**10.1 Fluid therapy**

Fluid resuscitation is the rapid delivery of fluids to patients who have acutely impaired hemodynamics. Resuscitative fluids are given universally to patients in hypovolemic shock and lesser forms of dehydration, as well as to almost all patients with severe sepsis and septic shock. In these situations, the preload to the heart is not enough for adequate cardiac output. To understand why these patients are given fluids we need to review the Frank-Starling curve as shown in **Figure 4**. According to the Frank-Starling Law, the length of myocardial tissue is directly related to the force of the subsequent contraction. The more myocardial fibers are stretched, the more they contract. Preload determines the degree of myocardial fiber stretching. Therefore, as shown in **Figure 4**, an increase in preload results in a responsive increase in stroke volume. Patients on the left side of the curve are those who are preload dependent. Towards the right, the curve flattens and increases in preload are met with a reduced rate of increase in stroke volume until we see no change in stoke volume with increasing preload. These patients are preload independent. Essentially, only if the patient is preload dependent will we see benefits to stroke volume if given fluid. Preload independent patients will not benefit from fluids. It is important to note that the shape and position of the curve will vary between individuals, and it is important to identify where on the curve the patient lies to determine whether it is suitable to give fluids.

Once we have decided which patient needs to be given fluids, we need to decide which fluids to give. The first decision to make is whether to give crystalloid or colloid. Crystalloids are fluids which contain water and various electrolytes and other small water-soluble molecules. Colloids are large, insoluble molecules and oftentimes proteins. Theoretically, colloid should be superior to crystalloid as it has an increased tendency to stay intravascular. However, a 2013 Cochrane review found no evidence from randomized controlled trials that resuscitation with colloids reduces the risk of death, compared to resuscitation with crystalloids, in patients with trauma, burns or following surgery [7]. Therefore, given their decreased cost and increased availability,

**Figure 4.** *Frank-Starling curve.*

as well as the low immunogenic response, crystalloids are almost always favored over colloids.

Crystalloid replacement is usually sufficient in hypovolemic shock caused by vomiting and diarrhea. The presence or absence of associated electrolyte disturbances (e.g., hypo- or hypernatremia) determines the type of crystalloid. The use of albumin as a replacement fluid for hypovolemic shock is probably best reserved for situations involving direct albumin loss (e.g., burns, open wounds, protein-losing enteropathies). Volume replacement with crystalloid or albumin may be appropriate in cases of hemorrhagic shock, but with significant blood loss, replacement of red blood cell mass will eventually become necessary.

While the majority of patients with hypovolemic shock tolerate relatively rapid correction of intravascular volume depletion, there are a few notable exceptions that may require slower correction. For example, in cases of hypovolemic shock accompanied by significant metabolic/electrolyte derangements (e.g., hypernatremia or diabetic ketoacidosis), volume deficit correction must be tempered so that the accompanying metabolic/electrolyte abnormalities are not corrected too quickly. Rapid correction of hypernatremia can lead to cerebral edema while rapid correction of hyponatremia can lead to central pontine myelinolysis.

Correction of hypovolemic shock in patients with underlying myocardial dysfunction must be done with greater caution than in patients with normal myocardial function to avoid further compromising myocardial function. Finally, in traumaspecific situations, very aggressive volume resuscitation for hemorrhagic shock may not be appropriate until surgical hemorrhage control is achieved.

#### **10.2 Blood products**

Oxygen delivery, as described in the first section, is dependent on two factors: cardiac output and arterial oxygen content. Vasoactive and fluid therapy both aim to enhance cardiac output and global perfusion to enhance oxygen deliver. In both these therapies the arterial oxygen content remains the same. The use of blood products aims to increase arterial oxygen content (CaO2) by infusing packed red blood cells (PRBC) thereby increasing hemoglobin levels, the main parameter determining arterial oxygen content. The use of PRBC is therefore most useful in situations where shock is caused or worsened by decreasing hemoglobin concentration such as in patients with hemolytic anemia. The goal of blood product therapy is to return hemoglobin concentrations to normal values with regards to age. Approximately 10 mL/kg of PRBC should increase hemoglobin concentration by 2 g/dL. A 20 kg child with an Hb concentration of 5 g/dL would therefore require 500 mL of PRBC to reach an Hb concentration of 10 g/dL. When considering blood transfusion, it is important to consider the hemodynamic changes that occur with increasing hematocrit. Experimentally it has been shown that a hematocrit of 30% is optimal for oxygen delivery while hematocrit levels exceeding 40% increase viscosity and hinder oxygen delivery [8].

### **10.3 Vasoactive therapy**

Vasoactive drugs used in the management of shock can be divided into inotropic, vasoconstrictive and vasodilative medication. The main goals of employing these medications are to increase cardiac output, decrease vascular resistance and increase

perfusion pressure. The administration of these drugs usually come after initial use of fluid and blood product therapies fail to produce adequate improvement.

**Inotropes:** Inotropes are generally used to increase cardiac output and stroke volume. Their mechanism of action usually involves stimulation of adrenergic receptors and includes endogenous catecholamines such as dopamine, epinephrine and norepinephrine and exogenous catecholamines such as dobutamine and phenylephrine. These drugs work to stimulate α-adrenergic, β-adrenergic and dopaminergic receptors which subsequently alter conditions such as contractility and systemic vascular resistance (vasodilation or vasoconstriction) thereby influencing cardiac output and perfusion pressures. In the setting of shock, the use of these drugs helps enhance cardiac function to improve oxygen delivery.

