary team can provide successful resuscitation and stabilization of the emergent patient.
Time is precious in an emergency situation, having the tools or supplies stocked, and readily
available when they are needed, is another key aspect to successful patient outcomes.
Table 1. Triage Classification
Class I patients:
Catastrophic and dying. Patients must receive treatment immediately
– these patients are dying before your eyes. Examples include
cardiopulmonary arrest, seizures, unconscious, gastric dilatation and
volvulus, penetrating thoracic wounds.
Class II patients:
Critical and most urgent. Patients must receive treatment within
minutes to an hour. Examples include toxicities, shock or multiple
injuries with adequate ventilation, hemorrhage, prolapsed organs,
dystocia, urethral obstructions.
Class III patients:
Urgent. Patients must be attended to within a few hours. Examples
include open fractures or wounds, profuse diarrhea and vomiting, blunt
trauma without shock or altered levels of consciousness.
Class IV patients:
Less seriously ill but still pressing concerns. Patients require therapy
within 24 hours. Examples include anorexia, lameness, severe
pruritis, etc.
The approach to the emergency patient starts when the owner calls the clinic notifying the
staff of the need for immediate care. Basic information (client and patient information, patient
size, reason for needing immediate care, etc.) should be obtained to allow the staff to adequately
prepare for the patient’s arrival. It should also be determined whether first aid is needed prior to
transport (ie. bleeding, fracture stabilization, etc.) and recommendations are provided based on
protocols approved by the hospital. Owners can provide significant medical assistance. It is
critical to remember that the owner’s safety should always come first. The owner should be
advised to take a quiet, gentle approach while handling an injured pet. If the animal is in pain or
acting aggressive, a strap muzzle should be placed or the patient can be lightly wrapped in a
large towel or blanket. A tight muzzle is contraindicated if the patient has nasal hemorrhage,
obvious maxillary or mandibular fractures, or if the nasal passages appear occluded.
When a patient presents on an emergency basis there is often a high level of anxiety from the
owner, others waiting in the reception area, and the veterinary staff. If an owner is under duress,
or the patient is displaying disturbing behavior (vomiting, diarrhea, etc), it is best to place the
owner and the patient immediately into an exam room where the patient is triaged. Triage means
“to sort” and allows prioritization of critically ill or injured animals into those requiring immediate
treatment (see table 1).
The person performing triage must possess excellent assessment skills as well as
interpersonal skills. The individual must be able to convey genuine concern, empathy,
willingness to listen, and the desire to help. One should approach the owner in a nonjudgmental
attitude and communicate that their complaints have been taken seriously. It is important to
approach the owner in a friendly, compassionate and professional manner. Establishing trust and
rapport are fundamental to providing emotional support.
Although the purpose of triage is not to diagnose, experienced triage nurses are able to
recognize clinical syndromes and use this knowledge when deciding on acuity. During triage, the
history is briefly reviewed and includes the nature of the emergency, the time it occurred and any
pertinent medical conditions or therapy. Further information can be obtained after initial
assessment and stabilization. When a patient is triaged a primary survey must be performed, in
addition to vital sign acquisition. A primary survey addresses the ABCs of Airway, Breathing,
Bleeding, Cardiovascular, Circulation and level of Consciousness.
Prior to approaching the patient, observe their ventilatory pattern (normal, tachypneic,
hyperpneic, orthopneic, etc.) and note whether there is an upper airway (stertorous or stridorous)
or a lower airway (small excursions, expiratory push) component. This is also the best time to
gain an initial assessment of the patient’s mentation. Patients that are having difficulty breathing
should always receive oxygen prior to be being stressed / handled. This is especially true for
cats, as handling a cat in
respiratory distress can lead to
severe bites and or scratches by
the frantic animal. Oxygen can be
provided by several different
methods (See table 2). The
method of administration is based
initially on the size and species of
the patient, then adjusted based
on the patient’s tolerance - oxygen
therapy may be detrimental if the
Table 2. Methods of Oxygen Administration
Temporary provision (minutes to hours)
Flow-by
Mask
Oxygen hood
Incubator
Oxygen cage/carrier in plastic bag
Nasal prongs
Long term provision (hours to days)
Oxygen hood
Incubator
Oxygen cage/carrier in plastic bag
Nasal, nasopharygeal or nasotracheal tube
Transtracheal oxygen tube
technique utilized is stressful to the patient. In addition to the collection of routine vital signs
(temperature, heart rate and respiratory rate), the primary survey includes the assessment of
respiratory effort, breathing pattern, heart rhythm, as well as perfusion parameters (pulse
pressure, mucous membranes color, and capillary refill time). These initial baseline values
provide a foundation to monitor trends obtained during continuous monitoring of the patient. If
blood is observed on the patient, gloves should be worn to protect the healthcare provider.
When it is determined that immediate intervention is required, the animal is moved to the
“ready area”. Although it has been traditional for the owner to be placed in an exam room, for
privacy, while the animal is brought to the ready area, there is an increasing trend of family being
allowed to be present during initial resuscitative measures. If the owner is not allowed to be
present initially, the owner must be assured that someone will be with them right away and the
front desk personnel should be ready to act as an intermediary between the treating staff and the
owners during this time. To accelerate treatment, permission for initial intervention (ie.
intravenous catheter placement, fluid administration, oxygen supplementation) should be
obtained from the owner prior to brining the patient to the ready area. It is important to avoid
placing a leash around the neck of a patient that has head, ocular, neck or respiratory injuries or
problems. Those patients requiring immediate management should be carried or moved on a
stretcher – avoid making them walk on their own. Patients in respiratory distress should not be
carried or supported by their thorax. In the ready area the patient should be placed on a towel or
circulating warm water blanket to prevent heat loss, unless already febrile or hyperthermic. The
veterinarian should perform their own primary survey, immediately followed by the resuscitative
phase of therapy, if indicated.
Many emergent patients require venous access (intravenous catheter or intraosseous
catheter), a procedure that should be performed by individuals who have proven to be proficient
at intravenous (IV) catheter placement. Sterile catheter placement is extremely important in
critically ill patients, as they commonly are immunocompromised and are more susceptible to
hospital-acquired infections. If a catheter is unable to be placed under sterile conditions, due to
time constraints, then a second catheter must be placed under sterile conditions as soon as the
patient is stable enough to allow. Only after the second IV catheter is secured in place, should
the “dirty” or “contaminated” catheter be removed. If IV fluids are indicated, then large volumes of
intravenous IV fluids are preferably administered through a short, large bore, peripheral
intravenous catheter. The rate of fluid flow is based on Poiseuille’s law:
Q = P r4 π
ηL8
Poiseuille’s law states that flow (Q) is directly proportional to the pressure (P) and the radius
(r) of the tube, while being indirectly proportional to the length (L) of the tube and viscosity of
blood (η). This equation supports that catheter radius has the greatest influence on maximum
fluid administration rate.
Isotonic crystalloids with an attached IV administration set should be primed and positioned in
an infusion bag. Supplemental oxygen, suction units, as well as pediatric and adult AMBU bags
should be readily available. A large mobile cart (crash cart) housing instruments and equipment
is of great value, alternatively, maintaining a tackle box with emergency equipment and drugs
should be available. All drawers should be organized and compartmentalized well, in addition to
being adequately stocked. Overstocking or crowding of materials may cause delays in
identification and extraction of the needed supplies during a crisis event. All drawers should be
labeled appropriately. These preparatory measures will make any veterinary team ready for most
emergency situations. Additional preparations can be made as incoming calls are taken and
information is gathered.
In a patient with upper airway or respiratory difficulties, the airway is cleared by gently
extending the head and neck, pulling the tongue forward, and carefully clearing the mouth of any
foreign objects, mucous, blood or vomitus. If a foreign body is unable to be easily removed, a
Heimlich-like maneuver can be performed. Tracheal intubation, either orally or via tracheotomy,
will provide an immediate airway. Mild sedation may be required in partially conscious animals.
If intubation is not necessary, oxygen is always supplemented.
Blood that is dark and slowly oozing is likely originating from the low pressure venous
system. This form of bleeding can be abated by direct pressure, followed by application of a
pressure bandage. If blood strikes through a pressure bandage, a new bandage should be
applied over the original bandage. Removal of the original pressure bandage will disrupt any
initial clot and can lead to further hemorrhage. Active, red, pulsatile blood is likely from the higher
pressure arterial system and may be arrested by direct digital pressure. If the wound is located
on the limb, application of a blood pressure cuff, proximal to the wound, followed by rapid
inflation, will help limit blood loss. A tourniquet should only be applied if the limb is not
salvageable, or if hemorrhage is considered to be life-threatening. If the bleeding vessel can be
visualized, ligation may be performed after temporary application of a hemostat.
A penetrating foreign body should not be removed until prepared for definitive surgical repair
due the risk of uncontrollable hemorrhage, pneumothorax, etc. Penetrating foreign bodies are
immediately removed only when they obstruct the airway, contributing to respiratory compromise.
In patients with suspected head trauma or altered levels of consciousness, never hold off
jugular veins for phlebotomy and do not allow the head to be positioned lower than the heart.
These same conditions are relative contraindications for jugular catheter placement.
An initial data base can be obtained from the blood that collects in the catheter stylet. A
minimum emergency data base includes a packed cell volume (PCV) and total solids (TS),
plasma color, buffy coat, Azostick and blood glucose. Additional information that may be
obtained if equipment is available is a venous blood gas and electrolytes.
Once the ABCs have been addressed and resuscitation measures have been initiated, the
secondary survey (reassessment of vital signs, and rapid, thorough examination of the patient) is
performed.
Important keys to successful patient management include:
-
Always treat the most life-threatening problem first.
-
Make the patient as stable as possible before undertaking stressful procedures.
-
Chemical restraint, rather than manual, is less stressful to both the patient and caregiver
when dealing with uncooperative animals.
-
The critical patient is rapidly changing and requires intensive monitoring and procedures
for early detection.
-
It is important to anticipate complications and initiate appropriate monitoring procedures
for early detection.
-
It is a trend of change in monitored parameters that is more significant than a single
value.
-
Many post-trauma complications do not become evident for 24-72 hours. Do not take a
patient’s stable condition for granted.
-
There is less tolerance for error, indecisiveness, or delay in the critical patient
REFERENCES AVAILABLE UPON REQUEST
COMPONENT TRANSFUSION THERAPY and ADVERSE EVENTS
Todd Duffy, DVM, DACVECC
Aratana Therapeutics
Blood component transfusion is generally provided as supportive therapy for correction of
one or more hematologic and/or hemostatic deficiencies, until the underlying disease process can
be controlled or corrected. Blood component administration and its immediate endpoints often
are only one part of a general therapeutic plan. Although appropriate endpoints may be achieved
in terms of measurable parameters or clinical response, the clinician needs evidence that the
traditional “outcomes” are relevant in relation to the final outcome for the patient. However,
evidence-based support of many transfusion practices, in many clinical settings, is limited.
Therefore, the clinician must base the administration of component therapy on good
understanding of the problem in terms of pathophysiology and indicators of severity.
Indiscriminate administration of blood products may pose unnecessary risk to the patient. The
basic principles of component therapy are:
a) transfuse only what is needed
b) transfuse only when there is a clinically significant problem
c) weigh benefits, risks and alternatives to transfusion therapy
COMPENSATORY MECHANISMS FOR ANEMIA
Adequate oxygen supply is a key factor in maintaining body function and cellular
homeostasis. Therefore there is a normal physiologic response to anemia which helps maintain
oxygen delivery to the peripheral tissues. This
Compenstation for Anemia
physiological response to anemia consists of cardiac
and peripheral tissue adaptations as well as changes in
Increased cardiac output
red blood cell (RBC) 2,3-diphosphoglycerate (2,3-DPG)
- Decreased vascular resistance
– see box. Animal studies suggest that lower limit of
- Decreased viscosity
cardiac tolerance for anemia in the presence of normal
- Increased heart rate
cardiovascular system is in the Hb of ~3-5 g/dL.
Increased extraction ratio
It should be noted that a hemoglobin/hematocrit
Increased capillary recruitment
that is adequate in a stable setting, may no longer be
Increased 2,3-DPG (chronic change)
adequate in the same patient in a stressful
postoperative setting, ie. awake, shivering, in pain, with a systemic inflammatory response after
surgery.
The decision to transfuse should be supported by the need to relieve clinical signs and
symptoms of impaired oxygen transport and to minimize morbidity and mortality. The question of
the lowest safe hematocrit continues to remain unanswered and likely varies between different
patient species, breed, comorbidities and underlying pathophysiologic states.
RED BLOOD CELL TRANSFUSIONS
In critically ill patients, decreased cardiac output, decreased red blood cell mass, and
acidosis can impair oxygen delivery and tissue use of oxygen. Administering RBCs may enhance
oxygen delivery to tissues. However, some investigators have found a significant association
between RBC transfusion and increased mortality in human ICU patients; transfused patients had
longer ICU stays, more severe organ failure, and higher mortality rates than non-transfused
patients. Although these associations may be explained by different underlying clinical conditions
and altered or blunted erythropoeitic responses that are characteristic of anemia of inflammation
(chronic disease), attendant risk of RBC transfusion include febrile, nonhemolytic transfusion
reactions, immunosuppression and alloimmunization. Using newer, rather than older, RBCs (ie.
