Although appropriate early resuscitative fluid therapy improves ICU patient outcomes, it must be balanced against excessive fluid therapy and fluid overload. Fluid overload in critically ill human patients is associated with longer hospitalization, increased mechanical ventilation, acute kidney injury, abdominal compartment syndrome, organ dysfunction and increased mortality. With evidence that critically ill patients may benefit from avoidance of excessive fluid administration during resuscitation, and further benefit from removal of excess fluids once shock has resolved, there is a trend in the human profession towards what has been termed “fluid stewardship.” This involves the 4 Ds of fluid therapy (drug, duration, dosing and de-escalation) as well as a 4-phase “ROSE” (resuscitation, optimization, stabilization and evacuation) fluid resuscitation strategy. Although the four Ds and the ROSE protocol are great in theory, determining which clinical phase of resuscitation a patient is experiencing, and subsequently the timing, dose, rate or even need for fluid removal can be very challenging. Furthermore, different types of shock may require different fluid resuscitation strategies. For example, ICU patients with sepsis tend to be more susceptible to fluid overload than patients suffering simple hypovolaemia secondary to vomiting/gastrointestinal losses. Not knowing the volume status of critically ill dogs and cats makes administration of fluid therapy in the resuscitation phases of shock challenging.
Blood Volume vs. Fluid Responsiveness
Fluid responsiveness can be defined by the extent to which fluid administration will improve cardiac output (CO) and is a reflection of the myocardium to improve contractility with increased sarcomere stretch due to preload (the Frank-Starling curve). Unfortunately, many human studies have shown that up to 50% of haemodynamically unstable children and adults in the ICU are not fluid responsive (regardless of blood volume). This is probably true in veterinary patients as well. Therefore, although knowing a patient’s intravascular volume status is important, it does not necessarily predict which haemodynamically unstable patients are fluid responders and which might need vasopressors. Ideally, knowing which patients are hypovolaemic, and subsequently which subcategory of patients within a hypovolaemic group are likely to respond to fluid challenges would allow fluid therapy to be tailored to individual patient needs. Patients unresponsive to fluid boluses (the flat portion of the Frank-Starling curve) are more likely to benefit from vasopressors and positive inotropes, while patients on the steep aspect of the Frank-Starling curve are likely to benefit from continued fluid boluses. The challenge lies in identifying the transition point along the Frank Starling curve where patients progress from being fluid responsive (steep curve where fluid boluses may be indicated) to fluid unresponsive (flat portion of the curve where vasoplegic and cardiac management may be more important).
Fluid Responsiveness vs. Fluid Tolerance vs. Fluid Requirements
It is important to keep in mind that “fluid responsiveness” does not equate to “fluid tolerance.” For example an animal that is septic may be a classified as a fluid responder (has improved CO following fluid administration - see below) but due to other complex interactions (e.g., increased vascular permeability, extravascular lung water, etc.) may not be able to tolerate additional fluid boluses. Finally, it is also important to realize that not all patients that are fluid responders require fluids; studies show that up to 50% of healthy volunteers are fluid responders (based on a 10% increase in CO following a passive leg raise manoeuvre) but obviously do not require fluids.
Static Indices
Although practical and important in the assessment of any critically ill patient, human and veterinary studies have shown the assessment of haemodynamic status based on physical examination and routine noninvasive monitoring is too nonspecific and is not sensitive at predicting intravascular volume status. Central venous pressure (CVP) and pulmonary artery occlusion pressure (PAOP) have traditionally been used to help guide fluid therapy in both human and veterinary patients, but recent studies have questioned the value of CVP and PAOP in predicting fluid responsiveness. Physical exam findings, CVP and PAOP are referred to as static indices of cardiac preload, and mounting evidence suggests static indices have limited value in guiding fluid resuscitation. A recent review of the use of CVP in veterinary medicine (Hutchinson, Shaw 2016) details the potential value and controversies of CVP in cats and dogs: The authors conclude that “CVP monitoring of critically ill canine and feline patients should not have a primary role in patient monitoring until such time that additional studies supporting its use are performed.” Despite this, recent surveys suggest up to 90% of human clinicians continue to use static indices to help guide decisions regarding fluid therapy, including CVP. There may however still be value in measuring CVP in extreme cases (patients on the far ends of hypovolaemia or volume overload spectrum) if CVP is trended over time, interpreted in conjunction with other factors, and its limitations are considered.
