VASCULAR ACCESS

INTRODUCTION

He who works with his hands is a laborer.
He who works with his head and his hands is a craftsman.
St. Francis of Assisi

The care of critically ill patients requires one or more pipelines to the vascular system, for both monitoring and interventions. This chapter presents some guidelines for the insertion of vascular catheters, including a brief description of the common percutaneous access routes (1-3). The emphasis here is on the craft of establishing vascular access. The labor of vascular cannulation is a skill learned at the bedside.

PREPARING FOR VASCULAR CANNULATION

HANDWASHING

Handwashing is mandatory (and often overlooked) before the insertion of vascular devices. Scrubbing with antimicrobial cleansing solutions does not reduce the incidence of catheter-related sepsis (4), so a simple soap-and-water scrub is sufficient.

UNIVERSAL PRECAUTIONS

In 1985, the Centers for Disease Control introduced a strategy for blood and body fluid precautions known as universal precautions (5). This strategy is based on the assumption that all patients are potential sources of human immunodeficiency virus (HIV) and other blood-borne pathogens (e.g., hepatitis viruses) until proven otherwise. The following recommendations apply to the insertion of vascular catheters.

Use protective gloves for all vascular cannulations.

Use sterile gloves for all cannulations except those involving the introduction of a short catheter into a peripheral vein.

Caps, gowns, masks, and protective eyewear are not necessary unless splashes of blood are anticipated (e.g., in a trauma victim). These measures do not reduce the incidence of catheter-related sepsis (6).

Avoid needlestick injuries. Do not recap needles or manually remove needles from syringes. Place all sharp instruments in puncture-resistant containers immediately after use.

If a needlestick injury is sustained during the procedure, follow the recommendations in Table 4.1.

Needlestick injuries are reported in up to 80% of medical students and interns (9). Therefore, in patients who are known risks for transmitting HIV or viral hepatitis, vascular cannulation should be performed only by an experienced senior-level resident or fellow.

LATEX ALLERGY

The increased use of rubber gloves (made of latex or vinyl) as protection against HIV infections has resulted in an increased recognition of allergic reactions to latex (10). These reactions can be manifest as a contact dermatitis (urticarial lesions of the hands and face), or as a conjunctivitis, rhinitis, or asthma. The latter three manifestations are reactions to airborne latex particles, and they do not require direct physical contact with gloves. They often appear when the affected individual enters an area where latex gloves are being used. Therefore, a latex allergy should be suspected in any ICU team member who develops atopic symptoms when in the ICU. When this occurs, a switch to vinyl gloves will eliminate the problem. Latex allergy can be manifest as anaphylaxis (10), so the transition to vinyl gloves for suspected latex allergy should not be delayed.

CLEANSING THE SKIN

Agents that reduce skin microflora are called antiseptics, whereas agents that reduce the microflora on inanimate objects are called disinfectants. Common antiseptic agents are listed in Table 4.2 (11,12). The most widely used antiseptic agents are alcohol and iodine, both of which have a broad spectrum of antimicrobial activity. Alcohol (commonly used as a 70% solution) may not work well on dirty skin (that is, it does not have a detergent action), so it is often used in combination with another antiseptic agent. The most popular antiseptic solution currently in use is a povidone-iodine preparation (e.g., Betadine), also known as an iodophor, a water-soluble complex of iodine and a carrier molecule. The iodine is released slowly from the carrier molecule, and this reduces the irritating effects of iodine on the skin. This preparation should be left in contact with the skin for at least 2 minutes to allow sufficient time for iodine to be released from the carrier molecule.

HAIR REMOVAL

Shaving is not recommended for hair removal because it abrades the skin and promotes bacterial colonization. If hair removal is necessary, the hair can be clipped or a depilatory can be applied (6).

CATHETER INSERTION DEVICES

Vascular cannulation can be performed by advancing the catheter over a needle or guidewire that is in contact with the lumen of a blood vessel.

CATHETER-OVER-NEEDLE

A catheter-over-needle device is shown in Figure 4.1. The catheter fits snugly over the insertion needle, and has a tapered end to minimize damage to the catheter tip and soft tissues during insertion. This device can be held like a pencil (i.e., between the thumb and forefinger) as it is inserted through the skin and directed to the target vessel. When the tip of the needle enters the lumen of a patent blood vessel, blood moves up the needle by capillary action and enters the flashback chamber. When this occurs, the catheter is threaded over the needle and into the lumen of the blood vessel as the needle is withdrawn.

The advantage of a catheter-over-needle device is the ability to cannulate vessels in a simple one-step procedure. The disadvantage is the tendency for the catheter tip to become frayed as it passes through the skin and soft tissues, and to subsequently damage the vascular endothelium and promote phlebitis and thrombosis. To minimize this risk, the catheter-over-needle device is usually reserved for cannulation of superficial vessels.

CATHETER-OVER-GUIDEWIRE

Guidewire-assisted vascular cannulation was introduced in the early 1950s and is often called the Seldinger technique, after its inventor. This technique is illustrated in Figure 4.2. A small-bore needle (usually 20 gauge) is used to probe for the target vessel. When the tip of the needle enters the vessel, a thin wire with a flexible tip (called a J-tip because of its shape) is passed through the needle and into the vessel lumen. The needle is then removed, leaving the wire in place to serve as a guide for cannulation of the vessel. When cannulating deep vessels, a rigid dilator catheter is first threaded over the guidewire and removed; this creates a tract that facilitates insertion of the vascular catheter.

The guidewire technique has the presumed advantage of minimizing damage to soft tissues and blood vessels by using a small-bore probe needle. However, the use of a rigid dilator catheter (as explained above) seems to nullify this advantage. Nevertheless, the guidewire technique is currently the preferred method for central venous and arterial cannulation (1,2).

