The epidermis is composed of five layers of squamous cells (Figure 10-2). From deepest to most superficial, the basal layer is closest to the dermis and contains interlocking ridges to maintain the integrity of the two structures. The prickle cell layer (stratum spinosum) contains Langerhans cells and a few lymphocytes. The granular layer (stratum granulosum) provides the principle barrier to prevent penetration by gases or liquids. The clear layer is only present in hairless skin of the palm and soles of the feet. The cornified layer (stratum corneum) is the most superficial layer with depths ranging from a few cells in thin skin to more than 50 cells in normal skin (Standring, 2005). These layers represent different stages of the maturation process. Individual cells are constantly maturing, moving upward to the surface and being replaced by new cells from the base. Loss of skin cells is only perceptible when it is excessive, such as peeling or scaling associated with certain skin disorders. Stressful agents such as prolonged exposure to sunlight, habitual pressure, and abrasion cause thickening of the cornified layer and can be measured by ultrasound (Matsumura and Anathaswamy, 2002 and Lopez et al., 2004). This may explain difficult venipunctures in some patients, especially those who are manual laborers or others whose lifestyle involves excessive exposure to sunlight.

Keratins, a large group of filament proteins in all epithelial cells, change as the cells mature and move upward through the layers. These proteins are a group of more than 50 distinct gene sequences in humans, and mutations can be the cause of several skin disorders (McLean, 2003).

Three other types of cells can be found in the epidermis: Langerhans cells, melanocytes, and Merkel cells. Langerhans cells are found in an extensive network throughout the epidermis. Their function is to detect antigens, react to inflammatory signals from the other keratinocytes, and then migrate to the nearest lymph nodes. Migration of Langerhans cells to lymph nodes has been demonstrated after mechanical tape stripping and exposure to antigens, but no such migration was seen after stripping and exposure to nonantigenic solutions. There is a growing body of information linking the loss of the skin’s barrier function to the development of atopic dermatitis and allergies (Callard and Harper, 2007).

Melanocytes contain melanin, the pigment that imparts color to the skin. Variation in color depends on the number and composition of melanocytes and on genetic, hormonal, and environmental factors. Melanin protects the skin from sun damage and is a scavenger for free radicals that can also cause cellular damage (Standring, 2005). Little is known about the physiology of Merkel cells, yet they are located close to sensory nerve endings in the epidermis and create and release numerous peptides (Boulais and Misery, 2007).

The dermis, the thickest layer of the skin, is composed of dense connective tissue with varying amounts of elastin fibers, collagen fibers, blood, and lymphatic vessels. Collagen is the largest component of the dermis and provides mechanical or tensile strength. Sebaceous glands, sweat glands and ducts, hair follicles, and arrector pili muscles surrounding hair follicles are also located in the dermis (see Figure 10-1).

The dermis is divided into the papillary and reticular layers. The papillary layer is immediately under the epidermis and serves to anchor the epidermis mechanically and support it metabolically. Fingerlike projections, known as rete ridges, extend into the base of the epidermis to mate with the rete pegs in the epidermis and enhance the bond between the two layers. The reticular layer is the deepest and is characterized by dense, irregular, connective tissue. This type of connective tissue is formed by strong collagen fiber bundles arranged in a multilayered network, providing the ability to stretch. Elastin fibers are usually thinner and have almost perfect recoil.

The hair bulb, responsible for generating the growth of hair, is located in the dermis and is surrounded by the hair follicle. Arrector pili muscles extend at an angle from the follicle into the dermis. When these muscles are stimulated by cold or emotion, the hair shaft is pulled upward and the skin appears dimpled. Sebaceous glands are located in the angle between the muscle and follicle and the muscular action expresses sebum, the secretion from the sebaceous glands. Sebum passes through a duct, into the hair follicle, and onto the skin surface. The function of sebum, composed of glycerides, cholesterol, and wax esters, is to lubricate and protect the hair and skin and contribute to body odor.

Sweat glands and ducts arise from the dermis and communicate with the skin surface. The greatest number is located on the face and hands with the fewest number on the surfaces of the extremities. These glands secrete a clear, odorless, hypotonic fluid containing urea, lactate, immunoglobulin, and other proteins as well as ions such as sodium, chloride, calcium, and bicarbonate. Secretion is stimulated by temperature elevation and emotional stimulation, with as much as 10 L of sweat produced daily (Standring, 2005).

Continuing downward to the next layer, the superficial fascia is a layer of loose connective tissue (see Figure 10-1). This layer contains the same collagen and elastin fibers as the dermis. Adipose tissue or fat cells are located in this layer, where they serve as energy stores and thermal insulation. A large variety of defensive cells similar to those found in the blood are found in this tissue. Among all these important components lie the superficial veins used for peripheral venipuncture.