Dynamic Indices
To help identify where an individual is on the Frank Starling curve many investigators have suggested monitoring “dynamic” indices of fluid responsiveness, as opposed to traditional “static” indices. Dynamic indices use heart-lung interactions to assess fluid responsiveness. The principle is to observe an effect on cardiac output induced by a change in preload in conjunction with the respiratory phases. This is most often assessed in mechanically ventilated patients but can be measured in spontaneously breathing patients in some instances. There are typically 3 factors involved in measuring dynamic variables: 1) measurement of an index reflective of blood volume (e.g., diameter of the inferior vena cava, pulse pressure variation, etc.), 2) intrathoracic pressure changes (which is one variable that affects preload) occurring as a result of the respiratory cycle and 3) a change in blood volume (a second known preload-changing factor) such as administration of a fluid challenge or performing some manoeuvre (e.g., passive leg raise, tidal volume challenge). The change in cardiac output is the dynamic response assessed, either measured directly (i.e., direct cardiac output monitoring), or indirectly (e.g., systolic blood pressure). Although multiple techniques are available to directly measure and estimate cardiac output, both invasively and noninvasively, the procedures tend to be somewhat time consuming and are not readily available in most veterinary clinical settings. Readers are referred elsewhere for a review of cardiac output measurement and its application in veterinary critical care (Marshal et al. 2016).
Indirect dynamic indices that have been successfully used to predict fluid responsiveness in mechanically ventilated humans and dogs most often include the respiratory variation in systolic pressure, pulse pressure, and stroke volume. During positive pressure ventilation there is a decrease in venous return and pulmonary artery blood flow during inspiration (vena cava blood flow is impeded during the inspiratory phase of positive pressure ventilation). Within 2–3 heartbeats (pulmonary transit time) the decrease in venous return is apparent at the level of the left heart, which results in a decrease in left ventricular end diastolic volume and consequently stroke arterial blood pressure (particularly systolic) and plethysmographic waveform amplitude. Under positive pressure ventilation, the magnitude of the variation at all levels is greater in hypovolaemic fluid responsive patients than non-fluid responsive patients, as fluid responsive patients are functioning on the steep portion of the Frank-Starling curve. Dynamic variables can be quantified as a percentage difference between the maximal and minimal measured value of a single PPV breath. For example, the systolic pressure variation can be calculated as: SPV (%)=(SAPmax-SAPmin)/[(SAPmax+SAPmin)/2]x100. Other dynamic variables can be calculated with similar equations. In human patients, a pulse pressure variation <12–13% indicates patients that are unlikely to respond to a fluid challenge as there is minimal effect of ventilation on venous return. In contrast, patients with a pulse pressure variation >13% may be relatively hypovolaemic and respond to a fluid bolus by increasing stroke volume. Several studies in dogs have demonstrated the value of dynamic variables in assessing responsiveness to blood loss and fluid therapy. A recent study in dogs demonstrated that pulse pressure variation can predict fluid responsiveness in isoflurane-anaesthetized dogs, and that it can be used to guide fluid therapy with a cut-off value of 15% distinguishing responders from non-responders, when mechanically ventilated with a tidal volume of 10 ml/kg and 3 cm H2O PEEP. Although a >15% increase in the dynamic variable measured is generally thought to be clinically meaningful in people, the threshold value to define fluid responsiveness varies between studies and smaller changes in variation may also indicate fluid responsiveness depending on the patient’s baseline values, age, vascular tone, underlying pathology, and the manoeuvre used to invoke the dynamic change. For example, some studies suggest a threshold of >10% in CO following passive leg raise manoeuvres or even >5% CO change following a tidal volume challenge (see below) are sufficient to identify fluid responders. Unfortunately, dynamic variables are limited by the fact they rely on patients receiving positive pressure ventilation and require an arterial catheter in most cases.
Furthermore, although dynamic variables show promise in adult humans and dogs, a recent systematic review found these variables were not predictive of fluid responsiveness or volume status in children. They have also been reported to be inaccurate in patients with decreased lung compliance (e.g., ARDS) and in patients being ventilated with low tidal volumes (<8 ml/kg). However, a novel approach in human medicine that may prove promising uses a “tidal volume” challenge when using PPV <8 ml/kg tidal volume. This test is performed to assess fluid responsiveness in patients in shock, ventilated using low tidal volume without spontaneous breathing activity. The pulse pressure variation is recorded from a bedside monitor at baseline (tidal volume 6 ml/kg). The tidal volume is then transiently increased from 6 ml/kg to 8 ml/kg for one minute and the pulse pressure variation is recorded. The tidal volume is returned to 6 ml/kg. The Δ pulse pressure variation 6–8 is calculated. A Δ pulse pressure variation 6–8 greater than 3.5% predicts fluid responsiveness with high accuracy. Alternatively, in humans a passive leg raise manoeuvre (PLRM) is often used as the preload manoeuvre (this is essentially a “virtual” fluid challenge that can be reversed as it relies on increasing venous return via fluids already contained in the vascular system). A PLRM is performed by bringing the patient’s trunk as close as possible to supine position with the legs elevated up to 45 degrees for 3 minutes. The legs are then returned to 0 degrees, reversing the transient increase in venous return.