THE CATHETERS

Vascular catheters are composed of plastic polymers impregnated with barium or tungsten salts to enhance radiopacity. Catheters intended for short-term cannulation (days) are usually made of polyurethane; catheters used for long-term venous access (weeks to months) are composed of a more flexible and less thrombogenic derivative of silicone. The silicone catheters (e.g., Hickman and Broviac catheters) are too flexible for routine percutaneous insertion, and are not appropriate for use in the ICU.

HEPARIN BONDING

Some vascular catheters are impregnated or coated with heparin to reduce thrombogenicity. However, this measure has not proven effective in reducing the incidence of catheter-associated thrombosis (13). Because heparin-coated catheters can be a source of heparin-induced thrombocytopenia (see Chapter 45), catheters used in the ICU should not be impregnated or coated with heparin.

CATHETER SIZE

The size of vascular catheters is commonly expressed in terms of the outside diameter, and the units of measurement are shown in Table 4.3. The French size is a metric derivative equivalent to the outside diameter in millimeters multiplied by 3; that is, French size = outside diameter (in mm) ´ 3. The gauge system was developed for wires and needles, and has been adopted for catheters. There is no simple mathematical relationship between gauge size and other units of measurement, and a table of reference values such as Table 4.3 is needed to make the appropriate conversions (14). Gauge sizes usually range from 14 (largest diameter) to 27 (smallest diameter).

As described in Chapter 1, the steady or laminar flow through a rigid tube is influenced most by the radius of the tube (see the Hagen-Poisseuille equation in the section on peripheral blood flow in Chapter 1). The influence of tube diameter on flow rate is demonstrated in Table 4.3 for gravity flow of one unit of packed red blood cells diluted with 250 mL normal saline flowing through catheters of equal length (15). Note that a little more than a doubling of tube diameter (from 0.7 mm to 1.65 mm) is associated with almost a quadrupling of flow rate (from 24.7 to 96.3 mL/minute). Thus, catheter size (diameter) is an important consideration if rapid flow rates are desired.

MULTILUMEN CATHETERS

Multilumen catheters were introduced for clinical use in the early 1980s, and are now used routinely for central venous cannulation. The design of a triple-lumen catheter is shown in Figure 4.3. These catheters have an outside diameter of 2.3 mm (6.9 French) and may have three channels of equal diameter (usually 18 gauge) or may have one larger channel (16 gauge) and two smaller channels of equal diameter (18 gauge). The distal opening of each channel is separated from the other by at least 1 cm to help minimize mixing of infusate solutions.

Multilumen catheters have proven to be valuable aids because they minimize the number of venipunctures needed for monitoring and infusion therapy, yet they do not increase the risk of thrombosis or infection when compared with single-lumen catheters (13).

INTRODUCER CATHETERS

Another valuable addition to the family of vascular catheters is the introducer catheter, shown in Figure 4.3. These large-bore catheters (8 to 9 French) can be used as conduits for insertion and removal of smaller vascular catheters (including multilumen catheters and pulmonary artery catheters) through a single venipuncture. The side-arm infusion port on the catheter provides an additional infusion line, and allows a continuous flush to prevent thrombus formation around smaller catheters that sit in the lumen of the introducer catheter. This side-arm infusion port also allows the introducer catheter to be used as a stand-alone infusion device (a rubber membrane on the hub of the catheter provides an effective seal when fluids are infusing through the side-arm port of the catheter). The large diameter of introducer catheters makes them particularly valuable as infusion devices when rapid infusion rates are necessary (e.g., in the resuscitation of massive hemorrhage).

ACCESS ROUTES

The following is a brief description of common vascular access routes in the arm (antecubital veins and radial artery), the thoracic inlet (subclavian and jugular veins), and the groin (femoral artery and vein).

ANTECUBITAL VEINS

The veins in the antecubital fossa provide rapid and safe vascular access for acute resuscitative therapy. Although long catheters can be inserted into the antecubital veins and advanced into the superior vena cava, such peripherally inserted central venous catheters (PICC devices) are more appropriate for home infusion therapy than for treating critically ill patients (16). Short catheters (5 to 7 cm) are preferred for acute resuscitation via the antecubital veins because they are more easily inserted and allow more rapid infusion rates than the longer PICC catheters.

Anatomy

The surface anatomy of the antecubital veins is shown in Figure 4.4. The basilic vein runs along the medial aspect of the antecubital fossa, and the cephalic vein is situated on the opposite side. The basilic vein is preferred for cannulation because it runs a straighter and less variable course up the arm than the cephalic vein.

Insertion Technique

The patient need not be supine, but the arm should be straight and abducted. The antecubital veins can be distended by tourniquet or by inflating a blood pressure cuff to just above the diastolic pressure (this allows arterial inflow while impeding venous outflow). Once the veins are visible or palpable, a catheter-over-needle device is used to insert a short 16- or 18-gauge catheter into the basilic or cephalic vein.

Blind Insertion

If the antecubital veins are neither visible nor palpable, palpate the brachial artery pulse at a point 1 inch above the antecubital crease. The basilic vein (or brachial vein) should lie just medial to the palpated pulse at this point, and can be entered by inserting the catheter-over-needle device through the skin at a 35° to 45° angle and advancing the needle until blood return is noted. This approach has a reported success rate of 80% (17). Injury to the median nerve (which is also medial to the artery, but deep to the veins) can occur with excessive movement of the probe needle.

Comment

Cannulation of the antecubital veins is recommended (18,19).

For rapid venous access (e.g., cardiopulmonary resuscitation)

For thrombolytic therapy in acute myocardial infarction

For trauma victims who require thoracotomy

Remember that the shorter the catheter, the more rapid the flow rate through the catheter (see Chapter 1). Thus, insertion of short catheters into the antecubital veins permits more rapid volume resuscitation than insertion of the longer central venous catheters.