RBC stored for fewer than 15 days) and leukocyte-depleted, rather than non-leukocyte-depleted,
RBC products may provide important benefits.
Most blood transfusions are allogeneic (collected from one individual and administered to
another of the same species). Some units of whole blood are administered as such, but most are
separated into 2 or more components – one unit of packed red blood cells (pRBCs), one unit of
plasma, and sometimes one unit of donor platelets. The plasma may be further separated into
one unit of cryoprecipitate and one unit of cryopoor plasma. Most red blood cell units contain an
additive solution that improves viability and shelf life.
In whole blood donation, a canine unit is 450-500 mls and feline unit is 55-60 mls and are
typically collected in citrate-based anticoagulant, contained in a sterile, plastic bag. Vacuum
bottles have fallen out of favor due to the inability to separate blood components, activation of
platelets, potential for air embolism and bottle breakage. In contrast, plastic bags allow easy
separation of blood components and are generally less expensive. Fresh whole blood contains
all cellular and protein blood constituents, and is administered within 6 hours of collection. Once
the first 12 hours have passed, labile coagulation protein activity (specifically factors V and VIII)
start to deteriorate and cannot be relied upon. Blood not administered within 6 hours of
collection, should be stored in a refrigerator (4ºC).
Clinical indications for administration of fresh whole blood are severe hemorrhage
induced hypovolemic shock, hemorrhage secondary to thrombocytopenia, thrombocytopathy,
coagulapathy (including hemophilia), or vonWillebrand disease. Use of fresh whole blood lacks
the concerns of “storage lesions” (see table) and provides
Storage Lesions
fully functional RBCs. Clinical indications for use of
Decreasing 2,3 DPG levels
stored whole blood include severe hemorrhage induced
Decreasing ATP levels
hypovolemic shock from trauma, neoplasia or vitamin K
Decreasing glucose levels
antagonist toxicity, while it is an inferior alternative to
Increasing NH3 levels
fresh whole blood for use in hemorrhage secondary to
Increasing acid load
thrombocytopenia, thrombocytopathy, hemophilia or
Increasing cytokine levels
vonWillebrand disease. With the latter two conditions
Decreased RBC deformability
administration of fresh frozen plasma is likely to be
necessary to help eradicate the source of hemorrhage.
Whole blood storage time is 35 days if collected in citrate-phosphate-dextrose-adenine (CPDA-1)
at 4ºC.
When plasma and platelets are removed, a 450-500 ml canine unit is reduced to 220-250
mls of packed red blood cells (pRBCs), and the hematocrit is about 80%. With the addition of a
preservative solution (ie. Adsol, Nutricell), the volume is increased to 320-350 mls and the
hematocrit drops to about 60%. Thus, canine pRBCs typically contain a preservative solution
(saline, adenine, dextrose) as well as about 25 mls of remaining plasma. Feline pRBCs typically
have a PCV that varies between 45-60%. Despite the presence of a preservative, RBCs undergo
storage lesions (biochemical and physical changes) in vitro. Most storage lesions are reversible
following transfusion, although it may impose excessive metabolic demands on a critically ill
patient. The clinical indications for the administration of pRBCs are typically anemia secondary to
chronic hemorrhage, immune-mediate RBC destruction or primary bone marrow failure. The
smaller volume, compared to whole blood, minimizes the risk of volume overload during
administration. Packed RBC storage time is 42 days (with addition of preservative) at 4ºC.
All blood components are ideally warmed prior to administration. Warming blood
products reduces viscosity and increases infusion rate. However, the main reason for warming
blood is prevention of hypothermia in the recipient. Generally RBC bags ware warmed by
protecting them in a sealed plastic bag and submerging them in warm water (not exceeding 37ºC
to prevent thermal injury to RBCs). When time does not allow for warming of the entire unit, the
blood administration line may be placed in a warm water bath. It has been shown that significant
warming does occur naturally during slow administration of a unit. All cellular blood components
must be administered through a standard blood filter (80-170 microns) to remove any aggregates
that may have formed during storage. These filters can become an impediment to flow as they
collect trapped debris, and thus they may need to be replaced periodically, especially if blood
clots had formed in the unit after collection.
Autologous blood collection or autotransfusion are alternatives to allogeneic blood
transfusion therapy. The former is available in several forms (acute normovolemic hemodilution,
preoperative autologous blood donation, etc.), but is typically limited to patients that are
knowingly going to experience a procedure that may predispose to substantial hemorrhage
(adrenalectomy involving large vascular invasion, etc). These procedures will require all of the
same precautions (blood filter, etc) that autologous units require. Collection of free blood from
the thoracic or abdominal cavity is considered devoid of platelets and fibrinogen and relative
contraindications to their use are contamination with infectious agents or neoplastic cells.
However, intact RBCs are immediately available for oxygen transport. Using recombinant
erythropoietin offers an alternative to RBC transfusion and is being evaluated in more detail at
this time.
When administering RBCs to a patient, one can estimate the amount of product need by
the following calculation:
mls of product = body weight (kg) X blood volume (ml/kg) X (desired PCV – patient PCV)
donor PCV
The blood volume in canines is 80-90 ml/kg and felines is 50-60 ml/kg. The other, less
accurate rule of thumb for administration volume is 20 ml/kg of whole blood will increase the PCV
by 10%, whereas 10 ml/kg of pRBCs will increase the PCV by 10 %. These calculations will vary
with age of the units administered as older units have a lower yield of RBCs 24 hours posttransfusion. Expiration dates are typically based on recovery of 75% of the RBCs administered,
24 hours after completion.
PLASMA TRANSFUSIONS, CRYOPRECIPITATE, CRYOFREE PLASMA
Clinically, spontaneous bleeding is rare in isolated factor deficiencies unless levels are <
5% of normal. Under conditions of stress (surgery, invasive procedures) bleeding often occurs
when factor levels start to fall below 20-30%, particularly in complex coagulopathies. Global
measures of coagulation (PT/PTT) normally are used for clinical assessment. Although
sensitivity to factor deficiencies is reagent-specific, in general the PT and PTT do not prolong until
factors are <30-40% of normal. Plasma should not be used as a volume expander, as a
nutritional supplement, or for non-urgent correction of vitamin K deficiency.
Plasma dosing of 20 ml/kg usually will restore coagulation factor levels to 30% in stable,
nonbleeding patients. Although plasma frequently is administered to correct mild prolongations of
the PT (>1.2-1.5) and PTT (>1.2-1.5) before invasive procedures, there is little evidence to
support this practice, and the skill of the operator doing the procedure is more predictive of
bleeding. It also should be noted that increasing the coagulation factors by 10% will have a
significant impact on the PT and PTT when they are prolonged > 2 times midrange normal but will
have only a minimal effect on more modest prolongations. It is difficult to correct coagulopathy of
severe liver disease with plasma because the short half-life (6 hours) of factor VII makes it difficult
to infuse the product quickly enough.
Fresh frozen plasma (FFP) is plasma that is separated from fresh whole blood within 6-8
hours of collection. FFP contains normal levels of all coagulation factors, natural inhibitors, and
plasma proteins. Canine FFP volume is approximately 200-225 mls, and shelf life is 1 year if
maintained in a frozen state.
Frozen plasma (FP) is plasma that is prepared more than 6-8 hours after blood collection
or when FFP goes beyond its 1 year, frozen shelf life. FP contains minimal amounts of factors V
and VIII, and vonWillebran factor (vWf). Frozen plasma has a total shelf life of about 5 years.
Cryoprecipitate is prepared when ultrafrozen (-70ºC) fresh frozen plasma is slowly and
partially thawed between 1-6ºC (refrigerator temperature), producing a white precipitate, which is
harvested and then refrozen. Cryoprecipitate contains fibrinogen, factor VIII, factor XIII, and vWf.
Therefore, therapeutic use is generally reserved for patients with hypofibrinogenemias (massive
transfusion or DIC), hemophilia A (factor VIII deficiency) or vonWillebrand disease.
Cryoprecipitate volume is generally 1/10th of the original plasma unit. Shelf life is
identical to FFP, but once thawed, cryoprecipitate keeps only 4 hours at room temperature.
Cyrofree plasma is the plasma that remains after cryoprecipitate has been harvested
from FFP. Cryofree plasma therefore contains albumin, immunoglobulin, and all vitamin Kdependent coagulation proteins. Clinical indications for use include vitamin K antagonist toxicity,
colostrum replacement and hypoproteinemia. Cryofree plasma has an expiration date of five
years from the time of blood collection.
It is important to understand that frozen components are fragile and cracking of the
collection bag is possible if not handled carefully. Therefore it is recommended to thaw all frozen
products in the box that the product is received in. The unit may then be removed once thawed.
Before thawing, the unit and box should be placed in a watertight, sealed, plastic bag to avoid
contamination of the spike ports. Once blood products have been warmed to room temperature,
they should be administered within 4-6 hours to minimize the risk of bacterial proliferation and
subsequent infectious complications in the recipient. Blood products that have been thawed at or
maintained at refrigerator temperature may be used over 24 hours, once the bag has been
entered. Therefore, if one anticipates that administration of the unit will require more than 4
hours, then the sample should be aliquoted into smaller volumes. Each smaller aliquot may then
be independently brought to room temperature and administered. Dilution of blood products (ie.
pRBCs) should be accomplished with a non-calcium containing, isotonic solutions (ie. avoid
lactated ringers solution) .
PLATELET TRANFUSIONS
Platelet transfusions are not routinely administered in veterinary patients due to cost,
short shelf-life and lack of availability. Platelets may be given both prophylactically and
therapeutically or to assure effective hemostasis during surgery or other invasive procedures
(biopsies, thoracocentesis, etc). Spontaneous bleeding is rare at platelet counts 10-25,000/ul
providing that platelet function is normal and no concomitant hemostatic defect exists. Platelet
counts of 40-50,000/ul of functional platelets, in the absence of other coagulation defects, are
usually enough to assure hemostasis. In patients with qualitative defects in platelet function,
platelet count is not a reliable indicator of transfusion, and transfusion decisions and monitoring
efficacy must be based on the setting and clinical features. Platelet-rich plasma is suspended
and frozen in dimethyl sulfoxide (DMSO) and stored for up to 6 months. Due to severely
shortened life span, the transfusion of platelet concentrate is not generally considered appropriate
when thrombocytopenia is due to immune-mediated destruction.
OTHER PLASMA PRODUCTS
Species specific albumin, unlike other blood products, comes in glass bottles and must
be vented for IV administration. The 5% solution is isotonic and the 25% solution is hypertonic.
Albumin products often are used to restore intravascular volume in patient with hypovolemia or
replenish albumin levels in patients that are severely hypoalbuminemic.
STORAGE, ANIT-COAGULANT, PRESERVATIVES
Red blood cell storage should occur in a refrigerator with limited activity and units stored
toward the back. Periodic agitation of blood units during the storage interval can help enhance
preservation of the RBCs. Frozen products should be kept in a freezer without automatic
defrosting ability. Frozen products should also be initially frozen with a rubber band around the
unit. Once the unit is frozen, the rubber band should be removed. Loss of a “waist” around the
unit suggests that the unit was thawed (intentionally or accidentally) and may not be suitable for
administration.
Heparin is an anti-coagulant with no preservative action, therefore heparinized blood
should be administered within 6-8 hours of collection. Heparin also causes platelet aggregation
and inhibits coagulation factors.
TRANSFUSION REACTIONS
As with many procedural related complications, early identification is key in minimizing the
severity of the adverse effects that the patient may experience. Although some transfusion
related complications occur during administration of the product, which allows for discontinuation
of the blood product if necessary, many occur hours to days after the transfusion has been
completed. Although some complications respond readily to treatment, there are some that are
life-threatening.
Transfusion related complications are generally divided into immediate and delayed
reactions, with each of these being partially or fully explained by immunologic or non-immunologic
mediated mechanisms. If it is decided to provide transfusion therapy to patients in need, then
with it comes the responsibility to understand how these reactions occur. Possessing a thorough
knowledge of the pathophysiology behind transfusion complications, provides one the capacity to
respond rapidly and with effective treatment.
IMMUNOLOGIC COMPLICATIONS
One of the most severe and life-threatening transfusion complications is an acute
hemolytic transfusion reaction, which occur when a patient,
Table 1. Clinical Signs of
with pre-existing antibodies to certain erythrocyte antigens, is
Acute Hemolytic Reactions
transfused with erythrocytes containing that antigen.
Fever
Classified as a type II hypersensitivity reaction, these
Tachycardia or bradycardia
reactions are mediated by IgM or IgG antibodies that fix
Hypotension
complement. Complement is capable of massive red blood
Dyspnea, cyanosis
cell (RBC) lyses, releasing large quantities of hemoglobin
Emesis
within the intravascular space, and ultimately in the urine
Defecation
after being filtered through the glomerulus. The presence of
Collapse
intravascular red blood cell carcasses, with subsequent
Opisthotonus
exposure of the internal phospholipid membrane, may trigger
Cardiac arrest
disseminated intravascular coagulation (DIC). See table 1
Hemoglobinemia
for signs that may be associated with acute hemolytic
Hemoglobinuria
reactions. These reactions can occur within minutes of
initiating the transfusion. Ramping up the rate of transfusion
administration helps detect these reactions before large amounts of RBC containing products
have been administered.