The PLRM is not practical in veterinary medicine, and therefore a true fluid challenge is often required to assess fluid responsiveness.
Although there is variation in the reported quantity and speed at which a fluid bolus must be given to assess fluid responsiveness, recent evidence in both human and veterinary literature suggests as little as 4 ml/kg of isotonic crystalloids given IV over 5 minutes might be adequate to assess fluid responsiveness.
Sonographic Assessment of Fluid Responsiveness
Caudal Vena Cava Evaluation
The inferior vena cava (IVC) has also been investigated as a noninvasive means of predicting blood volume in humans. The venous capacitance system contains two thirds of the intravascular volume, with the caudal vena cava (CVC) being the largest capacitance vessel in animals. The thin wall and elastic nature of the CVC makes it a responsive and dynamic blood vessel. Similar to other dynamic variables that fluctuate with changes in the respiratory cycle, the high compliance of the caval wall allows its size and geometry to fluctuate in response to relative and absolute intravascular volume changes depending on both the respiratory and cardiac cycle. Spontaneous and PPV respirations results in a change in positive and negative pressures within the thorax. These pressure changes influence the vascular volume within the thorax and abdomen. With spontaneous respirations, negative pressure draws blood into the thoracic CVC from the abdominal CVC, causing the CVC to decrease in size within the abdomen while the positive pressure of expiration pushes blood from the thoracic CVC into the abdominal CVC.
Measurement of the IVC can be performed in a static fashion, measuring the maximum and minimum values and/or calculating a ratio relative to the aorta, all of which has been shown to correlate well with CVP measurements in people. In human patients suffering trauma, patients in shock upon arrival had a smaller IVC diameter compared with those not in shock (7.7 vs. 13.4 mm). The IVC diameter has been shown to help predict response to fluid resuscitation of patients in shock states. A change in CVC diameter in response to hypovolaemia and fluid overload has also been shown to correlate well to CVP in dogs when measured via ultrasound at the level of the liver via a right parasternal window. A strong correlation between gall bladder wall thickness and increasing CVP in dogs has also been demonstrated. Given variation in body weight and patient size will impact IVC diameter references, the use of the IVC:aorta ratio has been validated in humans to account for differences in body size and weight, particularly in children and paediatric patients. A static index ratio of the CVC to aorta has recently been investigated in dogs undergoing blood donation. One study showed no change in CVC:aorta ratio in 8 dogs pre and post blood donation when measured at the suprailiac location. A more recent study demonstrated the CVC:aorta ratio measured at the sublumbar region of the left kidney (spleno-renal location of abdominal focused assessment with sonography for trauma) could be used to predict a change in blood volume following blood donation in 12 dogs. The technique was easily learned, performed in under a minute with good repeatability and shows promise in the veterinary emergency/critical care setting in helping to identify hypovolaemia, particularly as a result of haemorrhage. Further investigation is needed to determine the extent to which this protocol and be applied in veterinary patients and its ability to predicting fluid responsiveness in small animal patients.
Assessment of the IVC and IVC:aorta ratio has been criticized in human literature as being a static index, which implies similar limitations to the role of CVP in assessing volume status and fluid responsiveness. A dynamic measurement of the IVC has subsequently been investigated in human medicine and has shown promise predicting both volume status as well as responsiveness to fluid therapy. Initial dynamic indexes of the IVC were performed in patients undergoing PPV, but more recent studies have demonstrated the IVC index can be performed in critically ill spontaneously breathing human patients. The IVC collapsibility index (IVC-CI) is a dynamic index that involves calculating the percentage change in the diameter of the vena cava during the respiratory cycle. For example, in spontaneously breathing patients the IVC-CI=end-expiratory diameter(max IVC diameter)-end-inspiratory diameter(min IVC diameter)/end-expiratory diameter. The measurement is based on the impedance of vena cava blood flow during the respiratory cycle. The interpretation is different between PPV ventilated patients and spontaneously breathing patients because of the impact of intrathoracic pressures on the impedance of blood flow in the vena cava. With PPV, the extrathoracic vena cava diameter increases during inspiration, while the extra thoracic vena cava decreases in diameter during inspiration in spontaneously breathing patients. The CVC-CI values found in humans vary by study but the mean values for IVC-CI reported in healthy, adult human studies are 47.3%±8.9%. Changes less than 20% are associated with hypervolaemia while change greater than 60% are associated with hypovolaemia.