RADIAL ARTERY

The radial artery is a favored site for arterial cannulation because the vessel is superficial and accessible and the insertion site is easy to keep clean. The major disadvantage of the radial artery is its small size, which limits the success rate of cannulation and promotes vascular occlusion.

Anatomy

The surface anatomy of the radial and ulnar arteries is shown in Figure 4.4. The radial artery is usually palpable at a point just medial to the styloid process of the radius. The ulnar artery is on the opposite (medial) side of the wrist, just lateral to the pisiform bone. Although the radial artery is preferred, the ulnar artery is the larger of the two arteries and should be easier to cannulate (20).

The Allen Test

The Allen test evaluates the capacity of the ulnar artery to supply blood to the digits when the radial artery is occluded. The test is performed by first occluding the radial and ulnar arteries with the thumb and index finger. The patient is then instructed to raise the wrist above the head and to make a fist repeatedly until the fingers turn white. The ulnar artery is then released, and the time required for return of the normal color to the fingers is recorded. A normal response time is 7 seconds or less, and a delay of 14 seconds or greater is evidence of insufficient flow in the ulnar artery.

Although a positive Allen test (i.e., 14 seconds or longer for return of color to the digits) is often stated as a contraindication to radial artery cannulation, in numerous instances the Allen test has indicated inadequate flow in the ulnar artery, yet subsequent radial artery cannulation has been uneventful (2,21). Thus, a positive Allen test is not a contraindication to radial artery cannulation. Another limitation is the need for patient cooperation to perform the test. Therefore, this test is not worth the time it takes.

Insertion Technique

The wrist should be hyperextended to bring the artery closer to the surface. A short 20-gauge catheter is appropriate, and can be inserted by a catheter-over-needle device or by the guidewire technique. When using a catheter-over-needle device, the following through-and-through technique is recommended: When the needle tip first punctures the artery (and blood appears in the flashback chamber), the tip of the catheter is just outside the vessel. To position the catheter tip in the lumen of the vessel, the needle is passed completely through the artery and then withdrawn until blood returns again through the needle. At this point, the catheter tip should be in the lumen of the artery, and the catheter can be advanced while the needle is retracted. If two attempts at cannulation are unsuccessful, switch to an alternative site (to reduce trauma to the vessel).

Comment

Arterial occlusion occurs in as many as 25% of radial artery cannulations, but digital ischemia is rare (2,22). Despite being well tolerated in most patients, cannulation of the radial artery (or any artery) should be reserved for monitoring blood pressure, and is not to be used as a convenience measure for monitoring blood gases or other blood components (23).

THE SUBCLAVIAN VEIN

More than 3 million central venous cannulations are performed yearly in the United States (24), and a majority of these procedures are performed via the subclavian vein (25). The subclavian vein is well suited for cannulation because it is a large vessel (about 20 mm in diameter) and is prevented from collapsing by its surrounding structures. The immediate risks of subclavian vein cannulation include pneumothorax (1% to 2%) and hemothorax ( less than 1%) (25). The incidence of bleeding is no different in the presence or absence of a coagulopathy (26); that is, the presence of a coagulation disorder is not a contraindication to subclavian vein cannulation.

Anatomy

The subclavian vein is a continuation of the axillary vein as it passes over the first rib, and the apical pleura lies about 5 mm deep to the vein at its point of origin. As shown in Figure 4.5, the subclavian vein runs most of its course along the underside of the clavicle. The vein runs along the outer surface of the anterior scalene muscle, which separates the vein from its companion artery on the underbelly of the muscle. At the thoracic inlet, the subclavian vein meets the internal jugular vein to form the brachiocephalic vein. The convergence of the right and left brachiocephalic veins forms the superior vena cava.

Anatomic Distances

The lengths of the vascular segments involved in subclavian (and internal jugular) vein cannulation are shown in Table 4.4. The average distance from venipuncture site to the right atrium is 14.5 cm and 18.5 cm for right-sided and left-sided cannulations, respectively. These distances are far shorter than catheter lengths recommended for right-sided (20 cm) and left-sided (30 cm) central venous cannulations, and are more consistent with a recent report showing that the average distance to the right atrium is 16.5 cm in central venous cannulation from either side in adults (27). Therefore, to avoid placing catheter tips in the right atrium (which can lead to cardiac perforation and fatal cardiac tamponade), all central venous catheters should be no longer than 15 or 16 cm in length (27).

INSERTION TECHNIQUE

The patient is placed supine, with arms at the sides and head faced away from the insertion site. A towel roll can be placed between the shoulder blades, but this is uncomfortable and unnecessary. Identify the clavicular insertion of the sternocleidomastoid muscle. The subclavian vein lies just underneath the clavicle where the muscle inserts onto the clavicle. The vein can be entered from either side of the clavicle.

Infraclavicular Approach (Insertion Site 1 in Figure 4.5). Identify the lateral margin of the sternocleidomastoid muscle as it inserts on the clavicle. The catheter is inserted in line with this margin, but below the clavicle. Insert the probing needle (18 or 20 gauge) with the bevel pointing upward (toward the ceiling) and advance the needle along the underside of the clavicle and toward the suprasternal notch. The path of the needle should be parallel to the patient's back. When the vein is entered, turn the bevel of the needle to 3 o'clock so the guidewire threads in the direction of the superior vena cava.

Supraclavicular Approach (Insertion Site 2 in Figure 4.5). Identify the angle formed by the lateral margin of the sternocleidomastoid muscle and the clavicle. The probe needle is inserted so that it bisects this angle. Keep the bevel of the needle facing upward and direct the needle under the clavicle in the direction of the opposite nipple. The vein should be entered at a distance of 1 to 2 cm from the skin surface (the subclavian vein is more superficial in the supraclavicular approach). When the vein is entered, turn the bevel of the needle to 9 o'clock so the guidewire threads in the direction of the superior vena cava.