Prevention lies in performing pre-transfusion major crossmatches, which is intended to
screen the recipient’s plasma for antibodies to the donor’s RBCs. Further prevention is aided by
the use of type-specific blood products when available in dogs and always in cats. Although most
canine patients can receive their first transfusion without major risk or transfusion reaction, owing
to their absent or low levels of naturally occurring antibodies, this is not true for cats. Feline type
B cats have high titers of naturally occurring anti-A antibodies. In the rare situation where a type
AB cat requires a transfusion, they have no naturally occurring alloantibodies against either type
A or type B in their sera. Dog erythrocyte antigen (DEA) 1.1, 1.2 and 7 are considered highly
immunogenic, therefore sensitizing recipients lacking these antigens will predispose them to
severe hemolytic reactions if they receive a similar transfusion in the future. However, when
faced with an exsanguinating patient, the clinical risk/benefit is overwhelmingly in favor of using
uncrossmatched blood. Treatment of an acute hemolytic reaction involves immediate cessation
of the transfusion and symptomatic therapy to address clinical signs experienced by the patient.
Rapid infusion of intravenous crystalloid therapy, to maintain blood pressure and promote
diuresis, is typically a mainstay of therapy.
Non-hemolytic febrile reactions require documentation of a temperature rise of 1ºC or 2º
F occurring within 1-2 hours of transfusion, without hemolysis or other explanation. These
reactions are usually due to recipient antibodies directed toward donor leukocytes or rarely
platelet antigens. During storage, leukocytes and platelets release cytokines. Consequently,
stored blood products are more likely to induce a non-hemolytic febrile reaction. This may also
be an early sign of a hemolytic or septic reaction.
Acute hypersensitivity reactions are classified as a type I hypersensitivity reaction and
are most frequently observed with the administration of plasma containing products. Type I
hypersensitivities are mediated by IgE or IgG bound mast cells and basophils. Mast cell
degranulation releases vasoactive substances (ie. histamine, leukotrienes, prostaglandins, and
cytokines) resulting in urticaria, pruritis, erythema, bronchoconstriction, tachycardia, hypotension,
vomiting, diarrhea and pyrexia. Treatment commonly requires the administration of injectable
corticosteroid and/or diphenhydramine, based on severity of the reaction and underlying disease
present in the recipient. In rare situations, administration of epinephrine may be necessary to
alleviate bronchoconstriction and help maintain blood pressure. Although most animals will
respond to supportive therapy and slowing of the transfusion, cessation of the transfusion may be
warranted based on the severity of the reaction.
Transfusion-related acute lung injury (TRALI) is a form of noncardiogenic pulmonary
edema (NCPE). Typically, the onset of TRALI is within 1-2 hours of transfusion. Signs of
respiratory distress (cough, dyspnea, hypoxemia and fever) develop after infusion of volumes that
are too small to produce hypervolemia. A sample of pulmonary fluid would typically reveal fluid
that is high in protein (ie. has a protein level equal or greater than 70% of that found in plasma).
Treatment involves immediate cessation of blood product administration, followed by oxygen
therapy. Mechanical ventilation is required in the majority of patients experiencing this
complication.
Delayed hemolytic reactions can occur within a few days (anamnestic response) or
several weeks (primary response) following transfusion. Newly formed antibodies adhere to the
transfused RBCs, which are prematurely removed from the circulation. Unlike acute hemolytic
reactions, crossmatching does not help evaluate patients at risk for this reaction. Patients may
be asymptomatic or develop a fever or icterus with a dropping RBC level. Some patients will
have a positive Coomb’s test, which is supportive of, but not specific for a delayed hemolytic
transfusion reaction. The latter is especially true for patients with an immune-mediated hemolytic
anemia.
Thrombocytopenic purpura is a rare transfusion complication that manifests as
thrombocytopenia 7-14 days following a transfusion that contained platelets or platelet fragments.
Immunosuppressive therapy is usually administered to expedite improvement.
NON-IMMUNOLOGIC COMPLICATIONS
Some non-immunologic complications can be avoided by thorough donor screening for
infectious diseases, sterile technique during product collection and preparation, as well as having
strict protocols that need to be followed during product administration.
Transfusion associated circulatory overload (TACO) may be seen primarily in patients
with compromised cardiac or renal insufficiency, small breed canines, pediatrics, and felines.
Clinical signs mimic those of NCPE and include emesis, vocalization, dyspnea, and pulmonary
edema. Contrary to NCPE fluid, which is highly proteinaceous, pulmonary edema of fluid
overload is generally low in protein (ie. generally 30% or lower than that found in plasma). As a
general guideline, transfusions are administered at 5-10 ml/lb/hr in normovolemic patients or
more rapidly in hypovolemic patients. Therapy generally consists of stopping the transfusion and
starting IV furosemide therapy and O2 supplementation until the pulmonary edema has resolved.
In addition to circulatory overload, large volumes of blood product administration can
result in hypothermia (if blood products are not appropriately warmed), coagulopathies and
thrombocytopenia (from dilution of coagulation factors and platelets, respectively), citrate toxicity
(leading to hypocalcemia), acid-base imbalances (most commonly metabolic acidosis from citric
acid anticoagulation, as well as production of lactic and pyruvic acid), hyperammonemia
(ammonia levels may increase in stored products), hypokalemia and iron overload (IMHA).
Although hemolysis may occur through immunologic mechanisms, hemolysis may also
occur through non-immunologic mechanisms. Improper handling of RBC products includes their
exposure to extremes of temperature (ie. accidental freezing or applying excess heat during the
warming process) or mixing with hypotonic fluids (ie. dilution with D-5-W or half-strength saline).
Traumatic hemolysis can occur through the use of fluid pumps not intended for the administration
of cellular products, excess pressure applied across a blood filter or when administering through
a small bore catheter, as well as through a kinked catheter or IV line. Primary clinical signs are
hemoglobinemia and hemoglobinuria.
Septic complications generally occur when sterile technique is breached during donor
phlebotomy / donation. Risks for septic complications increases if the product is maintained at
room temperature for prolonged periods either before or during administration (should not exceed
4 hours). Less commonly, donor infections could result in bacterial contamination. Bacterial
contamination may be determined prior to administration of the blood product if the nurse is
astute and notes that the unit is discolored, has air bubbles or cell clumping. Systemic signs in
the recipient are generally secondary to endotoxemia, and therefore clinical signs include fever,
hypotension, hemolysis, DIC and renal failure. Cytology, in addition to aerobic and anaerobic
culture of the unit being transfused is recommended to confirm the clinician’s suspicion. Besides
discontinuing the administration of the product, supportive therapy, in the form of antibiotic
administration (guided by initial cytologic findings) and cardiopulmonary support, is a must.
Additional infectious complications in the recipient can occur after the administration of
blood products that were collected from an infected donor. Donor screening is an important
aspect of having a blood donor program. Table 2 includes some infections that are transmissible
through the administration of blood products.
Table 2. Infectious diseases transmissible through blood products
Canine
Feline
Babesia
FeLV
Rickettsia
FIV
Borrelia
FIP
Ehrlichia
Mycoplasma hemophilus
Dirofilaria immitis
Bartonella
Leishmaniasis
Bartonella
Brucella
Although the practice of administering blood products beyond their expiration date is not
recommended, accidental administration of outdated products may occasionally occur.
Hyperammonemia and non-immunologic acute, intravascular hemolysis are of greatest risk to the
recipient.
Transfusion therapy is increasingly recognized as an immunosuppressant, referred to as
transfusion-related immunomodulation (TRIM). It has been implicated as a cause for increased
transplant allograft survival, increased recurrence of malignancies and increased infection rates
for those receiving transfusion, especially in the trauma patients. An area of major controversy in
transfusion medicine is whether leukodepletion will abrogate this effect.
Autologous blood administration (predonation or autotransfusion) completely eliminates
the risk of all immunologic reactions, though it does not eliminate many of the non-immunologic
causes of blood transfusion complications. Additional measures to avoid allogeneic transfusion
therapy, and subsequently the complications they may be associated with, are to avoid excessive
phlebotomy and possibly the use of recombinant erythropoietin therapy.
With increasing knowledge of possible transfusion complications and the expanding
ability to test for some of them (typing, crossmatching, serologic testing of donor for infectious
disease, etc.) there comes the importance of owner education of these possible risks.
Documentation of the donor screening process, as well as the transfusion monitoring provided to
the recipient and occurrence of (or lack thereof) any recipient adverse event is of increasing
importance due to the litigious nature of today’s society. This requires that an information trail
allows one to trace all transfusion product(s), that were administered to the recipient, back to the
donor. In addition, documentation should also detail the treatments provided to limit the severity
of the reaction and whether there was any patient response to the treatments.
REFERENCES AVAILABLE UPON REQUEST
NURSING PEARLS - Parts 1 and 2
Todd Duffy, DVM, DACVECC
Aratana Therapeutics
The art of veterinary nursing must keep pace with the increasing demand that the intensive care
unit and its patients place on it. Much of what is taught in didactic lectures is how to identify specific
problems and what to do in response to these problems. Many times, however, time constraints don’t
allow information to be shared on HOW to do things. This lecture focuses on exactly that, with an
emphasis of how to improve upon procedures that are already common place in your hospital, through
maximizing efficiency as well as improve upon the quality of care that you provide to your patients.
Venous access and intravenous fluid administration are some of the most common patient
procedures performed in the emergency room. At times, provision of such care may seem mundane to
an experienced technician, which can lead to poor adherence to basic tenets of care. While those in the
veterinary arena may have a greater challenge than our human healthcare colleagues at avoiding the
development of catheter-associated bloodstream infection (CA-BSI), this additional challenge doesn’t
absolve us of the responsibility we have to provide our patients with the same level of care and
expectations that we have when we receive medical care. Points of reminder are to maintain sterile
technique (wash hands before catheter placement; use of a catheter tote or cart; use chlorhexidine-based
antiseptics; don’t touch surgically prepared skin; shave wide enough to avoid catheter from touching hair;
use designated clippers for catheter and surgery that are not used on contaminated surfaces – abscess,
diarrhea, etc.; periodic disinfection of catheter clipper brushes to prevent them from acting as fomites or
more ideally use compressed air for removal of bioburden from clipper blades; use or clipper blade
disinfectant). Secure catheters only with new, clean tape. The insertion site is best covered with a sterile
barrier – band aids work great. Ointments are no longer advised due to risk of manifesting resistance.
Pearls to add to your armamentarium are to cover the IV catheter sites with an impermeable barrier, in
patients with nasal discharge or animals with nausea or historical vomiting. Cover injection ports to
prevent them from being soiled with stool, urine or other bodily fluids. Regardless of whether gross
contamination is present, clean all ports with alcohol prior to injection. Limiting intentional intravenous
fluid line disconnects also helps limit the risk of a breach in sterility. Accidental introduction of air into the
IV line, is an example of a situation that can be managed in an alternative fashion. Air introduced in the
line at the level of the drip chamber can be managed by kinking the line and stripping the fluid in the line,
retrograde, after refilling the drip chamber with fluid. Less ideally a needle can be inserted into the
injection port, the line kinked on the patient side, and this path of least resistance will allow air to be
cleared from the line as fluids are allowed to flow.
Hypotension and pitting edema may place additional hurdles to successfully achieving peripheral
vascular access.
Avoiding overly aggressive vascular occlusion, proximal to the attempted
catheterization site is important when presented with a hypotensive patient. Overly aggressive venous
compression may actually compromise desired arterial flow to the distal limb, sabotaging your efforts to
promote venodilation. In a patient with pitting edema, gentle, sustained pressure to the designated
catheterization site typically suffices to disperse interstitial edema, allowing one to visualize and
successfully cannulate the vessel.
Infusion of more than one fluid type through a single intravenous catheter is sometimes indicated.
For facilities that do not stock Y-administration sets, some IV lines allow for the male end of one line to be
inserted into the foundation of an injection port, after the injection port has been aseptically removed.
Replacing catheters at fixed intervals is no longer advised, instead, monitor for signs of
inflammation (swelling, pain, redness). When replacing catheters due to concern for phlebitis, remember
the intravenous line and ideally fluids should also be changed. Troubleshooting swelling of the catheter
can sometimes be misinterpreted. Soft tissue swelling proximal to a peripheral catheter suggested fluid
accumulated secondary to phlebitis or displacement of the catheter tip. Swelling of the paw supports that
the taped used to secure the catheter is too tight. Consider cutting catheter tape and placing tape over it,
instead of re-taping the entire tape.
For euthanasia cases, remember to use rear limb catheters in paralyzed patients. If a patient
with catheter sensitivity is to be euthanized with an owner present, before the owner are patient are
united, you may occlude the catheterized vessel proximally and infuse a dilute lidocaine solution to
desensitize the vein to the pentobarbital solution. For identical reasons, patients on lidocaine infusions
for anti-arrhythmic or analgesic purposes, may not display sensitivity or pain upon palpation of the area.
Heparinizing flushes is no longer necessary for maintenance of peripheral IV catheter, instead,
0.9% NaCl alone is equally effective at preventing catheter thrombosis. Heparinized flushes are still
considered best for central line maintenance.