The skin does not have a great metabolic demand, yet the amount of blood flow far exceeds nutritional requirements and is equal to approximately 5% of cardiac output (Standring, 2005). Blood is supplied to the skin by a direct cutaneous network of vessels arising from the muscles and superficial fascia (Figure 10-3). Arterioles supply sweat and sebaceous glands and hair follicles; capillaries loop upward to the base of the epidermis through the rete ridges; and venules pass back through the dermis to join small veins in the superficial fascia. The skin is also served by a large number of small lymphatic vessels beginning in the papillary dermis. There are numerous anastomoses at all levels that are responsible for moving lymphocytes, Langerhans cells, and macrophages to lymph nodes (Standring, 2005).

Cutaneous circulation serves as a thermoregulator. Blood flow to the skin is 10 times greater than its nutritional requirements. In response to the need for heat loss or conservation, cutaneous blood flow can be increased or decreased by 20 times the normal capacity. Cold conditions can quickly cause vasoconstriction, making venipuncture difficult, yet heat application rapidly causes vasodilation (Standring, 2005).

The extensive nerve supply in the skin acts as a sensory organ and regulator of response to mechanical, thermal, painful, or noxious stimuli. Sensory receptors in the form of free nerve endings provide needed information about the external environment. Encapsulated mechanoreceptors are found in the deep dermal layer and respond to weight, pressure, and vibration.

There are five types of sensory receptors (mechanoreceptors, thermoreceptors, nociceptors, electromagnetic receptors, and chemoreceptors), with corresponding stimuli for each (Table 10-2). Except for electromagnetic receptors, all have an effect on parenteral therapy. Many types of stimulation, such as heat, light, cold, pressure, and sound, must be processed appropriately. All these variations in modalities of sensation are transmitted along different afferent fibers, ending at a specific point in the central nervous system. This is called the labeled line principle (Guyton and Hall, 2006), which means that pain receptors transmit a painful response whether it is caused by puncture, crushing, or electricity. The sensation of touch is transmitted along a single path, no matter how the stimulation occurs.

The sensation of pain can have a profound impact on parenteral therapy. Pain can be felt quickly or slowly. Fast pain is felt within 0.1 second after stimuli, but slow pain takes seconds to be felt and may increase over minutes (Guyton and Hall, 2006). Pain receptors in skin, subcutaneous tissue, and vessel walls are free nerve endings. Fast pain is associated with skin punctures, cuts, or electrical shock. Slow pain is more intense, occurring over a prolonged period, and is usually associated with tissue destruction that can occur with catheter complications such as thrombophlebitis, infiltration and extravasation. Mechanical, thermal, and chemical stimuli can activate pain receptors. Fast pain is evoked primarily by mechanical and thermal means, whereas slow pain is associated with all three stimuli. Histamine, bradykinin, potassium ions, serotonin, acetylcholine, and proteolytic enzymes can stimulate pain receptors. Bradykinin and potassium ions appear to be responsible for producing pain following tissue damage. Pain from ischemia is probably related to the formation of large amounts of lactic acid produced from anaerobic metabolism (Guyton and Hall, 2006). Phlebitis, infiltration, and extravasation injuries produce the tissue damage involving these chemicals.

Sensory information comes from all areas of the nervous system into the spinal cord, brain stem, and cerebrum where it produces muscular functions transmitted to the body along efferent nerve fibers. Specific areas of the cerebral cortex and brain stem control motor functions. The pyramidal tract (or corticospinal tract) is the principal pathway for the transmission of impulses from the motor cortex through the brain stem and down the spinal cord. Other pathways for impulses include the mesencephalon (midbrain) and the cerebellum. The term extrapyramidal motor system has been used clinically to describe those motor functions outside the pyramidal system. Because there are many functions and pathways included in this term, it is difficult to use it for physiological purposes. However, the term extrapyramidal side effects is used to describe uncoordinated motor movements of the neck, jaw, and extremities that are associated with the administration of some types of medications.

The autonomic nervous system regulates the body’s internal organs and controls such functions as glandular secretions, arterial blood pressure, sweating, and body temperature. Perhaps the most astonishing factor about this system is the speed with which changes occur. The heart rate can double within 3 to 5 seconds, the blood pressure can drop enough to cause fainting within 4 to 5 seconds, and sweating can occur within seconds (Guyton and Hall, 2006). The two major divisions of the autonomic nervous system are the sympathetic and parasympathetic, both of which send signals to specific organs (Figure 10-6). There is also a system of visceral or enteric reflexes that receives subconscious sensory signals from the viscera, sending back a reflex response to control that specific organ. The vagus nerves (cranial nerve X) contain about 75% of all parasympathetic nerve fibers, extending to the thoracic and abdominal areas of the body.

Synaptic transmission involves primarily acetylcholine (known as cholinergic fibers) and norepinephrine (known as adrenergic fibers). Virtually all parasympathetic nerve endings secrete acetylcholine, and almost all sympathetic nerves secrete norepinephrine.

Sympathetic stimulation may cause excitation in some organs but has an inhibitory effect on others. The same can be said for the parasympathetic system. Also, the two systems may work in a reciprocal arrangement, with one causing excitation and the other producing inhibition. For example, sympathetic stimulation increases the rate and force of heart contraction, and parasympathetic stimulation has the opposite effect. Systemic blood vessels, especially in the skin of extremities, are constricted by sympathetic stimulation, thus increasing the difficulty of peripheral venipuncture. Parasympathetic stimulation has no effect on blood vessels except for those in the face that react in the form of a blush (Guyton and Hall, 2006). Table 10-3 provides a list of autonomic effects on various body organs.