Comment

Patient comfort and ease of insertion are the most compelling reasons to select the subclavian vein for central venous access. Selection of the infraclavicular versus supraclavicular approach is largely a matter of personal preference. Some recommend avoiding the subclavian vein in ventilator-dependent patients because of the risk of pneumothorax. However, the risk of pneumothorax is too small to justify abandoning the subclavian vein in patients with respiratory failure.

THE INTERNAL JUGULAR VEIN

Cannulation of the internal jugular vein reduces (but does not eliminate) the risk of pneumothorax, but introduces new risks (e.g., carotid artery puncture and thoracic duct injury).

Anatomy

The internal jugular vein is located under the sternocleidomastoid muscle in the neck and, as shown in Figure 4.5, the vein follows an oblique course as it runs down the neck. When the head is turned to the opposite side, the vein forms a straight line from the pinna of the ear to the sternoclavicular joint. Near the base of the neck, the internal jugular vein becomes the most lateral structure in the carotid sheath (which contains the carotid artery sandwiched between the vein laterally and the vagus nerve medially).

Insertion Technique

The right side is preferred because the vessels run a straighter course to the right atrium. The patient is placed in a supine or Trendelenburg position, with the head turned to the opposite side. The internal jugular vein can be entered from an anterior or posterior approach.

The Anterior Approach (Insertion Site 4 in Figure 4.5). The anterior approach is through a triangular region created by two heads of the sternocleidomastoid muscle. The carotid artery is palpated in the triangle and retracted medially. The probe needle is inserted at the apex of the triangle with the bevel facing up, and the needle is advanced toward the ipsilateral nipple, at a 45° angle with the skin surface. If the vein is not encountered by a depth of 5 cm, the needle is withdrawn 4 cm and advanced again in a more lateral direction. When a vessel is entered, look for pulsations. If the blood is red and pulsating, you have entered the carotid artery. In this situation, remove the needle and tamponade the area for 5 to 10 minutes. When the carotid artery has been punctured, no further attempts should be made on either side because puncture of both arteries can have serious consequences.

The Posterior Approach (Insertion Site 3 in Figure 4.5). The insertion site for this approach is 1 centimeter superior to the point where the external jugular vein crosses over the lateral edge of the sternocleidomastoid muscle. The probe needle is inserted with the bevel positioned at 3 o'clock. The needle is advanced along the underbelly of the muscle in a direction pointing to the suprasternal notch. The internal jugular vein should be encountered 5 to 6 cm from the skin surface with this approach (28).

Carotid Artery Puncture. If the carotid artery has been punctured with a probing needle, the needle should be removed and pressure should be applied to the site for at least 5 minutes (10 minutes is recommended for patients with a coagulopathy). No further attempts should be made to cannulate the internal jugular vein on either side, to avoid puncture of both carotid arteries. If the carotid artery has been inadvertently cannulated, the catheter should not be removed, as this could provoke serious hemorrhage. In this situation, a vascular surgeon should be consulted immediately.

Comment

As with the subclavian vein, cannulation of the internal jugular vein is safe and effective when performed by skilled operators. However, several disadvantages of internal jugular cannulation deserve mention. (a) Accidental puncture of the carotid artery is reported in 2 to 10% of attempted cannulations (28). (b) Awake patients often complain of the limited neck mobility when the internal jugular vein is cannulated. (c) In agitated patients, inappropriate neck flexion can result in thrombotic occlusion of the catheter and vein. (d) In patients with tracheostomies, the insertion site can be exposed to infected secretions that drain from the tracheal stoma.

THE EXTERNAL JUGULAR VEIN

Cannulation of the external jugular vein has two advantages: (a) There is no risk of pneumothorax, and (b) hemorrhage is easily controlled. The major drawback is difficulty advancing the catheter.

Anatomy

The external jugular vein runs along a line extending from the angle of the jaw to a point midway along the clavicle. The vein runs obliquely across the surface of the sternocleidomastoid muscle and joins the subclavian vein at an acute angle. This acute angle is the major impediment to advancing catheters that have been inserted into the external jugular vein.

Insertion Technique

The patient is placed in the supine or Trendelenburg position, with the head turned away from the insertion site. If necessary, the vein can be occluded just above the clavicle (with the forefinger of the nondominant hand) to engorge the entry site. As many as 15% of patients so not have an identifiable external jugular vein, even under optimal conditions of vein engorgement (28).

The external jugular vein has little support from surrounding structures, so the vein should be anchored between the thumb and forefinger when the needle is inserted. The bevel of the needle should be pointing upward when it enters the vein. The recommended insertion point is midway between the angle of the jaw and the clavicle (see Fig. 4.5). Use a 16-gauge single-lumen catheter that is 10 to 15 cm in length. If the catheter does not advance easily, do not force it, as this may result in vascular perforation at the junction between the external jugular and subclavian veins.

Comment

This approach is best reserved for temporary access in patients with a severe coagulopathy, particularly when the operator is inexperienced and does not feel comfortable cannulating the subclavian or internal jugular veins. Contrary to popular belief, cannulation of the external jugular is not always easier to accomplish than central venous cannulation because of the difficulty in advancing catheters past the acute angle at the junction of the subclavian vein.

THE FEMORAL VEIN

The femoral vein is the easiest of the large veins to cannulate and also does not carry a risk of pneumothorax. The disadvantages associated with this route are venous thrombosis (10%), femoral artery puncture (5%), and limited ability to flex the hip (which can be bothersome for awake patients). Contrary to popular belief, the infection rate with femoral vein catheters is no different from that of subclavian or internal jugular vein catheters (28).

Anatomy

The anatomy of the femoral sheath is shown in Figure 4.6. The femoral vein is the most medial structure in the femoral sheath and is situated just medial to the femoral artery. At the inguinal ligament, the femoral vessels are just a few centimeters below the skin surface.

