Volume disorders and fluid resuscitation

Volume homeostasis

Under normal physiologic conditions, the human body tightly regulates fluid volume. This is critical to maintain adequate perfusion of organs and ultimately to provide nutrients to cells and remove waste products. The system for regulating volume is complex, and it consists of a number of afferent sensors and efferent pathways that adapt to fluid changes to maintain homeostasis ( Fig. 5.1 ). Central to volume homeostasis are the kidneys, which regulate salt and water excretion. Additional critical components include the heart, the central nervous system, the vascular tree, and both volume and pressure baroreceptors. Although direct insults to any of these organ components can result in a fluid disorder, so too can insults to nearly any other organ system in the body, irrespective of its primary role in volume homeostasis. As an example, volume disorders are ubiquitous with damage to organs such as the kidneys and heart; however, disease processes involving other organs, such as the intestines, skin, and liver are also commonly associated with significant volume disturbances. For this reason, cancer patients are at significant risk for fluid disorders from a number of different pathologies.

It is important to appreciate that the body does not function like a water-filled balloon, shrinking when water is removed, and expanding when water is added. Rather, the central teaching in volume homeostasis is that there are several key fluid compartments within the body and adequate distribution of water between these compartments is critical ( Fig. 5.2 ). Total body water volume is roughly equal to 60% of the body weight in men, and 50% of the body weight in women and the elderly. The intracellular fluid (ICF) compartment contains 55% to 65% of total body water, and the ECF compartment contains the remaining 35% to 45%. The ECF compartment is further divided into the interstitial fluid compartment (approximately 75% of the ECF volume) and the intravascular compartment (approximately 25% of the ECF volume). Fluid can readily move across cell membranes, and therefore the volume of both the ICF and the ECF is dependent upon the gradient of effective osmotic agents between these two spaces. Sodium is the predominant osmotic agent in the ECF, and potassium is the predominant osmotic agent in the ICF. The Na ⁺ /K ⁺ adenosine triphosphatase pump, which is found in the cell membrane of nearly every cell within the body, maintains the distribution of sodium in the ECF compartment and potassium in the ICF compartment. Water will shift across cell membranes to maintain balanced osmolality between the ECF and ICF. Because the body’s regulatory mechanisms for sensing volume are mainly present in the ECF, sodium is the major factor that impacts the volume status of the entire body. Excessive sodium intake can lead to increases in ECF fluid volume that clinically manifest as hypertension, edema, and dyspnea. Alternatively, sodium losses can lead to decreases in ECF volume that clinically manifest as hypotension, increased skin turgor, and dizziness.

Volume regulation

The body’s ability to regulate volume is critical to one’s survival; as such, a complex set of mechanisms is present to preserve homeostasis. When the body begins to accumulate excess fluid, the fluid will distribute into the ECF and ICF based on the concentration of effective osmolytes within each compartment (predominantly sodium in the ECF and potassium in the ICF). When ECF volume increases, the body’s volume regulatory mechanisms will lead to adaptations that ultimately result in an increase in salt and water excretion by the kidneys to reduce the body volume. Alternatively, when ECF volume decreases, regulatory mechanisms will lead to adaptations that result in a decrease in salt and water excretion by the kidneys, in an effort to preserve body volume. The volume sensing components within the body predominantly respond to changes within the intravascular compartment of the ECF. Therefore even though the intravascular volume consists of less than 10% of the total body water, its role in regulating body volume is critical. In healthy physiology, the intravascular volume and the ECF are in equilibrium. From a physiologic stand point, the emphasized importance of the intravascular volume, and in particular the arterial vascular volume, makes a lot of sense, as this is what determines organ perfusion and overall survival. The term effective arterial blood volume specifically refers to the arterial volume that interacts with the volume sensing components and ultimately drives the response of the kidneys and other vascular mediators.

Integrated responses to volume changes

Changes in ECF volume trigger a number of mechanisms that act to adjust sodium and water excretion by the kidneys ( Fig. 5.3 ). These mechanisms include low pressure receptors in the right atrium and pulmonary blood vessels, as well as baroreceptors in the carotid sinus and aortic arch. In volume depleted states, stretch receptors at these sites upregulate sympathetic nerve activity in the kidneys. This results in a number of effects: (1) reduced glomerular filtration rate (GFR) via afferent arteriole constriction; (2) upregulation of sodium reabsorption in the nephron tubule; and (3) activation of the renin-aldosterone-angiotensin-system (RAAS). In addition, volume depleted states result in a decrease in atrial natriuretic peptide release by the cardiac atria, which further decreases GFR and also promotes sodium and water reabsorption along the nephron, in particular in the collecting duct. Volume overloaded states have the opposite effect on these systems, as they promote sodium and water excretion in the kidney. These integrated responses work together to restore body volume in healthy states. However, in maladaptive states, such as heart failure and cirrhosis, these mechanisms become disassociated from the body volume. More specifically, the ECF and intravascular volumes are no longer in equilibrium. Therefore, elevated ECF volumes are actually worsened because of the coexistence of low effective arterial volumes.

Volume depletion

The cancer patient is particularly vulnerable to volume depletion because of disorders of the gastrointestinal tract. Reduced fluid intake is common in cancer patients and etiologies for this include anorexia, mucositis, refractory nausea, and dysfunction of the oropharynx and esophagus. These insults can be direct consequences of the underlying malignancy, as well as the chemotherapeutic agents used to treat the underlying cancer. Despite severe reductions in fluid intake in this setting, the body continues to have unregulated insensible water losses from the skin and respiratory tract, and this can account for up to a liter or more per day. Patients in this scenario tend to develop hypernatremic hypovolemia, or what is more commonly referred to as dehydration , given the net loss of more free water than sodium. Another common cause of volume depletion in cancer patients is extensive sodium and water losses from vomiting or diarrhea. Patients may maintain oral hydration in this scenario, but it is often not enough to match the losses, and patients ultimately become volume depleted. The net result in these patients is more sodium loss than water loss, and they typically develop hyponatremic hypovolemia. Patients with substantial vomiting will also be at risk for metabolic alkalosis, given the significant amount of hydrogen and chloride loss in the gastric fluids. This can further promote potassium losses from the kidney because of sodium and bicarbonate delivery to the distal nephron, so called bicarbonaturia . On the other hand, in those subjects with diarrhea, a nonanion gap metabolic acidosis typically occurs because of bicarbonate losses from the intestinal fluids.

Polyuria in the setting of diabetes insipidus is another potential cause for volume depletion in patients with cancer. Central diabetes insipidus can result from metastatic tumors in lung cancer, leukemia, and lymphoma. Alternatively, nephrogenic diabetes insipidus can occur in the setting of tumor related obstructive uropathy, hypercalcemia, or ifosfamide and pemetrexed administration. ^, These patients present with polyuria and polydipsia, and often times daily urine output will exceed 5 L. Typically, they maintain euvolemia and isonatremia by drinking excess amounts of free water; however, in settings of impaired thirst or when patients are unable to access water because of barriers from changes in mentation or physical barriers, these subjects then develop hypernatremia and hypovolemia.