While avoiding indwelling urinary catheters is preferred, whenever possible, if one is deemed
necessary, they should always be connected to a closed collection system and not left open to the
environment. The major complication associated with these indwelling devices is an ascending urinary
tract infection. Meticulous handling of the urinary line and bag can assist with preventing this hospitalacquired infection. One, commonly overlooked component to the care of an indwelling urinary catheter is
to ALWAYS keep the collection bag below the patient, unless the line has been temporarily occluded. If
colonization of the system occurs, the level of contamination increases in the collection bag, and
therefore this urine should NEVER flow back toward the patient. Similarly to IV fluid lines, breaching the
integrity of a urinary collection system should be limited as much as possible. Trouble shooting the line
can commonly be performed without introducing fluid into the line. Similar to IV fluid lines, stripping fluid
retrograde or into the bag, after occluding the line, can be useful and confirming patency. Using sterile
water for foley catheter bulbs has been shown to most optimally maintain bulb inflation.
Utilizing 25g needles can prove beneficial under multiple situations. Using a 25 G needle and
capillary tubes can be useful for small volume phlebotomy (PCV/TS, platelet estimates, I-stats). Using
25g 1.5” needles for cystocentesis in animals with minimal vesicular volumes (cystitis cats, etc) increases
success rates of harvesting these smaller volumes. A NEW 25g needle can limit discomfort associated
with the administration (IV, SQ or IM) of small volume injections. Applying gentle, sustained pressure
over the proposed injection site can also desensitize nerves in the area and limit injection associated
pain. The use of a 25g needle for intravenous administration of propofol can also help prevent apnea
associated administration that is too rapid.
A culture of safety takes cognitive effort.
Accidental administration of unintended products
through indwelling lines is well detailed in the human medical literature. While these events are certainly
underreported in veterinary medicine, some precautions can help limit the risk of such errors. Amongst
these are distinct and consistent external fixation of nasal feeding (laterally over masseters) and nasal
oxygen tubes (over bridge of nose) that are unique to each tube purpose (oxygen or food administration).
Making sure that caps, which typically share common adapter ends to intravenous lines, are labelled
appropriately to prevent accidental exchange between sterile lines (urinary, intravenous) and non-sterile
lines (feeding, oxygen, etc). Having secured connections to prevent accidental disconnects that vary in
magnitude from being a nuisance (disconnected feeding tube that is being administered continuously), to
being subtle (contamination colonization of sterile IV or urinary lines), to being burdensome (nasal oxygen
lines) or catastrophic (chest tube) to the patient and caregivers.
Most endotracheal intubations are routine.
However, some basic precautions can aid in
preventing complications associated with difficult (known or unknown) intubations. Pre-oxygenation of
the patient is only inappropriate if a patient is moribund and requires emergency intubation. Use of a
laryngoscope should be routine and not interpreted as a weakness in ones skill set. Confirmation of tube
placement may consist of the “5 ations” – 1) visualization of the tube passing through the arytenoids; 2)
palpation of one tube in the neck, palpation of two tubes suggests esophageal intubation; 3) observation
of the rise of fall of the chest with provision of manual respirations; 4) auscultation of air flow in both
hemithoraces with provision of manual inspiration; 5) condensation of humidified air on expiration, if clear
ET tubes are used – and possible use of end-tidal CO2.
Intubations that prove difficult due to
oropharyngeal pathology (mass, trauma, etc), may be facilitated by the use of a stylet (commonly used is
a polypropylene catheter). Under emergency conditions it is uncommon for a patient to be appropriately
fasted, or the patient may have not eaten but contains substantial amounts of gastric fluid due to gastric
paresis or a complete GI obstruction. A modified sellick maneuver (compression of the esophagus by
external pressure strategically applied to the neck) can be beneficial for both situations, alternatively,
placement of a NG tube for gastric decompression can be useful in the latter circumstances. In addition,
placing sterile lubricant on the ET cuff, prior to placement, may help prevent “wicking” of fluid toward the
carina, should regurgitation occur under anesthesia.
Successful nasal feeding tube placement can be fostered by remembering to ventroflex the neck
as the tube tip passes through the pharynx. Gold standard confirmation of successful NG tube placement
is accomplished when gastric fluid is suctioned from the tube. Alternatively, a lateral radiograph may be
taken, which also allows for assessment of tip location.
Avoiding premature removal of a nasal feeding or oxygen tube is best achieved by suturing the
tube to the nasal planum, instead of the laterally nares, which is a more common practice. The latter may
still allow for premature removal of the tube with aggressive sneezing. Discomfort associated with the
placement of nasal and dermal sutures can be limited by the use of a 22g hypodermic needle, for 3-0
suture, instead of using the swaged-on needle. Only administer medication solutions and liquid food
through small bore feedings tubes, while medication suspensions and pureed foods should be avoided or
reserved for feeding tubes of >12 fr. NEVER administer crushed medications through small bore feeding
tubes and administration through any feeding tube should be seriously questioned.
If a tourniquet is deemed necessary, use an inflated blood pressure cuff to control hemorrhage,
avoiding the risk of pressure induced injury that can occur with more routine tourniquets.
Nothing can be more frustrating than having a perfectly good bandage bunching up or
prematurely slide off. Consider placing stir-ups in the center of the bandage, as well as those at the
bottom, providing another tethering site to secure the bandage.
Consider manufacturing a pelvic sling from disposable leashes and basic bandage material, in
place of a flat sling that supports a patient by the abdomen. The former doesn’t interfere with urinations
or cause premature or reflex urination, as the latter can.
When looking through a 40x objective lens for cytology, consider placing a drop of immersion oil
on the slide, followed by a COVERSLIP, then scan under 40x objective. This added step improves the
refraction of light to allow for improved visual clarity.
The blood contained in a full catheter stylet is sufficient to run a PCV/TS, buffy coat, plasma color,
blood glucose and azostick. If only a limit amount of blood could be collected in the stylet, then use the
50% mark on your hematocrit card, as your top line, and multiply your Hct reading by 2.
Human
glucometer
volume
results are
usually artificially low when
an
increased
red
blood
cell
(hemoconcentration or erythrocytosis) exists.
Reminder that both pulse oximetry and oscillometric blood pressure MUST have accurate heart
rates in order for the measured variable to be considered accurate.
Donning gloves during patient care can be performed for two reasons: 1) to protect the patient; 2)
to protect the environment and other patients. Your actions may differ depending on the circumstances.
Consider having “dirty” and “clean” clippers to be used on procedures deemed appropriate to limit cross
contamination of your catheter sites from your diarrhea patients and rectal abscesses. Remember to use
different cleaning brushes as well!!
Lastly, using local anesthetics for nerve blocks, don’t forget about them!
ANALGESIA OF THE EMERGENT & CRITICALLY ILL PATIENT
Todd Duffy, DVM, DACVECC
Aratana Therapeutics
Although we may not be able to prevent all of our patients from dying, we can make sure that we
alleviate their pain and suffering. Acute pain may originate from surgical or post-traumatic wounds and
injuries, the use of invasive monitoring devices, mechanical ventilation, prolonged immobilization and
nursing care procedures. The primary goal is to ensure patient comfort while preventing overmedication
and its attendant complications. Unfortunately, pain is often undertreated because of concerns about
adverse effects. However, it should be kept in mind that unrelieved pain contributes to patient distress,
evokes a stress response, complicates the management of life-saving devices, and may negatively affect
outcome. With increasing knowledge of pain physiology and its detrimental influences on the patient
(sympathetic stimulation, atalectasis, hypoxemia, immunosuppression, catabolism, arrhythmias, ileus,
etc), analgesia therapy should not be considered elective therapy. Adequate analgesia promotes normal
respiratory function and allows for appropriate expectoration, modulates the stress response, and
promotes hemodynamic stability, these in turn help prevent complications, while reducing the utilization of
patient resources.
Pain assessment needs to be performed regularly and consistently in the ICU setting to ensure that
the analgesic regimen is adequate and appropriate. This includes
evaluation of sympathetic physical manifestations or behavioral
changes (see table 1) of the patient. However, critically ill patients
may not display overt clinical signs, in addition, these signs are
relatively nonspecific in the ICU patient who may have fever,
anxiety, or physiologic dysfunction that is unrelated to pain, yet
manifests similar signs. Therefore, pain must be assumed if the
patient has clinical entities that are associated with pain
(inflammation, injuries, organ distension, diagnostics or
therapeutic procedures, immobilization or thrombosis). Other
variables that are not painful in and of themselves, but may
potentiate patient stress and possibly pain, include absence of
familiar surroundings and companionship, strange odors, loud
noises (vacuums, slamming cages doors), and bright lights.
Pain may be difficult to control with use of a single agent,
Table 1. Clinical signs a painful
animal may display
Physical manifestations
Tachycardia
Tachypnea
Mydriasis
Increased blood pressure
Behavioral changes
Posturing
Protecting, licking or selfmutilating areas
Inactivity or restlessness
Anorexia
Unexplained aggression
Vocalizing
Trembling
Splinting
Lack of grooming
Anxiety
Apprehension
Facial Expression
especially if its onset did not lend itself to preemptive
(preventative) treatment, thus necessitating combination therapy. Combination therapy, as referred to as
multimodal analgesia, allows the clinician to manage pain through more than one of the four major
mechanisms (transduction, transmission, modulation and perception) responsible for the sensation of
pain. While the term “polypharmacy” often has negative connotations, combining sedatives and
analgesics, can be logical and beneficial for the patient.
The administration of analgesics may be provided as a “therapeutic trial” to further identify if
clinical signs are related to pain. Analgesics may be administered systemically (intravenous [IV],
intramuscular [IM], subcutaneous [SQ], transmucosal, oral, or transdermal), or regionally (epidural, local
infiltration, intraperitoneal, or intraarticular). In general, the preferred route for systemic administration in
the critically ill is IV, which eliminates the concern for possible altered absorption from a deposit of
medication. Secondary routes in general order of preference are IM, SQ, transmucosal and lastly
transdermal. Obviously each medication has its own limitations based on drug approval, as well as its
pharmacokinetics.
OPIOIDS
Opioids are the backbone of analgesic therapy in the moderate to severely painful critically ill
patients, however, they are not amnestic agents. Opioids bind to a variable degree with various opioid
receptor subtypes (μ, ∆, κ) located in the brain, spinal cord and peripheral sites and modulate the
transmission (peripheral and spinal receptors) and processing (brain receptors) of nociceptive signals.
Opioids are typically classified as pure agonists, partial agonists, agonist-antagonist or full antagonists.
Although GI absorption tends to be rapid, the oral bioavailability of many opioids is limited by extensive
first-pass hepatic metabolism. Opioids are metabolized by the liver to metabolites with greater (morphine)
or lesser activity than the parent compound which are commonly renally excreted, therefore, possibly
necessitating dosage adjustment in hepatic or renal patients. Feline patients do not reliably convert
morphine to the active metabolite, making morphine a poor choice in cats. However, not all opioids
(hydromorphone) have intermediary metabolites. Pure u-agonists (fentanyl, morphine, hydromorphone,
meperidine, methadone, oxymorphone) are typically administered with standard dosages and frequency.
While intermittent IV injections provide great analgesia, they pose a risk of heavy sedation immediately
following the injection and break through pain just before the next dose. The preferred method of
intermittent injections is to titrate small, incremental dosages until a satisfactory level of analgesia is
achieved. Constant or continuous rate infusions (CRIs) minimize these peak and trough effects. Infusion
rates may be increased or decreased as needed to achieve the optimal analgesia. A traditional analgesic
end-point in cats has been development of mydriasis, but this has recently been called into question.
Pure u-agonists are characterized by rapid onset, dose-dependent analgesia, but also dose-dependent
side effects (vomiting, respiratory depression, bradycardia, hypotension, ileus and urine retention).
Vomiting and dysphoria are infrequently experienced in dogs that are already painful. The heightened
concern of respiratory depression is a reflection of experience in human medicine. This concern has been
overstated and has been an infrequently documented complication in the majority of veterinary patients
when pure u-agonists are used at recommended dosages. Respiratory depression is a concern, however,
in patients with primary CNS disease. Increases in intracranial pressure may occur secondary to
hypoventilation-induced hypercapnia and secondary cerebral vasodilation. Bradycardia is also uncommon
unless the patient is predisposed to it already from other drugs or disorders. Bradycardia is readily
reversed with the administration of atropine. Hypotension is primarily a concern in patients that are
hypovolemic and is typically readily remedied with administration of IV fluids. Morphine and meperidine
have the added side effects of histamine release, causing a dose-dependent vasodilation, possibly
precipitating hypotension. Enteral administration of minimally absorbed opioid antagonists (ie. naloxone)
may help prevent opioid-related ileus and constipation. Promising results have been observed with oral
naloxone in small preliminary studies. Urine retention occasionally warrants passage of a urinary
catheter. Decreased urine production may occur through an increase in ADH release. Hypothermia, after
opioid-induced “resetting” of the thermoregulatory center, develops secondary to panting, which may be
undesirable. Hyperthermia is more common in other species (cats). Some opioids are centrally acting
antitussives (dogs), which may not be desirable in some patients. Reversal of pure μ-agonists side
effects is generally performed by slow infusion of dilute naloxone IV. Rapid infusion predisposes the
patient to complete reversal, possibly leading to severe onset of pain. Partial reversal may be achieved by
the administration of butorphanol. Duration of action of morphine (short-term) and hydromorphone
(intermediate acting) is generally 2-4 hours and 4-6 hours, respectively. Although fentanyl has the least
negative cardiovascular influences, its ultra-short duration of action (about 20-30 minutes) lends itself to
administration via CRI.