Insertion Technique

Palpate the femoral artery just below the inguinal crease and insert the needle (bevel up) 1 to 2 cm medial to the palpated pulse. Advance the needle at a 45° angle to the skin surface, entering the vein at a depth of 2 to 4 cm. Once in the vessel, if the catheter or guidewire will not pass beyond the tip of the needle, tilt the needle so that it is more parallel to the skin surface (this may move the needle tip away from the far side of the vessel wall and into more direct contact with the lumen of the vessel). Femoral vein catheters should be at least 15 cm long.

Blind Insertion

If the femoral artery pulse is not palpable, draw an imaginary line from the anterior superior iliac crest to the pubic tubercle, and divide the line into three equal segments. The femoral artery lies at the junction between the middle and most medial segment, and the femoral vein is 1 to 2 cm medial to this point. This method of locating the femoral vein has a reported success rate of over 90% (29).

Comment

Femoral vein cannulation is usually reserved for patients who are paralyzed or comatose and immobile. This approach is not recommended for cardiopulmonary resuscitation (because of the delayed transit times for bolus drug injections) (18) or in patients with bleeding disorders (28).

THE FEMORAL ARTERY

Cannulation of the femoral artery is usually reserved for situations where radial artery cannulation is unsuccessful or contraindicated. Despite its reserve status, the femoral artery is larger than the radial artery, and is easier to cannulate. The complications of femoral artery cannulation are the same as for radial artery cannulation (thrombosis, bleeding, and infection). The incidence of infection is the same with radial and femoral artery catheters, and the incidence of thrombosis is lower with femoral artery cannulation (2). Thrombosis of the femoral artery, like that in the radial artery, only rarely results in troublesome ischemia in the distal extremity (2).

Localization and cannulation of the femoral artery proceeds as described in the section on femoral vein cannulation. The Seldinger technique is preferred for catheter insertion, and catheters should be 18 gauge in diameter and 15 to 20 cm long.

Comment

Femoral artery cannulation is a viable alternative and may be preferable to radial artery cannulation in patients who are paralyzed or otherwise immobile, unless they have a significant coagulopathy (in which case the radial artery is preferred). The incidence of thrombotic complications is lower in femoral artery cannulations, and the pressure in the femoral artery more closely approximates the pressure in the aorta than does the pressure in the radial artery (see Chapter 8).

IMMEDIATE CONCERNS

VENOUS AIR EMBOLISM

Inadvertent air entry is one of the most feared complications of central venous cannulation. The importance of maintaining a closed system during insertion is highlighted by the following statement:

A pressure gradient of 4 mm Hg along a 14-gauge catheter can entrain air at a rate of 90 mL/second and can produce a fatal air embolus in 1 second (30).

Preventive Measures

Prevention is the hallmark of reducing the morbidity and mortality of venous air embolism. The most effective method of preventing air entry is to keep the venous pressure more positive than atmospheric pressure. This is facilitated by placing the patient in the Trendelenburg position with the head 15° below the horizontal plane. Remember that the Trendelenburg position does not prevent venous air entry because patients still generate negative intrathoracic pressures while in the Trendelenburg position. When changing connections in a central venous line, a temporary positive pressure can be created by having the patient hum audibly. This not only produces a positive intrathoracic pressure, but allows clinicians to hear when the intrathoracic pressure is positive. In ventilator-dependent patients, the nurse or respiratory therapist should initiate a mechanical lung inflation when changing connections.

Clinical Presentation

The usual presentation is acute onset of dyspnea that occurs during the procedure. Hypotension and cardiac arrest can develop rapidly. Air can pass across a patent foramen ovale and obstruct the cerebral circulation, producing an acute ischemic stroke. A characteristic "mill wheel" murmur can be heard over the right heart, but this murmur may be fleeting.

Therapeutic Maneuvers

If a venous air embolism is suspected, immediately place the patient with the left side down, and attempt to aspirate air directly from the venous line. In dire circumstances, a needle should be inserted through the chest wall and into the right ventricle to aspirate the air. Unfortunately, the mortality in severe cases of venous air embolism remains high despite these maneuvers.

PNEUMOTHORAX

Pneumothorax is a concern primarily with subclavian vein cannulation but can also complicate jugular vein cannulation (2,30). This is one reason that postinsertion chest films are recommended after all central venous cannulations (or attempts). If possible, postinsertion films should be obtained in the upright position and during expiration. Expiratory films facilitate the detection of small pneumothoraxes because expiration decreases the volume of air in the lungs, but not the volume of air in the pleural space. Thus, during expiration, the volume of air in the pleural space is a larger fraction of the total volume of the hemithorax, thereby magnifying the radiographic appearance of the pneumothorax (31).

Upright films are not always possible in ICU patients. When supine films are necessary, remember that pleural air does not often collect at the apex of the lung when the patient is in the supine position (32,33). In this situation, pleural air tends to collect in the subpulmonic recess and along the anteromedial border of the mediastinum (see Chapter 28).

Delayed Pneumothorax

Pneumothoraxes may not be radiographically evident until 24 to 48 hours after central venous cannulation (31,33). Therefore, the absence of a pneumothorax on an immediate postinsertion chest film does not absolutely exclude the possibility of a catheter-induced pneumothorax. This is an important consideration in patients who develop dyspnea or other signs of pneumothorax in the first few days after central venous cannulation. In the absence of signs and symptoms, there is little justification for serial chest films following central venous catheter placement.

CATHETER TIP POSITION

The properly placed central venous catheter should run parallel to the superior vena cava, and the tip of the catheter should be positioned above the junction of the superior vena cava and right atrium. The following conditions warrant corrective measures.