In humans and dogs, the location and technique to assess the percentage change in CVC diameter with respiratory cycle varies. In people, the IVC can be measured at the subxyphoid, lateral, and even suprailiac locations. The superior vena cava has also been evaluated in people, however it requires transoesophageal echocardiography (TOE) to obtain accurate and reliable measurements. Body condition and formation can be a potential barrier in obtaining accurate measurements in people. Further limitations to the IVC measurement in people have been demonstrated in patients with high intra-abdominal pressures, patients with marked respiratory disease/effort, and pressure artifact.
In dogs, the vena cava has been evaluated via a right sided transverse intercostal view of the liver where the CVC, aorta and portal vein are all visualized in the same sonographic view. It has also been evaluated at the subxiphoid site where the CVC crosses the diaphragm, at the suprailiac location and at the level of the kidneys. Further studies are needed to determine the role of the CVC diameter, CVC collapsibility index, and CVC:aorta ratio in determining the blood volume of dogs, which dogs are more likely to be responsive to fluid challenges, and dogs at risk for volume overload. To date, there is limited to no veterinary literature available on the role of the CVC in estimating blood volume or response to fluid therapy in cats. Studies in dogs have demonstrated there is good inter and intra-rater variability for some but not all CVC measurements.
Cardiac Evaluation
There are also limited studies in dogs assessing echocardiographic changes in the heart in relation to blood volume status. In most species, including cats and dogs, hypovolaemia can induce a decrease in left ventricular lumen size with thickening of the intraventricular septum and left ventricular free wall referred to as “pseudohypertrophy.” Pseudohypertrophy is reversible following adequate fluid resuscitation. The left atrial size decreases in size with hypovolaemia and increases with overzealous fluid administration. The contractility of the heart is also worth assessing as it will change with alterations in intravascular volume status. Although used in several hospitals in a clinical setting, scientific evidence on the use of echocardiographic assessment of the hypovolaemic heart is lacking in veterinary medicine.
Fluid Intolerance and Overzealous Fluid Therapy
There are a number of sonography protocols used in human ICU patients to help determine if a patient is fluid intolerant and at risk of complications due to continued fluid therapy. For example, combining the evaluation of IVC changes, cardiac assessment with screening for alveolar interstitial syndrome (AIS, often reflective of pulmonary oedema), in people allows for individually tailored fluid therapy (e.g., FALLS protocol). Although veterinary evidence to support the use of such protocols in our small animal patients is currently lacking, some institutions have already started to incorporate some of these principles into veterinary point of care ultrasound. By doing so, clinicians gain a better systemic picture of the patients volume status, fluid responsiveness and fluid tolerance, although proof of improved outcome is also lacking at this time. Through evaluation of the caudal vena cava and monitoring of the LA/Ao-ratios and screening for the appearance of B-lines and/or gall bladder wall oedema, point of care thoracic ultrasonography should allow volume replacement to be tailored to the individual small animal patient that presents with hypovolaemic shock.
Wet or dry lung determined via ultrasound: Knowing if fluid is present in the lungs (along with volume estimation/cardiac function) is very helpful when deciding what fluid rates might be tolerated by the patient. Sonographic evaluation of the lungs has been used in humans and veterinary patients to evaluate the lung to determine if it is “wet” or “dry.” The “wet” vs. “dry” lung is based on detecting the presence of absence of B lines (also called lung rockets), which are vertical white lines extending form the pleural line distally through the far field of the ultrasound image which move to and fro with respirations. The presence of one to three B line is considered normal in dogs, however, the presence of multiple (>3) to coalescing B lines at a single site, particularly if they are present at more than one site over the thorax, is suggestive of interstitial alveolar syndrome. For example, the presence of numerous easily detectable B lines following trauma suggests pulmonary contusions while the presence of multiple B lines in a dog with cough and a heart murmur is more suggestive of cardiogenic pulmonary oedema, particularly if evaluation of the heart supports cardiac disease. By recording the number and location of B lines within lung fields it is possible to gain a greater understanding of the degree of fluid in the lungs, which can be used to help guide fluid therapy decisions. If a patient presents with dry lungs and then develops >3 B lines in a single ultrasound window during fluid resuscitation, the patient’s CVC, cardiac chamber size and cardiac contractility should all be assessed to help decide further treatment options. Aggressive fluid therapy should be discontinued until all the sonographic parameters in conjunction with the overall clinical picture can be evaluated more thoroughly.
In Summary
The first question to decide is does the patient require fluids? If yes, will the patient benefit from fluids (is the patient fluid responsive), and finally can the patient tolerate fluids (is the patient fluid tolerant). Layered on top of this question one must ask if the patient also requires vasoplegic and cardiac management, and if so when should they be initiated, but the latter is a discussion for another time.
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