The partial μ-agonist, buprenorphine, primarily is used for moderate pain and has a prolonged
duration of action (6-12 hours). The longer duration of action (compared to pure μ-agonists) is explained
by its high affinity for the μ-receptor, which also prevents it from being readily reversible with naloxone.
This high affinity also causes buprenorphine to antagonize the analgesic benefits of pure u-agonists.
Duration of action is also influenced by dose. Slow, peak onset of action (up to 20 minutes IV and 40
minutes following IM or transmucosal administration) may limit its use in the acutely painful patient.
Transmucosal absorption in cats is not considered as complete as earlier studies suggested, warranting
dosage increases under select circumstances. Canine TM dosing also warrants dosage increases.
Subcutaneous administered of the standard buprenorphine product is not advised due to poor absorption.
Simbadol®, FDA approved over a year ago for cats, provides analgesia of 24-hour duration using
the recommended dose of 0.24 mg/kg via SQ administration route. Approved for up to 3, once daily
doses – total of 72 hours of pain control. No other route of administration of this product can be
recommended at this time. Label advises to give one hour prior to anesthesia. Dose reduction may be
necessary in elderly, sick patients.
Butorphanol is a k-agonist and u-antagonist (referred to as a mixed agonist/antagonist).
Butorphanol is most commonly used to treat mild to moderate pain. It is characterized by a low
therapeutic ceiling which limits its therapeutic efficacy, but this also limits its respiratory and
cardiovascular side effects. Butorphanol is reversible with naloxone. While common teaching is that
butorphanol will antagonize the analgesia provided by pure u-agonists, others feel that low doses of
butorphanol may be used simultaneously with pure u-agonists to enhance analgesia. The very short
duration of action (45-90 minutes), makes this product unsuitable for analgesia under most
circumstances. Use as a sedative remains valid.
NSAIDs
Non-steroidal anti-inflammatories are commonly used to help manage pain because of the
substantial role that inflammation plays in the pain process. However, NSAIDs should be used cautiously
in those with existing or recent hypovolemia or hypotension, and those with renal, hepatic or
gastrointestinal (GI) disease. Each of the aforementioned conditions places the patient at higher risk for
GI ulceration and renal impairment. Dosage adjustments are also encouraged in patients with
hypoalbuminemia, due to the high protein binding of all currently approved NSAIDs in veterinary
medicine. Some veterinary approved NSAIDs are available in an injectable form and is a preferred route
of administration if GI motility or tolerance is questionable. Concomitant administration of NSAIDs with
food helps reduce the incidence of nausea and possibly gastric ulceration. NSAIDs generally provide
analgesia for a more extended duration than most other classes of analgesics and provide a combined
therapeutic effect when used simultaneously with opioids. Although post-operative, first dose
administration of NSAIDs may not fulfill the theoretical advantages of preemptive analgesia, it does allow
one to avoid the additional risk that the all too common, anesthesia-induced hypotensive event plays in
the critically ill patient. The most common adverse effects include nausea, vomiting, GI bleeding,
inhibition of platelet function, and renal insufficiency. The latter being of greatest concern in cats.
NMDA ANTAGONIST
Ketamine is a dissociative anesthetic that also acts as a noncompetitive N-methyl-D-aspartate
(NMDA) antagonist. Subanesthetic doses of ketamine are typically utilized if the clinician is interested in
the NMDA antagonist activity only, and helps prevent wind-up activity and central sensitization.
Intermittent bolus doses range from 0.1 – 1.0 mg/kg IV, but may also be provided by a CRI at 2
ug/kg/min. Ketamine is also absorbed transmucosally, which may be useful for chronic administration.
The latter is primarily utilized to provide pain relief following burn injuries or to provide additional
analgesia following orthopedic surgical procedures. Ketamine increases sympathetic tone in the general
population, but may act as a direct myocardial depressant in critically ill patients that are sympathetically
exhausted. Ketamine maintains laryngeal protective reflexes and produces less ventilatory depression
compared to opioids.
LOCAL ANESTHETICS
Local anesthetics commonly used in veterinary medicine are currently limited to lidocaine and
bupivacaine. These may be infiltrated into local tissues, administered regionally through specific nerve or
nerve plexus blockade, or intraarticularly, intrapleurally, intercostally or testicular. A major advantage of
these agents is that they provide analgesia without sedation or respiratory depression. These agents are
acidic and may cause pain during injection. This pain experienced may be minimized by warming the
solution to body temperature prior to administration and by adding 10% of the volume as sodium
bicarbonate for lidocaine or 5% of the volume for bupivacaine. Dilution of these agents may limit toxicity
while providing an adequate volume to achieve full regional anesthesia. Lidocaine has a more rapid onset
of action of < 2 minutes and a short duration of action (1-2 hours) compared to bupivacaine which has an
onset of action of about 20 minutes and a longer duration of action of 4-6 hours. Lidocaine may be
administered as a CRI at a dose of 1 mg/kg/hr for supplemental analgesia in dogs (cat use may be
returning). Lidocaine CRI has also been shown to provide a dose-dependent reduction in mean alveolar
concentration in dogs. Intrathoracic bupivacaine administration is contraindicated in the absence of an
intact pericardium, as it may cause acute myocardial toxicity. There is a 72-hour, sustained release
bupivacaine product being developed at this time.
ALPHA2-AGONISTS
The α2-agonists, xylazine, medetomidine and dexmedetomidine, bind to receptors in the CNS and
peripherally to produce profound sedation, analgesia and muscle relaxation. Significant cardiorespiratory
depression may occur at clinically recommended doses. Generally, only low dose administration is
sparingly utilized in critically ill patients. A decrease in blood pressure (due to severe bradycardia) and
hypoventilation are common side effects with these agents. Additional adverse effects include the
potential for vomiting, mild diuresis and increased sensitivity to sound.
NONPHARMACOLOGIC INTERVENTIONS
Patient care procedures that should always be tried first to help alleviate pain include proper
positioning of the patient with periodic turning and sufficient bedding (towels, bubble wrap, etc.), as well
as wound stabilization (fractures, etc.). Further measures that may help reduce stress include affection,
brushing, petting, keeping the patient clean and dry, giving feline patients a place to hide or allowing dogs
to feel like they are a part of the activity, in addition to owner visits.
SEDATIVES
Benzodiazepine medications are centrally acting muscle relaxants with minimal cardiorespiratory
depression. These agents are short term anxiolytics that do not have direct analgesic benefits, but may
help improve the level of analgesia provided by other analgesics. When combined with opioids that
produce neuroleptanalgesia or with ketamine to produce short-term general anesthesia. Benzodiazepines
decrease the dose necessary to induce or maintain anesthesia and are amnestic. If given alone, may
cause aggression or severe dysphoria. These agents are generally highly protein bound. Diazepam is
solubilized in 40% propylene glycol and generally does not mix well with other drugs. It should only be
given IV due to pain during IM or SQ injection. Prolonged administrations (hours to days) may produce a
delayed recovery due to accumulation of active metabolites. Midazolam is water soluble and mixes with
other water-soluble drugs (opioids, ketamine). This may be given IV, IM or SQ without substantial pain.
Phenothiazine derivatives cause selective arteriodilation at low doses, which may improve
cardiac output in some patients. However, they are best avoided in the critically ill as they may lead to
refractory hypotension. Phenothiazines have anti-emetic properties.
EPIDURALS
Epidural administration of analgesic agents appears to provide equally or more effective
analgesia than systemic administration, while limiting the systemic adverse effects (respiratory
depression, urine retention, nausea, vomiting). When opioids are administered, its lipid solubility is
directly related to its speed of onset, extent of dermatomal spread and duration of effect. Morphine is
highly lipophobic and thus has a long onset of action, extended duration of action, and significant
dermatomal spread (cephalad migration). This latter property predisposes to adverse effects such as
respiratory depression. Fentanyl with is highly lipophilic, with a rapid onset and short duration of action,
has the tendency to stay localized. This latter property may allow for more focal treatment with the use of
an epidural catheter. Critically ill patients may benefit from epidural catheter placement, therefore allowing
repeated administration of preservative-free agents.
Local anesthetics may be used in the epidural space, but they carry added risk of side effects,
specifically, hypotension, motor weakness, and inability to ambulate. Epidural administration is
contraindicated in patients with coagulopathies or receiving anticoagulant therapy, patients with systemic
infections or skin infection over the injection site, or adjacent spinal skeletal fractures that are unstable.
A coccygeal block, a simpler procedure with less risk of complications associated with epidurals,
may be considered for procedures of the perineum (feline neuters and urethral obstructions, anal sac
procedures, tail amputations, etc.).
TRANSDERMALS
Use of transdermal fentanyl is limited in the acutely ill patient due to its prolonged onset of action
(> 12-24 hours) and unpredictable absorption and effectiveness – only about 1/3 of patients have a
complete (therapeutic) response to fentanyl patches. Topical local anesthetic creams such as EMLA
(which is made of prilocaine and lidocaine) are very useful in preparing for elective procedures. Generally
takes 30-60 minutes for adequate local anesthesia.
Recuvyra® is a transdermal fentanyl solution that was recently FDA approved for use in dogs.
The solution is 1000 time more concentrated than the injectable formulation with onset of action of about
4 hours, providing analgesia for up to 96 hours. The manufacturer advises that treated dogs are kept
separate from children for the first 72 hours, with adult humans avoiding direct contact with the application
area (shoulder area) during this same time period. Individual dogs that are sensitive to the effects of
fentanyl may develop ileus and pronounced sedation. A single vial treats between 300 and 417 lbs of
total patient, with a shelf-life of 30 days once the vial seal has been broken. There is a mandatory online
training program for veterinarians before ordering the product. NOT for use in cats, due to vital
differences in skin absorption.
MAROPITANT
Some evidence that maropitant may provide some inhalant sparing effect when used at antiemetic doses. Considered best for visceral pain.
REFERENCES AVAILABLE UPON REQUEST
EMERGENCY DIAGNOSTIC PROCEDURES
Todd Duffy, DVM, DACVECC
Aratana Therapeutics
PCV/TS, BUFFY COAT, PLASMA
SUPPLIES
2 hematocrit tubes (PCV tubes)
Hematocrit reader card
Lens paper or paper towel
Critoseal putty
Blood sample
Hematocrit centrifuge
PREREQUISITE KNOWLEDGE
A packed cell volume (PCV) is an estimation of the percentage of blood that is red blood cells. A PCV is
similar to a hematocrit (Hct), but typically differs in absolute value by a few percentages. A total solids (TS) is
a measure of dissolved solute in plasma and is measured as a surrogate for total protein. The term TS is
more accurate that total protein (TP), as it also it also includes fats. Lipemia (fats in the plasma) will elevate
the total solids, making a total solids less accurate as a surrogate for total protein.
PROCEDURAL HIGHLIGHTS:
1. Wash hands.
2. Thoroughly mix the blood sample by inverting the blood tube several times. Do not shake the tube.
3. Place the striped end of the tube into the blood sample, the tube will fill by capillary action. You may
tip the sample and tube slightly to encourage filling. Fill the PCV tube about ¾ full. You can place
your finger over the end of the tube to prevent the blood from running out of the tube once it has
been filled.
4. Wipe the outside of the tube with the paper towel.
5. Seal the end with the stripe on it with the Critoseal clay. The color of the stripe on the Hct tube
indicates what is inside the tube (Red = heparin; Blue = No additives). This end has also been slightly
polished so that the centrifuge pads are not cut while spinning the tubes.
6. Prepare 2 tubes for every sample.
7. Place the tubes putty end out in the hematocrit centrifuge, with the tubes directly opposite of each
other. Make sure you have the tubes filled with similar volumes so they are balanced.
8. Screw down the locking plate over the tubes.
9. Latch the lid and press the start button.
10. Remove the tubes from the centrifuge when it has finished spinning. Keep the tubes in an upright
position to prevent the cells and liquid from sliding (the Critoseal container has small notches to
place the tubes).
11. Using the hematocrit reader card determine the packed cell volume for the sample.
a. Place the bottom of the red cells (where the red cells meet the putty) on the red “0” line
b. Slide the tube along the chart until the meniscus of the serum intersects the red “100” line
c. The height of the column of red cells is read as the percent cell volume. Do not include the
white layer between the red cells and the plasma/serum.
12. Record this number as _____%. This corresponds to the % of RBCs in the circulating blood.
13. If there is a significant white layer (buffy coat) in the tube also note this on the report sheet. This
layer contains WBCs and platelets.
14. Also note the color and clarity of the serum/plasma in the tube. The following terminology can be
used:
 Normal = clear or straw
 Icteric = yellow (liver or gall bladder problem, or possible IMHA or delayed transfusion reaction)
 Lipemic = white or cloudy (high amounts of fat in the blood)
 Hemolyzed = pink or red (RBC lysis secondary to traumatic venipuncture, during transfer from
syringe to tube, IMHA or acute transfusion reaction)
 Any of the aforementioned conditions may exist together
15. Record the results, along with the total solids. If the patient is in the ICU, then the results should also
be documented on the ICU treatment sheets.