Tip Against the Wall of the Vena Cava

Catheters inserted from the left side must make an acute turn downward when they reach the superior vena cava. If they fail to make this turn, the catheters can end up in a position like the one shown in Figure 4.7. The tip of the catheter is up against the lateral wall of the vena cava, and in this position, the catheter tip can stab the vessel wall and perforate the vena cava. Therefore, catheters that abut the wall of the vena cava should be repositioned as soon as possible. (The problem of vascular perforation is discussed in more detail in Chapter 5.)

Tip in the Right Atrium

The Food and Drug Administration has issued a strong warning about the risk of cardiac perforation from catheter tips that are advanced into the heart (24). However, cardiac perforation is a rare complication of central venous cannulation (27), even though over half of central venous catheters may be misplaced in the right atrium (27). Nevertheless, tamponade is often fatal, so cardiac placement of catheters should be avoided. A few measures help to minimize the risk of cardiac perforation. The most effective measure is to use shorter catheters, as recommended earlier. The tip of indwelling catheters should be above the third right costal cartilage (this is the level where the vena cava meets the right atrium). If the anterior portion of the third rib cannot be visualized, keep the catheter tip at or above the tracheal carina.

THE THREAT OF OXIDANT INJURY

INTRODUCTION

All human things are subject to decay.
John Dryden

The treatment of critically ill patients is dominated by the notion that promoting the supply of oxygen to the vital organs is a necessary and life-sustaining measure. Oxygen is provided in a liberal and unregulated fashion, while the tendency for oxygen to degrade and decompose organic (carbon-based) matter is either overlooked or underestimated. In contrast to the notion that oxygen protects cells from injury in the critically ill patient, the accumulated evidence over the past 15 years suggests that oxygen is responsible for the cell injury that accompanies critical illness. Oxygen's ability to act as a lethal toxin has monumental implications for the way we treat critically ill patients.

THE OXIDATION REACTION

An oxidation reaction is a chemical reaction between oxygen and another chemical species. Because oxygen removes electrons from other atoms and molecules, oxidation is also described as the loss of electrons by an atom or molecule. The chemical species that removes the electrons is called an oxidizing agent or oxidant. The companion process (i.e., the gain of electrons by an atom or molecule) is called a reduction reaction, and the chemical species that donates the electrons is called a reducing agent. Because oxidation of one atom or molecule must be accompanied by reduction of another atom or molecule, the overall reaction is often called a redox reaction.

When an organic molecule (a molecule with a carbon skeleton) reacts with oxygen, electrons are removed from carbon atoms in the molecule. This disrupts one or more covalent bonds, and as each bond ruptures, energy is released in the form of heat and light (and sometimes sound). The organic molecule then breaks into smaller fragments. When oxidation is complete, the parent molecule is broken down into the smallest molecules capable of independent existence. Because organic matter is composed mainly of carbon and hydrogen, the end-products of oxidation are simple combinations of oxygen with carbon and hydrogen: carbon dioxide and water.

OXYGEN METABOLISM

Oxygen is a weak oxidizing agent, but some of its metabolites are potent oxidants capable of producing widespread and lethal cell injury (1). The mechanism whereby oxygen metabolism can produce more powerful oxidants than the parent molecule is related to the atomic structure of the oxygen molecule, which is described below.

THE OXYGEN MOLECULE

Oxygen in its natural state is a diatomic molecule, as shown by the familiar O2 symbol at the top of Figure 3.1. The orbital diagram to the right of the O2 symbol shows how the outer electrons of the oxygen molecule are arranged. The circles in the diagram represent orbitals. (An orbital is an energy field that can be occupied by electrons. It is distinct from an orbit, which is a path that represents a specific point in space and time.) The arrows in the diagram represent electrons that are spinning in the same or opposite directions (indicated by the direction of the arrows). Note that one of oxygen's orbitals contains two electrons with opposing spins, and the other two orbitals each contain a single electron spinning in the same direction. The orbital with the paired electrons is obeying one of the basic rules of the quantum atom: An electron orbital can be occupied by two electrons if they have opposing spins. Thus, the two outermost orbitals that contain single electrons are only half full, and their electrons are unpaired. An atom or molecule that has one or more unpaired electrons in its outer orbitals is called a free radical (2). (The term free indicates that the atom or molecule is capable of independent existence—it is free-living.)

Free radicals tend to be highly reactive chemical species by virtue of their unpaired electrons. However, not all free radicals are highly reactive. This is the case with oxygen, which is not a highly reactive molecule despite having two unpaired electrons.

The reason for oxygen's sluggish reactivity is the directional spin of its two unpaired electrons. No two electrons can occupy the same orbital if they have the same directional spin. Thus, an electron pair cannot be added to oxygen because one orbital would have two electrons with the same directional spin, which is a quantum impossibility. This spin restriction limits oxygen to single electron additions, and this not only increases the number of reactions needed to reduce molecular oxygen to water, but it also produces more highly reactive intermediates.

THE METABOLIC PATHWAY

Oxygen is metabolized at the very end of the electron transport chain, where the electrons and protons that have completed the transport process are left to accumulate. The complete reduction of molecular oxygen to water requires the addition of four electrons and four protons, as shown in the reaction sequence in Figure 3.1. Each metabolite in this sequence is accompanied by an orbital diagram to demonstrate the changes occurring at each point in the pathway.

Superoxide Radical

The first reaction adds one electron to oxygen, and produces the superoxide radical.

O2 = e- --» O2.
(3.1)

Note the superscript dot on the superoxide symbol. This signifies an unpaired electron, and is the conventional symbol for a free radical. The superoxide radical has one unpaired electron, and thus is less of a free radical than oxygen. Superoxide is neither a highly reactive radical nor a potent oxidant (3). Nevertheless, it has been implicated in conditions associated with widespread tissue damage, such as the reperfusion injury that follows a period of ischemia (2). The toxicity of superoxide may be caused by the large daily production, which is estimated at 1 billion molecules per cell, or 1.75 kg (4 lb) for a 70-kg adult (4).