Numerous intravenous medications act on the autonomic nervous system. Adrenergic or sympathomimetic drugs stimulate organs that respond to the sympathetic system and include epinephrine, methoxamine, phenylephrine, isoproterenol, and albuterol. Other drugs block adrenergic activity, including reserpine, phentolamine, propranolol, and metoprolol. Parasympathomimetic drugs include pilocarpine and methacholine, while atropine and scopolamine block cholinergic activity.

The spinal cord extends from the medulla oblongata and occupies about two thirds of the length of the vertebral column. In most adults, the cord terminates between the first and second lumbar vertebrae. The cord is enclosed within three protective layers. The pia mater is the most proximal to the cord, the arachnoid mater is next, and the dura mater is the most distal. Between the pia and arachnoid mater is the subarachnoid space, which contains cerebrospinal fluid. The subdural space lies between the arachnoid and dura mater and does not contain fluid. The subdural space below the level of the cord can be used for the epidural infusion of medication, such as that used for pain management.

Twelve pairs of cranial nerves and 31 pairs of spinal nerves compose this system. Cranial nerves originate at the base of the brain and have four functions: motor, somatic sensory, special senses, and parasympathetic.

Of primary importance for parenteral therapy is the vagus nerve, which has the longest course of any cranial nerve. It descends behind the internal jugular vein, crosses the subclavian artery, and enters the thorax where it passes behind the brachiocephalic vein and superior vena cava (Figure 10-7). Numerous branches extend to the pharynx, larynx, heart, lungs, esophagus, stomach, liver, pancreas, spleen, small intestines, and kidneys. Six branches of the vagus nerve innervate the heart. Venipuncture of the internal jugular vein can result in damage to the vagus nerve (Nakayama et al, 1994).

The phrenic nerve arises from the cervical area of the neck and descends into the thorax where it serves as the motor nerve to the diaphragm. The right phrenic nerve follows the right brachiocephalic vein and superior vena cava while the left phrenic nerve lies close to the left subclavian artery, left brachiocephalic vein, and aortic arch (see Figure 10-7). Numerous reports link right phrenic nerve damage to both left- and right-sided insertions of central venous catheters. Paralysis of the diaphragm results, although shoulder pain is the most frequent initial symptom (Rigg et al., 1997, Aggarwal et al., 2000, Takasaki and Arai, 2001, Reeves and Anderson, 2002 and Mandala et al., 2004).

The brachial plexus arises from cervical and thoracic spinal nerves, passing posteriorly to the clavicle in close proximity to the subclavian artery and vein. There are two large branches of this plexus: the supraclavicular and infraclavicular (Figure 10-8). These branches bifurcate into smaller nerves that serve the muscles and cutaneous areas of the shoulder, chest, and upper and lower arm. The close proximity of this group of nerves to the puncture sites of the subclavian vein makes damage to the nerves and ultimately the areas served by that nerve a real possibility.

The median, ulnar, and radial nerves are all branches of the brachial plexus. The median nerve passes laterally to the brachial artery and then crosses the artery, descending medially into the antecubital fossa and then into the forearm and palm of the hand. Branches of the median nerve can be superficial in the volar aspect or palm side of the wrist (Figure 10-9). Veins in this area appear to be good for cannulation, but venipuncture is usually painful in this area because of the close proximity of the nerve.

Multiple intersections between the cephalic vein and the sensory branches of the radial nerve were found when researchers dissected the forearm and wrists of 33 cadavers at the origin of the cephalic vein (Figure 10-10) (Vialle et al, 2001). The researchers suggest that to avoid nerve damage from venipuncture in the cephalic vein of the lower forearm, the insertion site should be at least 12 centimeters (cm) above the level of the styloid process at the distal end of the radius. Other reports of peripheral nerve damage resulting from venipuncture include the medial and lateral antebrachial cutaneous nerves in the antecubital fossa (Rayegani and Azadi, 2007), the posterior interosseous nerve branching from the radial nerve in the antecubital fossa (Ragoowansi, Kirkpatrick, Moss, 1999), the anterior interosseous nerve branching from the median nerve at the antecubital fossa (Zubairy, 2002 and Puhaindran and Wong, 2003), and radial nerve injury in the wrist (Stahl et al., 1996, So et al., 1999 and Boeson et al., 2000).

In the lower extremity, the sacral plexus arises from the sacral vertebrae and descends the leg in much the same manner as the brachial plexus in the arm (Figure 10-11). Of particular importance is the medial plantar nerve, which passes on the medial aspect of the foot near the ankle. The saphenous nerve passes close to the saphenous vein on the anterior aspect of the foot. When the foot of an infant is used for venipuncture, with subsequent immobilization of the joint, the nerves can be damaged if adequate padding and range-of-motion exercises are not used.