16. Wash hands.
MANUAL DIFFERENTIAL & MICROSCOPIC BLOOD SMEAR EVALUATION
Standard CBC procedures will vary depending on in-house instrumentation. Microscopic slide
evaluation should accompany all CBCs to evaluate cellular morphology - left shifts (regenerative or
degenerative), platelet size, shape and clumping, etc - as we as for cellular abnormalities such as, nRBCs, red
blood cell parasites, schistocytosis, spherocytosis. Identifying each of these can drastically change automated
cell counts, as well as differential list and prescribed therapy.
CROSSMATCH
Standard crossmatching procedure is well explained in the literature. However, if you do blood
transfusions infrequently, performing crossmatches can be confusing, laborious and time consuming.
Consider purchasing a gel kit at http://www.rapidvet.com/xmatch.html providing a simple, sensitive, and
standardized technique.
GLUCOMETER – BLOOD GLUCOSE
SUPPLIES
Glucometer and test strips
Fresh whole blood sample
PREREQUISITE KNOWLEDGE
Blood glucose concentration is a balance between peripheral utilization and production. Normally, blood
glucose concentration is tightly controlled in the range of about 70-150 mg/dl. While many tissues have the
ability to use non-carbohydrate sources (usually fatty-acids) for energy, some tissues depend solely on
glucose for metabolism – primarily brain, erythrocytes, and renal medulla.
Since the cerebral cortex uses glucose preferentially for fuel, clinical signs of hypoglycemia relate primarily to
neurological status. Clinical signs are not usually apparent until glucose falls to <50mg/dl. Mental dullness or
obtundation can be seen early in the course, as well as ataxia and unusual behavior. Progression to coma or
seizures occurs if the hypoglycemia is not corrected, and is most likely when glucose concentration is
<20mg/dl. Additional clinical signs include tremors, mydriasis, vocalization, restlessness or nervousness.
Obviously, signs related to any underlying or comorbid conditions may accompany signs of hypoglycemia.
Whipple’s triad refers to the clinical criteria needed to diagnose hypoglycemia – compatible symptoms,
documented hypoglycemia and alleviation of symptoms by the restoration of euglycemia.
Most point-of-care glucometers are only accurate within +/-15% of the actual value, and generally read
lower than the actual value to discourage insulin overdose in diabetic patients.
Differentials for hypoglycemia
Lab error (operator error or high PCV)
Sepsis
Insulinoma/other neoplasia
Insulin OD
Hepatic failure
Hypoadrenocorticism
Neonatal/toy breed
Hunting dog hypoglycemia
+/- eclampsia, polycythemia, bacterial endocarditis, pancreatitis, hypopituitarism
Differentials for hyperglycemia
Diabetes mellitus
Stress
Critical illness
For a mildly symptomatic hypoglycemia animal with a functional GI tract, feeding a meal may suffice as
therapy. Patients with altered mental status should not be fed. More severe signs of hypoglycemia should be
managed with IV bolus 50% dextrose, 0.5-1 ml/kg (0.25-0.5 gm/kg). Dilution to 25% with sterile saline and
slow administration reduces the chance of phlebitis due to the high tonicity of 50% dextrose. Alleviation of
signs is generally seen within 1-2 minutes, but may be longer dependent on how long the hypoglycemic crisis
lasted. Once signs of hypoglycemia have abated to the point that the patient is alert, a meal should be
offered unless contraindicated. If there is suspicion of persistent hypoglycemia, which is the case for most
patients, administration of supplemental dextrose in IV fluids is recommended. A solution containing 2.5% to
5% dextrose generally suffices to maintain euglycemia. Concentrations higher than 5% to 7.5% should be
administered in a large-bore central line to reduce the risk of phlebitis. For cases of symptomatic
hypoglycemia refractory to glucose supplementation, glucagon can be administered, although it is rarely
needed.
PROCEDURE
1. Wash hands
2. Place the sensor (there is one in the laboratory area and one in the isolation area) on a clean, flat, dry
surface away from drafts with the display window facing upward.
3. Obtain a test strip from the test strip container.
*Do not use a test strip if it is expired, bent, scratched, wet, or damaged in any way.
4. Gently push the test strip into the sensor until it stops. The sensor will turn on and indicate when it is
ready to receive a blood sample.
*Do not touch the target area of the test strip.
5. Obtain a non-anticoagulated blood sample.
6. Place a bandage over the venipuncture site, especially if patient is getting repeated sampling (ie. glucose
curve, etc)
7. Apply a drop of whole blood directly to the target area of the test strip. Do not touch the target area
while apply the drop of blood. The blood drop will spread onto the target area by itself, forming a dome
that covers the target area completely. *It is very important that this step is done correctly to obtain
accurate results. NOTE: in patients with a high normal or an elevated PCV, results may be more accurate
if performed on a plasma sample from a PCV tube.
8. The countdown begins and the blood glucose result is displayed after a few seconds.
9. To turn off the sensor, press and release the button.
10. Remove the test strip and discard it properly.
11. Wash hands
DOCUMENTATION
Record the results on the patient’s chart
Notify the primary clinician if glucose reading is < 80 or > 250, or at any other time as directed by the
primary clinician.
URINALYSIS
SUPPLIES:
Non-sterile gloves
Urine tube
Coverslip
Plastic pipette
Volu-sol stain
Fresh urine sample
Multi-stick test strip
Glass slide
Refractometer
Timer
PROCEDURE:
1. Wash hands and don gloves (this is especially important if the patient may have an infectious disease –
ie. Leptospirosis)
2. Urine samples must be less than 12 hours old (preferably less than one hour old if concerned about the
presence of crystals). If the sample cannot be tested within 30 minutes it should be refrigerated (unless
looking for crystals).
3. A urine sample may be collected by the following 3 methods:
a) Free catch = urine is voided in the normal fashion and a midstream sample is caught in a clean
container
b) Cystocentesis = urine is obtained by inserting a needle through the abdominal wall, directly into the
urinary bladder; use 25 g needle for patients with very small vesicular volumes
c) Catheterization = a catheter is inserted into the urethra, utilizing sterile technique, and into the
urinary bladder
NOTE: for urine cultures, cystocentesis is the gold standard collection technique with urinary
catheterization being the best alternative and a voided sample being rarely used.
4. Specific gravity (S.G.) - place 1 drop on the glass surface of the refractometer. Carefully close the cover.
5. Hold the refractometer to a light source (as you would a kaleidoscope). Read the scale to the far right. If
the “line” of urine is above 1.040 (1.060 on some refractometers) record the results as “>1.040”.
6. Dipstick evaluation - remove 1 multi-stick from the bottle and place it on a flat surface (the sink is best).
7. Place 1 drop of urine on each test pad of the stick – it is strongly recommended that urine from different
test pads do not mix, as this may alter the results). Note the time for each test on the bottle.
8. When the appropriate time has passed, hold the test strip to the bottle and record each of the results.
9. Sediment examination - place 1-2 mls of urine in a clean conical shaped tube. Put this tube and a
balance tube (filled with an equal amount of water) in the centrifuge.
10. Centrifuge the sample for 10 minutes at 1000-1500 rpms
11. When the urine has finished spinning, you will see that it has separated into 2 portions, the supernatant
(liquid) and the pellet (sediment in the bottom of the tube).
12. Pour off the supernatant being careful not to disturb the sediment.
13. Loosen the sediment in the bottom of the tube by flicking the tube with your finger. Make sure the
entire pellet is back in solution before taking a sample for the slide. If this is not done, heavy elements
such as casts may remain in the bottom of the tube.
14. Check with whomever is reading the sample to see if they want the sample stained with the Volu-sol
stain. If so, ask if they stain directly on the slide or in the tube. If you are not sure, make an unstained
slide (first) and a stained slide (second).
15. With a plastic pipette remove a small amount of sediment and put a drop on a clean slide.
16. Cover the drop of urine with a coverslip. The coverslip should not float. If it does, carefully slide the
coverslip to one side.
17. Read the sample on 10X and 40X to thoroughly evaluate the sample.
18. If the amount of sample provided is very small (<1cc), you may spin the sample before performing the
other tests. Once the sample has been spun, carefully remove a small amount of the supernatant with a
pipette and use this to do the S.G. and multi-stick.
19. Suspicion of bacteriuria is best confirmed through Diff-Quick staining of a dried prep, or less ideally Gram
staining.
20. Discard any disposable materials and remove gloves
21. Wash hands
22. Document results
23. Notify the DVM on staff of any emergent abnormal results (ie. ketones, bacteria, etc)
* It is important to try and use a standard amount of urine (1-2 mls) for centrifugation. If you use a large
amount of urine and then re-suspend into a very small amount of a supernatant, the amount of
cells/organisms/debris will be artificially increased. The opposite will happen if you use a short sample.
THORACENTESIS
SUPPLIES
Clean clippers
Chlorhexidine scrub
Alcohol
35 or 60 cc syringe depending on patient size
3-way stopcock
Gloves
Extension and needle or peripheral catheter
OR butterfly catheter
24 G – puppies or kittens
22 G – cats, small dogs
20 G – medium to large dogs
18 G – large to extra large dogs
Bowl and syringe or graduated cylinder for quantifying
Purple top tube, red top tube and culturette
Analgesics/sedation +/- local anesthetic
Assistant(s)
PREREQUISITE KNOWLEDGE
Knowledge of normal anatomy, as well as understanding principles of aseptic technique and infection
control is needed.
Thoracocentesis, or chest tap, is a common ED procedure and is generally performed to remove either
fluid or air from the thoracic cavity. This procedure may be a diagnostic (to determine what type of fluid is
present) or therapeutic (to remove the fluid or air so the patient may breathe easier) one. Most patients
undergoing thoracocentesis need sedation/analgesia +/- local anesthesia and should be handled with
minimal restraint. For sedation, a combination of an opioid and a benzodiazepine, such as midazolam (a
combination referred to as a neuroleptanalgesic), will usually suffice. Any patient having a therapeutic
thoracocentesis should be provided with oxygen supplementation during the procedure, since they are
typically in respiratory distress. Due to the fragility of these patients, secured venous access is encouraged in
the event the patient’s clinical condition rapidly deteriorates.
The primary risks associated with thoracocentesis include hemorrhage and pneumothorax. The risk of
pneumothorax is greater with long-standing pleural effusion (such as with chylothorax) since many of these
patients will have fibrosing pleuritis, which is prone to leakage. The main relative contraindication to
thoracocentesis is an underlying thrombocytopenia and/or coagulopathy.
Fluid samples recovered from thoracocentesis should be quantified and the side of the chest they were
recovered from recorded. A portion of the sample should be placed in a purple top tube (which preserves the
cells for fluid analysis and cytology) and a red top tube and/or culturette for bacteriology. A transudate is
typically associated with systemic disease, where an exudate is typically associated with localized disease.
PROCEDURE
1. Administer oxygen and sedation as directed by the primary clinician
2. Wash hands and don gloves
3. Allow the patient position itself, such that they are comfortable and unlikely to move.
4. Clip the appropriate side(s) and area of the chest. NOTE: this is typically determined by auscultation
(absence of lung sounds) or on radiographs.
5. Shave and prep the area(s), alternating chlorhexidine scrub with alcohol. Generally repeated a
minimum of 3 times – 2 minute contact time.
6. The actual thoracocentesis procedure can be performed in several different ways (hanging drop
technique, ultrasound guided, etc). With the stopcock positioned “off” to the open female port
(allowing the syringe and the extension set or butterfly to be “open” to each other), insert the
needle cranial to the nearest rib (to avoid the neurovascular bundle on the caudal aspect of the rib),
usually somewhere between the 6-10th intercostal spaces. NOTE: generally recommendations are to
tap in the caudodorsal region for air and in the caudoventral region for fluid, if the patient is in the
sternal position. NOTE: the presence of a thick thoracic fluid may warranted using a fenestrated
catheter instead of a needle.
AIR
FLUID
7. Once fluid or air is obtained, flatten the needle against the inside of the pleural cavity if possible to
avoid damage to the lungs or heart. In most acute cases, it is recommended to remove all of the
fluid or air present. In some animals with chronic pleural effusion, removing only a portion of the
fluid is recommended to prevent the formation of re-expansion edema.
8. As long as sterility was not breached during the initial procedure, save the apparatus (with a new
needle on it) in case the patient needs a repeat thoracocentesis in the following 12-24 hours.
9. Label and submit the appropriate samples.
10. Measure and document total amount of fluid obtained, and from which hemithoraces.
11. Wash hands and discard remaining fluid (after owners see it, if they are interested).
12. The decision to perform follow-up radiographs, after thoracocentesis has been completed, should be
individualized for each patient. The main indication for follow-up radiographs is if one is looking for
an etiology (mass, bulla, etc) that precipitated the fluid or air to collect.
13. Monitor patient closely over the following minutes to days to help assess for recurrence or
complications. Monitoring parameters include, but aren’t limited to:
a. Respiratory rate
b. Respiratory pattern
i. Pleural space disease typically has a “dysynchronous” pattern
c.
Thoracic auscultation
i. Crackles may support edema from CHF or reexpansion pulmonary edema
ii. Decreased or absent lung sounds may support reaccumulation of fluid or air
d. Anxiety or restlessness
NOTE: Thoracic radiographs may be requested immediately or hours after the procedure. Without concrete
clinical indications, thoracic radiographs are not necessary after routine thoracocentesis.