Hydrogen Peroxide

The addition of one electron to superoxide creates hydrogen peroxide, a strong oxidizing agent (and the source of acid rain in the atmosphere) (5).

O2. + e- + 2H+ -- H2O2
(3.2)

Hydrogen peroxide is very mobile, and crosses cell membranes easily. It is a powerful cytotoxin and is well known for its ability to damage endothelial cells. It is not a free radical, but it may have to generate a free radical (a hydroxyl radical) to express its toxicity.

Hydrogen peroxide is loosely held together by a weak oxygen-oxygen bond (this bond is represented by the lower orbital in the orbital diagram for hydrogen peroxide). This bond ruptures easily, producing two hydroxyl radicals, each with one unpaired electron. An electron is donated to one of the hydroxyl radicals, creating one hydroxyl ion (OH-) and one hydroxyl radical (•OH). The electron is donated by iron in its reduced form, Fe(II), which serves as a catalyst for the reaction. Iron is involved in many free radical reactions, and is considered a powerful pro-oxidant. The role of transition metals in free radical reactions is discussed again later in the chapter.

Hydroxyl Radical

The iron-catalyzed dissociation of hydrogen peroxide proceeds as follows:

H2O2 + FE(II) --» OH- + .OH + FE(III)
(3.3)

(Note that Roman numerals are used instead of plus signs to designate the oxidation state of iron, as recommended by the International Union of Chemistry.) The hydroxyl radical is the ace of free radicals. It is one of the most reactive molecules in biochemistry and often reacts with another chemical species within five molecular diameters from its point of origin (2). This high degree of reactivity limits the mobility of the hydroxyl radical, and this may serve as a protective device to limit the toxicity of the hydroxyl radical. However, the hydroxyl radical is always dangerous because it can oxidize any molecule in the human body.

Hypochlorous Acid

The metabolism of oxygen in neutrophils has an additional pathway (not shown in Figure 3.1) that uses a myeloperoxidase enzyme to chlorinate hydrogen peroxide, creating hypochlorous acid (hypochlorite).

H2O2 + 2Cl- --» 2HOCL
(3.4)

When neutrophils are activated, the conversion of oxygen to superoxide increases twentyfold. This is called the respiratory burst, which is an unfortunate term because the increased O2 consumption has nothing to do with energy metabolism. When the increased metabolic traffic reaches hydrogen peroxide, about 40% is diverted to hypochlorite production and the remainder forms hydroxyl radicals (6). Hypochlorite is the active ingredient in household bleach. It is a powerful germicidal agent and requires only milliseconds to produce lethal damage in bacteria (7).

Water

The final reaction in oxygen metabolism adds an electron to the hydroxyl radical and produces two molecules of water.

.OH + OH- + e- + 2H+ -- 2H2O
(3.5)

Therefore, the metabolism of one molecule of oxygen requires four chemical reactions, each involving the addition of a single electron. This process, then, requires four reducing equivalents (electrons and protons).

Under normal conditions, about 98% of the oxygen metabolism is completed, and less than 2% of the metabolites escape into the cytoplasm (3). This is a tribute to cytochrome oxidase, which carries on the reactions in a deep recess that effectively blocks any radical escape. This degree of suppression is necessary because of the ability of free radicals to start chain reactions (see next section).

Proposed Scheme

The superoxide radical is mobile but not toxic, whereas the hydroxyl radical is toxic but not mobile. Combining the advantages of each oxidant yields a scheme that has the mobile oxidant serving as a transport vehicle that can reach distant places. Once at the desired location, this metabolite could then generate hydroxyl radicals to produce local damage (3). This scheme is intuitively satisfying, regardless of its validity.

FREE RADICAL REACTIONS

The damaging effects of oxidation are largely the result of free radical reactions. This section describes the two basic types of free radical reactions: those involving free radicals and nonradicals and those involving two free radicals.

RADICAL AND NONRADICAL

When a free radical reacts with a nonradical, the nonradical loses an electron and is transformed into a free radical. Therefore, the union of a radical and a nonradical begets another radical (thus illustrating the survival value of the free radical). Because free radicals are often highly reactive in nature. This type of radical-regenerating reaction tends to become repetitive, creating a series of self-sustaining reactions known collectively as a chain reaction (3). The tendency to produce chain reactions is one of the most characteristic features of free radical reactions. A fire is one example of a chain reaction involving free radicals, and fires illustrate a very important feature of chain reactions: the tendency to produce widespread damage. A chain reaction that is capable of producing widespread organ damage is described below.

Lipid Peroxidation

The rancidity that develops in decaying food is the result of oxidative changes in polyunsaturated fatty acids (8). This same process, called lipid peroxidation, is also responsible for the oxidative damage of membrane lipids. The lipophilic interior of cell membranes is rich in polyunsaturated fatty acids (e.g., arachidonic acid) and the characteristic low melting point of these fatty acids may be responsible for the fluidity of cell membranes. Oxidation increases the melting point of membrane fatty acids and reduces membrane fluidity. The membranes eventually lose their selective permeability and become leaky, predisposing cells to osmotic disruption (8).

The peroxidation of membrane lipids proceeds as shown in Figure 3.2. The reaction sequence is initiated by a strong oxidant such as the hydroxyl radical, which removes an entire hydrogen atom (proton and electron) from one of the carbon atoms in a polyunsaturated fatty acid. This creates a carbon-centered radical (C•), which is then transformed into an oxygen-centered peroxy radical (COO•) that can remove a hydrogen atom from an adjacent fatty acid and initiate a new series of reactions. The final propagation reaction creates a self-sustaining chain reaction that will continue until the substrate (i.e., fatty acid) is exhausted, or until something interferes with the propagation reaction. (The latter mechanism is the basis for the antioxidant action of vitamin E, which is described later.)