Aside from drugs such as phenylephrine, most inotropic drugs will stimulate multiple receptor types with varying selectivity. For example, as shown in **Table 7**, dopamine will preferentially stimulate dopaminergic receptors but will also stimulate β- and α-adrenergic receptors and will therefore exhibit varying and multiple physiological changes in a dose dependent manner. It is therefore important to know drugs selectivity and the physiological response of each receptor type. **β1-adrenergic receptors** are primary expressed in myocardial tissue and have positive inotropic and chronotropic activity when stimulated. Stimulation of this receptor directly enhances cardiac output by increasing heart rate and contractility (stroke volume). **β2-adrenergic receptors** act on smooth muscle of vascular tissue and bronchial tissue and produce vasodilation and bronchodilation respectively. **α1-adrenergic receptors** work mainly on vascular smooth muscles contraction and cause peripheral vasoconstriction. **α2-adrenergic receptors** one the other hand causes vasodilation via the inhibition of norepinephrine secretion from presynaptic sympathetic neurons. **Dopaminergic receptors (DA)** receptors act on renal vasculature and causing renal arterial vasodilation.

**Dopamine**, in terms of inotropic therapy, displays dose-dependent activity on dopaminergic, β- and α-adrenergic receptors. At low doses (0-3 μg/kg/min) dopamine acts as a mild vasodilator in peripheral vasculature by stimulating the release of norepinephrine [9]. Additionally, it inhibits norepinephrine reuptake in presynaptic sympathetic neurons indirectly enhancing contractility and heart rate [9]. Activation of dopaminergic receptors at low doses also improves renal and splanchnic perfusion via D2 presynaptic receptors potentially providing renal protective activity [8, 9], but it remains matter of debate. Stimulation of D2 presynaptic receptors enhances vasodilation in coronary, renal, mesenteric and cerebral vasculature promoting improved blood flow to these organs [9]. While inhibition of norepinephrine reuptake in sympathetic neurons does have vasoconstrictive activity, the direct vasodilatory effects in peripheral vasculature offsets the level of constriction resulting in mild elevation of SVR. Ultimately, dopamine has the combined effect of significantly improving contractility and heart rate with only mild changes in SVR resulting in effective improvement in cardiac output. At higher doses (>10 μg/kg/min) α-adrenergic activity is stimulated causing vasoconstriction and aids in increasing blood pressure [8, 9].

**Epinephrine** is a nonselective catecholamine stimulating both adrenergic receptors of all types. Therefore, is produces both increases in CO and increases in SVR. When administered at a low dose at an infusion rate of 0.03–0.3 μg/kg/min, epinephrine mostly exhibits inotropic activity via β-adrenergic receptors increasing cardiac output. As higher infusion rates >0.3 μg/kg/min are used, α-adrenergic activity is also activated resulting in vasoconstriction and an increase in SVR. Because of its selective inotropic activity at low doses, epinephrine is reliable choice in patients with

hypotension without myocardial dysfunction. In high doses epinephrine has also been seen to cause atrial and ventricular arrhythmias [9]. One aspect of inotropic therapy using epinephrine is its administration in correlation with elevated lactate levels. Studies have shown that epinephrine may elevate lactate levels, interfering with lactate trends. It is therefore important to interpret lactate trends with skepticism when assessing response to therapy and concomitant resuscitation goals should be viewed when using epinephrine.

**Norepinephrine** preferentially binds α1-adrenergic receptors over β-adrenergic receptors resulting in more vasoconstrictive activity than inotropic activity. Because of its potent α-receptor stimulation, norepinephrine is the vasopressor drug of choice in distributive shock with hypotension [9]. At low doses of 0.01–0.05 μg/kg/min its inotropic activity can be appreciated with an improvement in cardiac output. However, at higher doses, its affinity for α-adrenergic receptors takes over, vastly increasing vasoconstriction and blood pressure. This shift in receptor activity can impede cardiac output especially in patients with cardiac dysfunction.

**Dobutamine** is a synthetic catecholamine that has mixed β- and α-adrenergic stimulation at varying dosages. It primary acts as an inotrope increasing contractility with minimal increases in SVR indicating its use in patients with cardiogenic shock. Additionally, at infusion rates >10 μg/kg/min dobutamine can reduce afterload by stimulating α2-adrenergic stimulation causing vasodilation [8]. In this setting dobutamine can improve cardiac output [8]. At low doses of <5 μg/kg/min, dobutamine can exhibit α1-aderenergic antagonism resulting in vasodilation and decreased afterload.

**Phenylephrine** is a pure α1-adrengeric agonist and has strong vasoconstrictor activity. It can be used as an additional therapy where an increase in vascular tone is needed without changes in cardiac function.

**Phosphodiesterase inhibitors (Milrinone)** work as an inotrope via a different mechanism than the catecholamines described above. By inhibiting phosphodiesterase, it causes an increase in intracellular cAMP levels thereby increasing intracellular Ca2+. These changes subsequently increase both inotropic activity in myocytes and


**Table 7.**

*Mechanism of action and effects of inotropes and vasopressors.*

vasodilation in vascular smooth muscle. It has the advantage of achieving these results without acting on adrenergic receptors and is therefore ideal in situations where receptor downregulation has developed due to chronic inotrope usage such as in those patients with chronic heart failure [9].

**Vasopressin** maintains perfusion pressure through two main mechanisms. Firstly, it acts on blood vessels to produce vasoconstriction via the activation of V1-receptors. This causes an increase in SVR and thereby increases arterial pressure. Secondly, it stimulates V2-receptors on renal tubular cells to enhance fluid reabsorption via aquaporin channels. Vasopressin is also known to stimulate CRH release from the hypothalamus, thereby increasing downstream ACTH and cortisol secretion. Cortisol in turn enhances vasoconstriction and inhibits secretion of vasodilators such as PGE2 and nitric oxide.

Mechanisms of these drugs and their effect on the cardiovascular system are summarized in **Table 7**.