DOCUMENTATION
Type and amount of sedation, if utilized (verify any controlled substance was logged appropriately)
Quantity and character of fluid and/or air, and from which hemithorax it was obtained from
Laboratory samples submitted
Complications, if any:
Obtaining blood if aspirating non-hemorrhagic fluid or air
Obtaining air if removing fluid only
PERICARDIOCENTESIS
SUPPLIES
Clean clippers
Chlorhexidine scrub
Alcohol
35 or 60 cc syringe depending on patient size
3-way stopcock
Gloves
Peripheral catheter – over the needle typically, but through-the-needle used by some
Bowl and syringe or graduated cylinder for quantifying
Purple top tube, red top tube and culturette
Analgesics/sedation +/- local anesthetic
Assistant(s)
PROCEDURE
1. Administer oxygen and sedation as directed by the primary clinician
2. Wash hands and don gloves
3. Patient may be in either lateral recumbency, or sternal position, depending on clinician preference
and patient tolerance.
4. Clip and aseptically prepare (generally repeated a minimum of 3 times – 2 minute contact time) the
right 5th - 7th intercostal spaces. Right side chosen due to the presence of a cardiac notch in the
pulmonary parenchyma, as well as the absence of coronary vessels in this area.
5. Patient is prepared using either analgesia/sedation and/or with the use of a lidocaine block over the
appropriate intercostal spacing.
6. Using a long over-the-needle catheter (preferred) or through-the-needle catheter, advance through
the skin and intercostal muscles, into the pericardial sac (generally just ventral or at the
costochondral junction). Advancement of the catheter system should be stopped if cardiac
pulsations or ventricular arrhythmias are noted. Fluid may be drawn slowly by syringe, or sometimes
it is best to allow passive drainage into an open container.
NOTE: Procedure is best performed with the aid of an ultrasound, less ideally, while monitoring an ECG
for evidence of arrhythmias (suggestive of cardiac trauma).
The presence of a thick thoracic fluid may warranted using a fenestrated catheter instead of a needle.
7. Effusion collected is typically bloody, a clear fluid is less common. The latter may be from the
thoracic space if pleural effusion is present. If concern arises regarding intracardiac puncture,
monitor hemorrhage effusion for clotting (pericardial effusion does not clot).
8. Vital parameters should all normalize if procedure was successful without complications.
NOTE: Cardiopulmonary arrest during or immediately following procedure warrants open-chest CPR.
9. Label and submit the appropriate samples – cytology, occasionally culture.
10. Measure and document total amount of fluid obtained.
11. Wash hands and discard remaining fluid (after owners see it, if they are interested).
12. Monitor patient closely over the following minutes to days to help assess for recurrence or
complications. Monitoring parameters include, but aren’t limited to:
a. Heart rate
b. Audibility of heart sounds
c. Pulse quality
d. Mucous membrane color
13. Flashing pericardium with ultrasound probe is most sensitive means to assess for recurrence.
DOCUMENTATION
Type and amount of sedation, if utilized
Quantity and character of fluid
Laboratory samples submitted
Complications, if any:
Obtaining blood if aspirating non-hemorrhagic fluid, a coagulating hemorrhagic effusion or air
Significant arrhythmias
TRANSOROTRACHEAL / TRANSTRACHEAL WASH
SUPPLIES:
*Sterile lubricant
*Sterile endotracheal tube – conservative size for patient
*Laryngoscope
*Sterile argyle or red rubber catheter or suction device
Sterile gloves
Three aliquots of sterile isotonic crystalloid solution
*IV catheter
*Short acting anesthetic agent (propofol or alfaxalone +/- low-dose opioid and/or benzodiazepine)
Supplemental oxygen
EDTA tubes for cytology
Plain tube or culturette for bacterial culture
Monitoring equipment (pulse oximeter, ECG)
Anesthetic machine or AMBU bag – in the event of hypoventilation
***Local anesthetic (eg, lidocaine)
***Clippers
***Chlorhexidine scrub
***Alcohol
***Through-the-needle catheter (preferred) or needle and polypropylene or red rubber catheter (small
enough to feed through the needle)
*Specific to TOTW
***Specific to TTW
In most cases of suspected lower airway disease, the technique for pulmonary sample collection is a
tracheal wash. Most candidates will have a productive cough, presence of a dry cough is more likely to yield a
poor quality sample (alternative sampling technique is a bronchoalveolar lavage). Tracheal wash samples are
useful for airway cytologic evaluation and bacterial culture and sensitivity testing, generally not used for
patients with pulmonary masses (under most conditions, these are best sample by fine needle aspiration).
Once airway sampling is deemed indicated, selection between a TTW and TOTW is commonly
dependent on patient variables (size, neck conformation, tolerance to handling, etc.) and clinician
preference. TTW are general reserved for larger, more tolerant patients. Most patients are experiencing
some level of respiratory compromise
While detailed procedural notes are not included, pearls of wisdom are shared. Pre-oxygenation
should be performed prior to both procedures. Infusion aliquots generally range between 3-15 mls,
depending on patient size. Coupaging patient immediately following infusion helps stimulate a cough reflex.
Under the best of circumstances, usually less than ½ of the infused fluid is recovered. Good quality samples
are typically heterogenous with floating pools of phlegm evident. In addition to samples being submitted to
an outside reference laboratory for cytology and culture, in-house cytology is strongly advised. Close patient
evaluation, during recovery is a must, with continued oxygen supplementation strongly advised.
BLOOD PRESSURES MEASUREMENTS
Traditionally, the Doppler blood pressure monitor has been the most accurate NIBP technique to
measure blood pressure. The crystal on the Doppler unit picks up flowing blood and translates it into an
audible sound. When the cuff pressure is less than the pressure of the blood beneath the cuff, blood begins
to flow and the sound can be picked up by the crystal distal to the cuff. The Doppler can only accurately
measure SAP.
The oscillometric technique measures both SAP and DAP, while it calculates the mean arterial pressure
(MAP). Oscillometric means that it measures blood pressure by detecting tiny vibrations (oscillations) in
those blood vessels compressed under the cuff, as the heart beats.
While certain limitations are inherent in the oscillometric technique, which makes this technique less
than ideal for some emergency department applications. It is best for monitoring large, stable, patients that
do not have altered pulse pressures due to the presence of arrhythmias. Its performance at the extremes of
blood pressure are questionable and it gives variable results in cats.
The Doppler is ideal for blood pressure measurement in the ED and ICU due to its accuracy and use in
patients of varying sizes and at various levels of blood pressure. For cats, however, it may give variable
results, and some authors recommend compensating for this by adding 10-15mmHg to readings in this
species.
Regardless of which technique is utilized, stress is a clinically significant factor that must be minimized to
obtain meaningful readings. Measurements should be obtained only in calm, minimally restrained, and
motionless patients. It is best to perform the measurement in an area of the clinic that will minimize anxiety
(i.e. avoid noises, restraint or odors that may induce anxiety) after the animal has acclimated itself for 5-15
minutes. If possible the owner should be present.
Patient position is the one in which the animal is most comfortable. A towel under the patient adds to
overall comfort. It is best to have the cuff at the same level as the heart. Therefore, in a standing patient,
cuff placement on the tail is best. The limb being utilized for measurement should be in extension. If the
limb is flexed, the blood flow may be impaired, giving falsely low readings.
General selection of cuff size is cuff width ~40-50% of limb or tail circumference
Limb circumference = 10cm
Choose a 4 cm cuff
Inaccurate results can be divided into operator error OR patient variables:
Operator errors
a. cuff size
i. cuff too small= falsely high reading
ii. cuff too large= falsely low reading
b. improper cuff location (over joint, cuff balloon not centered over artery if using oscillometric
technique)
c. kinking of cuff hoses
d. undetected leaking cuff, hoses or connectors
e. cuff not at the level of the heart
f. external cuff compressions (external motion artifact)
i. bumping cuff, etc
Patient variables
a. stress or “white coat” effect
b. internal cuff compressions (internal motion artifact)
i. shivering
ii. seizures
iii. limb movement
c. extremity position causing vascular compression
d. edema of the extremity used for measurement
e. arrhythmias (if using the oscillometric technique)
The most common causes are incorrect blood pressure results are inexperienced operator or incorrect cuff
size.
General clinical indications for blood pressure measurements to be obtained are:
a.
b.
c.
d.
e.
f.
g.
h.
i.
j.
k.
trauma patients or those experiencing blood loss
anesthesia (including pre and/or post-anesthesia)
retinal detachment
neurologic signs
proteinuria
epistaxis
heart murmur
renal disease
obesity
endocrinopathies (hyperthyroidism, Cushing’s disease, pheochromocytoma, etc)
history of systemic hypertension
PROCEDURE
Doppler
1. Wash hands and find a quiet area, away from loud animals or distractions. Ideally the patient should
be acclimated for 5-10 minutes. Allow the owner to present if possible.
2. Decide on the location that the measurement will be taken.
3. Place cuff around the limb or tail, proximal to the region that the Doppler probe will be placed. Tape
the cuff in place.
4. Attach one end of cuff tubing to the manometer and the other end to a 3-way stop-cock that is
closed off toward the cuff. NEVER tie or clamp tubing directly.
5. Shave an area immediately proximal to the tarsal pad or carpal pad or on the ventral surface of the
tail about 4-5 cm away from the body.
6. Place coupling gel on the transducer and then position the transducer, in a parallel position, over the
artery.
7. Turn the unit on and adjust the volume if needed. Using the maximum volume that is comfortable
for both you and the patient is preferred. You may hold the transducer in place or tape it to the limb
and listen for the “swooshing” sound of blood flow.
Note: Holding the probe rather than taping it to the limb can provide variable readings as changes in pressure
over the vessel can influence the presence/absence of flow.
8. Inflate the cuff with the sphygmomanometer to 30-40 mmHg above the point that blood flow is
occluded (no audible pulse or “swooshing”). Please note that filling the pressure too rapidly may
startle the patient.
9. Slowly reduce the pressure on the manometer by using the trigger. The pressure at which blood
flow (“swooshing”) returns, is the SAP.
10. Take a minimum of 3 readings that are similar (< than 15% variation maximum).
11. Turn the unit off unless instructed to leave it on the patient to hear audible pulse rate.
12. Record the average systolic that was obtain, the cuff size used and the location of the cuff.
NOTE: headphones may be used to minimize environmental noise and avoid scaring the patient if artifact is
experienced through the Doppler speaker.
ANOTHER NOTE: The Doppler crystal (transducer) is very fragile (and expensive to replace) so care should be
taken to avoid damage. Clean only with water and do not drop or allow it to strike against something solid.
It should be protected when stored.
FINAL NOTE: Use of ultrasound gel is essential. Do not use K-Y jelly, ECG paste, baby oil or alcohol. The
latter products may cause deterioration of the resin surface of the transducer.
Oscillometric
1. Wash hands and find a quiet area, away from loud animals or distractions. Ideally the patient should
be acclimated for 5-10 minutes. Allow the owner to present if possible.
2. Decide on the location that the measurement will be taken.
3. Place the cuff around the limb or tail, over the artery. The cuff bladder should be positioned over an
artery (area says “artery” and its boundaries and signaled by the indicator lines), this is where pulse
waves/vibrations that occur as blood flow passes under the cuff, are detected. Tape the cuff in place.
4. Attach to the cuff tubing to the machine cord.
5. Turn on the machine & press the BP button to obtain an automatic blood pressure measurement.
6. The cuff is inflated and deflated automatically.
7. Systolic, mean and diastolic pressures are obtained.
8. Confirm that the pulse rate obtained by the unit matches the heart rate obtained by either palpation
or auscultation. For maximum accuracy, these numbers must match.
9. Take 5 readings, discard the high and low values, then average the remaining 3.
10. Wash hands.
NOTE: Cleaning blood pressure cuffs is important between patients, but fluid should never be allowed to
enter in the tubing, as this can cause dysfunction and failure of the oscillometric units.
YET ANOTHER NOTE: If the blood pressure is high, then consider rechecking it 1-2 more times over the
ensuing hours to ensure that the hypertension is real. The exception would be in those animals with obvious
signs compatible with hypertension (i.e. retinal detachment or hemorrhage, neurologic signs, etc.), in which
case treatment for the hypertension should be treated immediately.
FINALLY, THE LAST NOTE: If the blood pressure is low, the doctor should be notified and appropriate therapy
implemented. Blood pressures should be rechecked until the pressure is documented to be normal for
several measurements.
INTERESTING CASES IN EMERGENCY AND CRITICAL CARE - PARTS 1 & 2
Todd Duffy, DVM, DACVECC
Aratana Therapeutics
CASE #1
History:
Physical Exam:
Diagnostics:
Therapy:
“Kayla”
4 yr F/S Maltese
CASE #2
History:
Physical Exam:
Diagnostics:
Therapy:
“Jack”
5 yr M/N Greyhound
CASE #3
History:
Physical Exam:
Diagnostics:
Therapy:
“Morsel”
14 yr M/N Italian Greyhound
CASE #4
History:
Physical Exam:
Diagnostics:
Therapy:
“Tasha”
2 yr F/S Australian Shepard
CASE #5
History:
Physical Exam:
Diagnostics:
Therapy:
“Mondavi”
7 yr M/N Shih Tzu
CASE #6
History:
Physical Exam:
Diagnostics:
Therapy:
“Winston”
12 yr MN Shepherd-X
CASE #7
History:
Physical Exam:
Diagnostics:
Therapy:
“General ”
MONOCLONAL ANTIBODY THERAPY – DON’T BE IMMUNE TO THE BENEFITS
Todd Duffy, DVM, DACVECC
Aratana Therapeutics
The concept of Antibody discovery and characterization has a history as long as immunology
itself, dating back to the late 19th century. During this time period, Von Behring and Kitasato laid the
foundations of humoral immunity when they discovered that serum produced substances that
neutrolized diphtheria toxin. Prior to the beginning of the 20th century, Ehrlich described that blood
cells produced side chains that reacted specifically against the toxins, much in the same way as a key to
its lock.1 In the mid-twentieth century, the term “toxin” was replaced by “antigen”, followed shortly
thereafter was the cell origin of antibodies being B cells and plasma cells. The next step was when Jerne
proposed that antibodies pre-existed in the organism.
STRUCTURE AND BASIC CHARACTERISTICS OF
ANTIBODIES
DEFINITIONS
Each antibody (Ab) molecule is made up of 4
Paratope - the site on the Ig at which the
chains: 1) two light chains; 2) two heavy chains. Each
antigen binds.
respective pair is identical to the other and is joined
by disulphide bridges, forming a “Y” structure.
Epitope - the site on the antigen that is
Antibodies have 2 basic functions: 1) recognize and
bound by the paratope.
bind antigens, through the two amino terminal ends –
Idiotype(s) - individual determinants
fragment antigen binding domain (Fab region); 2)
contained within the V domains.
effector function (such as activation of complement
or binding to Fc receptors on various cells), carried
Isotypes - common determinants, specific
out via the carboxyl terminal end of the heavy chains
to the constant portion, responsible for
– fragment crystallizable domain (Fc domain). Both
defining immunoglobulin class.
the light and the heavy chains have a variable region,
as well as a constant region. The variable portions of
Cross-reactivity - when an antibody binds
the light chains and the heavy chains are juxtaposed,
divergent antigens that share equivalent
determining antigen specificity (complementarityor similar epitopes.
determining region – CDR), and are duplicated,
yielding two antigen binding sites in each antibody molecule. The constant regions of the light chains
differ according to whether they are κ or λ light chains. In contrast, the constant regions of the heavy
chains determine which of the five main immunoglobulin (Ig) class or isotype (IgG, IgM, IgA, IgD, and IgE)
they belong to, with some classes having subclasses (IgA and IgG). Some Ig are secreted as monomers
(IgG, IgD, IgE), some as dimers (IgA) and others as pentamers (IgM). IgG is the predominant isotype
found in the body and has the longest serum half-life of all Ig isotypes.
As described above, the effector function of IgG is determined by the Fc region. This region may
bind to plasma proteins, such as complement, triggering complement-dependent cytotoxicity (CDC). IgG
Fc region may also bind with FcγR (subclasses exist), this is in contrast to engagement between IgA and
IgE and FcαR and FcεR, respectively. Binding with FcγR on effector cells (phagocytes, B cells, NK cells,
etc) can elicit another key effector function for IgG Abs known as antibody-dependent cellular
cytotoxicity (ADCC). Effector cells destroy the antibody coated target via phagocytosis, opsonization or
cytotoxic cell killing. Human FcγR polymorphisms have been documented and may influence response
to mAb therapy. In addition to FcγR, Fc regions also bind FcRn, which influences pharmacokinetics (see
below).
ENDOGENOUS IMMUNOGLOBULIN SYNTHESIS
Immunoglobulins are glycoproteins that are secreted by plasma cells, which are derived from
lymphocyte B cells of the immune system. B-cells recognize a host of protein and non-protein antigens
(in contrast to T-cells) and become activated when they come into contact and bind their specific
antigens. Following activation, B cells migrate to follicles in lymph nodes and the spleen, where they
mature into plasma cells by means of somatic hypermutation with even more affinity for the antigen.
Those with the greatest affinity for the antigen survive. Each plasma cell clone produces a single type of
antibody.
MONOCLONAL ANTIBODY PRODUCTION
Immunoglobulin based therapies, such as intravenous (polyclonal) immunoglobulin (IVIg), have
been advocated by some for patients experiencing immune-mediated conditions, who do not respond
to conventional anti-inflammatory therapy. This IVIg is obtained from pooled plasma from healthy
human donors. While the first FDA approved monoclonal antibody (mAb) to treat illness in humans was
introduced in 1986, cost has been the greatest barrier in this therapy being pursued in veterinary
medicine. Recent technological advances have allowed monoclonal antibody therapies to enter into
clinical trials in veterinary medicine. The indications being pursued are typically chronic conditions,
requiring repeated and sustained administration (rarely curative).
The modern era of therapeutic monoclonal antibodies originated with the invention of the
murine hybridoma technology. This was discovered in the 1970s by Milstein and Köhler, who were
awarded the Nobel Prize, following publication of their work. This murine hybridoma model, was
founded on three key principles: 1) each B cell produces only one antibody; 2) the lymphocytes used for
the fusion are derived from donors that were sensitized with specific immunogens; 3) B cells can be
immortalized into immunoglobulin-secreting in vitro cell lines. This technology produced murine mAb,
which were the first mAbs approved by the Food and Drug Administration (FDA) for use in humans.
Unfortunately, immunogenicity and short serum half-life (via production of human, anti-murine Abs),
lack of effector functions, and hypersensitivities (infusion related allergic reactions), were common side
effects.
To overcome side effects, genetic engineering techniques where implemented in the 1980s to
graft the entire antigen-specific domain of a murine antibody onto the constant domains of a human
antibody, referred to as chimerization.
Technology for the manufacturing of hyperchimerized or humanized Abs soon followed, where
only the hypervariable regions of the light and heavy chains are murine. Humanized mAbs are now the
fastest growing group of biotechnology-derived molecules in clinical trials currently2.
Most recently, fully human mAbs, produced in
transgenic animals carrying human Ig genes or phages
systems. Human monoclonal antibodies offer more
advantages as they are less antigenic and better tolerated,
SUFFIX REVEALS mAb GENERATION
Murine ends in – omab
Chimeric ends in – ximab
Humanized ends in – zumab
Human ends in – mumab
while having longer circulation times in comparison to chimeric mAbs.
In addition to being focused on new product development, current human research is focused
on improving Ab efficacy (limiting immunogenicity, improving Ag:Ab binding affinity, effector functions)
and pharmacokinetics .
Antibody proteolysis enables production of different fragments: 1) one constant fragment (Fc);
and 2) single dimeric Fab fragments joined by the hinge – F(ab’)2; or 3) two independent Fab fragments –
F(ab). These fragments make it possible to overcome some of the problems related to the complete
molecule of the antibody, to improve avidity and enhance binding to certain targets, as well as limit
immunogenicity (absences of Fc domain). Examples of such products in veterinary use are Digibind Fab
for digoxin overdose and CroFab antivenom for snake bites.
APPLICATION OF MONOCLONAL ANTIBODIES IN DISEASE
While monoclonal antibodies (mAbs) have revolutionized the diagnosis of many diseases (flow
cytometry, ELISA, etc), they are a relatively new innovation, increasingly utilized to aid in the treatment
of numerous disease states. Administration of Abs (monoclonal or polyclonal) to a patient, is a form of
passive immunity. While once reserved for patients with primary immunodeficiency disorders, Ab
therapy is now being considered for many different conditions. The fundamental basis of using mAbs as
therapeutics is based on the presence of a specific antigen that can be targeted, to mediate alterations
in ligand / antigen or receptor function (such as an agonist [inducing intracellular signals – apoptosis,
etc.] or antagonist function [keeping soluble factors from binding to receptors]), modulating the
immune system to induce cytolysis (ADCC, CDC), or delivering a specific drug that is conjugated to an Ab
that targets a specific antigen (payload delivery). As such, areas of intense focus are cancer (directed at
cell surface antigens, epidermal growth factor - EGF, or vascular endothelial growth factor - VEGF),
autoimmune conditions (anti-cytokine), and transplants, while less common conditions include
cardiovascular disease, inflammatory (allergy, asthma) and infectious disease, as well as treatment of
drug poisoning. Since the first mAbs were approved (US 1986 – muromonab-CD3), this therapeutic class
has become the fastest growing group of pharmaceutical molecules, and has expanded to cover Abs, Ab
fragments and Ab-fusion proteins. There are over 250 therapeutic mAb undergoing clinical trials at this
time.
Next-generation mAbs can be derived through two broad modification: 1) modification of
existing antibody properties (modulation of Fc-mediated functions); 2) enhancing antibodies with new
capabilities (examples being bispecific antibodies or antibody-drug complexes). Bispecific antibodies
are capable of binding to two different antigens or two distinct epitopes on the same antigen. Antibodydrug complexes are formed through conjugating the mAb with small molecules (drugs), through toxins,
radiation drugs or cytokines. Pharmacologically, ADCs equip small molecules with the PK and PD
properties of the antibody molecule.
Monoclonal Abs have key features of precision (high specificity and affinity for antigens –
selective binding) and local confinement of the large Ab molecule (~150 kDa) to the circulatory system
and interstitial spaces, which is unique when compared to the majority of commonly used drugs ( <1
kDa) that commonly have intracellular influences.
PHARMACOKINETICS AND PHARMACODYNAMICS
While most mAbs are administered intravenously (IV), some have been evaluated for
intramuscular and subcutaneous use. The latter are anticipated to be associated with an improved ease
of administration, however, this may be associated with a lower bioavailability compared to IV use.
Subsequent delay in absorption may be associated with decreased risk of infusion hypersensitivity
reactions.
Distribution of mAb is generally low and can be influenced by the tissues (vascularization,
intracapillar:interstitial pressure gradient) and characteristics of the mAb (affinity, MW). Relevance of
this varies with type of disease being treated. Penetration of mAb into tumors can be limited by
“binding site barrier”, while this partially counteracted by increasing mAb dose, therapeutic potential is
best enhanced by combining with conventional chemotherapy. Plasma mAb is generally excluded from
the central nervous system.
Elimination of mAb is predominantly influenced by binding FcRn receptors. FcRn is expressed in
tissues involved in perinatal immunity transmission, in adults, FcRn is largely expressed in the vascular
endothelial cells (the most endocytically active tissue in adults), and to a lesser extent on monocyte cell
surfaces and a small subset of tissue macrophages. Monoclonal Abs are internalized in low pH
endosomes, where binding of the Fc domain with the FcRn is promoted. The bound mAb is then
recycled to the cell surface and released, while excess, unbound, undergoes degradation in the
lysosomes.
The biological half-life of the Fc fragment has shown to be similar to that of an intact antibody,
whereas the Fab fragments are cleared quickly. The biological half-lives of isotypes vary, with the
average half-life of IgG1, IgG2 and IgG4 being 21 days, while that of the IgG3 being 7 days. The
pharmacokinetic behavior of different subclasses of IgGs has been shown to be dependent on the Fc
region, due to its different interactions with FcRn. Clearance of Abs is primarily through proteolytic
catabolism.
While much is to be learned about mAb pharmacokinetics, parameters can be
influenced by tumor burden, presence of shed target, and theoretically serum concentrations of
endogenous IgG (multiple myeloma).
ADVERSE EFFECTS
Adverse events are generally mild, and self-limiting and can be classified as immediate
(occurring during the infusion) or delayed (occurring after the infusion has ceased). An alternate means
of classification is whether the reaction is caused by on-target (mechanisms-associated effects) or off
target (may be caused by immune reactions or via metabolites). Adverse events most commonly
include rash, fever, nausea, head-ache, chills, fatigue, proteinuria, blood pressure fluctuations
(predominantly with anti-angiogenesis products) and bronchospasm. With some products, cytopenias
can occur. Frequency of infusion-related adverse events (typically type 1 hypersensitivity reaction)
varies from one patient to another and from one product to another, but is generally, directly
proportional to the infusion rate. Clinical manifestations typically subside when the rate of infusion is
slowed, and/or treatment with antihistamines +/- corticosteroids occurs. While infrequent, the risk of
delayed adverse events can be quite varied (glomerulonephritis from immune-complex deposition, etc).
VETERINARY PRODUCTS IN DEVELOPMENT
Currently there are three mAb therapies in development, each from a different company. The
first mAbs are NV-01 and NV-02, which target and inhibit nerve-growth factor (NGF) in dogs and cats,
respectively. Nerve growth factor is shown to be involved in the pain of osteoarthritis. Using described
“PETization” technology, achieving 100% species specificity is anticipated. Administration has been
done both IV and SQ, and estimated to be performed monthly. The product is currently in pilot studies.
The second product is an anti-IL-31, a puritogenic cytokine that binds to the surface of neurons,
stimulating Janus-kinase enzymes (JAK) responsible for triggering an itch signal from the brain. This antiIL-31 mAb is being evaluated as a neutralizing mAb for the use in atopic dermatitis.
The third product is a lymphoma mAb, for B-cell lymphoma. Clinical trials are in progress. While
safety studies appear promising, efficacy studies are fully enrolled with efficacy data maturing. Unlike
the previous two mAbs in development, this mAb functions through modification of the immune
response, triggering “effector functions” against the targeted malignant cells.
REFERENCES
1. Ehrlich P. On Immunity: with special reference to cell life. Proc R Soc Lond. 1900;66:424-48.
2. Nelson AI, Dhimolea E, Reichert JM. Development trends for human antibody therapeutics. Nat
Rev Drug Discov 2010;9(10):767-74.