Implications

Free radical reactions have been implicated in the pathogenesis of more than 100 diseases (9), but it is not clear whether oxidant injury is a cause or a consequence of disease (9,10). However, a chain reaction is an independent process (i.e., independent of the initiating process), and if it causes tissue injury it becomes an independent pathologic process (a primary illness).

RADICAL AND RADICAL

Two radicals can react by sharing electrons to form a covalent bond. This eliminates the free radicals but does not necessarily eliminate the risk of toxicity. In the example below, the product of a radical-radical reaction is much more destructive than both radicals combined.

Nitric Oxide Transformation

Nitric oxide has been placed in a category of its own as a free radical because of its beneficial actions as a vasodilator, neurotransmitter, and bactericidal agent (11). The regard for nitric oxide has been so favorable that it was named "Molecule of the Year" by Science Magazine in 1992. However, despite its favorable profile, nitric oxide can become a toxin in the presence of superoxide. The reaction of superoxide with nitric oxide generates a powerful oxidant called peroxynitrite, which is 2000 times more potent than hydrogen peroxide as an oxidizing agent (12). Peroxynitrite can either cause direct tissue damage or can decompose and produce hydroxyl radicals and nitrogen dioxide.

NO. + O2. --» ONOOO-(peroxynitrite)
(3.6)

ONOOOH --» .OH + NO2
(3.7)

The transformation of nitric oxide into a source of oxidant injury demonstrates how free radicals can promote oxidant damage indirectly.

ANTIOXIDANT PROTECTION

Evidence for endogenous antioxidant protection is provided by the simple observation that accelerated decay begins at the moment of death. This section presents the substances that are believed to play a major role in this protection.

An antioxidant is defined as any chemical species that can reduce or delay the oxidation of an oxidizable substrate (2). The nonenzyme antioxidants are included in Table 3.1.

ENZYME ANTIOXIDANTS

There are three enzymes that function as antioxidants, shown in Figure 3.3. Note that the reaction sequence in this figure is the same as in Figure 3.1.

Superoxide Dismutase

The discovery of superoxide dismutase (SOD) enzyme in 1969 was the first indication of free radical activity in humans, and this began the frenzy of interest in free radicals. The role of SOD as an antioxidant is not clear. In fact, SOD promotes the formation of hydrogen peroxide, which is an oxidant. How can an enzyme that promotes the formation of an oxidant be defined as an antioxidant? In fact, if SOD increases the metabolic traffic flowing through hydrogen peroxide, and the catalase and peroxidase reactions are unable to increase their activity proportionally, the hydrogen peroxide levels may rise, and in this situation SOD functions as a pro-oxidant (13). Thus, SOD is not an antioxidant at least some of the time.

Catalase

Catalase is an iron-containing heme protein that reduces hydrogen peroxide to water. It is present in most cells, but is lowest in cardiac cells and neurones. Inhibition of the catalase enzyme does not enhance the toxicity of hydrogen peroxide for endothelial cells (14), so the role of this enzyme as an antioxidant is unclear.

Glutathione Peroxidase

The peroxidase enzyme reduces hydrogen peroxide to water by removing electrons from glutathione in its reduced form and then donating the electrons to hydrogen peroxide. Glutathione is returned to its reduced state by a reductase enzyme that transfers the reducing equivalents from NADPH. The total reaction can be written as follows:

Peroxidase reaction: H2O2 + 2GSH --» 2H2O + GSSG
(3.8)

Reductase reaction: NADPH + H + GSSG --» 2GSH + NADP
(3.9)

where GSSG and GSH are oxidized and reduced glutathione, respectively.

Selenium

The activity of the glutathione peroxidase enzyme in humans depends on the trace element selenium. Selenium is an essential nutrient with a recommended dietary allowance of 70 ug daily for men and 55 ug daily for women (15). Despite this recommendation, selenium is not included in most total parenteral nutrition regimens. Because the absence of dietary selenium produces measurable differences in glutathione peroxidase activity after just 1 week (16), the routine administration of selenium seems justified. However, selenium, has no clear-cut deficiency syndrome in humans, so there is little impetus to provide selenium on a routine basis.

Selenium status can be monitored with whole blood selenium levels. The normal range is 0.5 to 2.5 mg/L. Selenium can be provided intravenously as sodium selenite (17). The highest daily dose that is considered safe is 200 ug, given in divided doses (50 ug intravenously every 6 hours).

NONENZYME ANTIOXIDANTS

Glutathione

One of the major antioxidants in the human body is a sulfur-containing tripeptide glutathione (glycine-cysteine-glutamine), which is present in molar concentrations (0.5 to 10 mM/L) in most cells (18,19). Glutathione is a reducing agent by virtue of a sulfhydryl group in the cysteine residue of the molecule. It is normally in the reduced state (GSH), and the ratio of reduced to oxidized forms is 10:1. The major antioxidant action of glutathione is to reduce hydrogen peroxide directly to water, which diverts hydrogen peroxide from producing hydroxyl radicals. Glutathione is found in all organs, but is particularly prevalent in the lung, liver, endothelium, and intestinal mucosa. It is primarily an intracellular antioxidant, and plasma levels of glutathione are three orders of magnitude lower than intracellular levels.

Glutathione does not cross cell membranes directly, but is broken down first into its constituent amino acids and then reconstituted on the other side of the membrane. It is synthesized in every cell of the body, and largely remains sequestered within cells. Exogenous glutathione has little effect on intracellular levels (20), which limits the therapeutic value of this agent.

N-Acetylcysteine

N-Acetylcysteine, a popular mucolytic agent (Mucomyst), is a sulfhydryl-containing glutathione analog capable of passing readily across cell membranes. N-Acetylcysteine is effective as a glutathione analog in acetaminophen toxicity, which is the result of an overwhelmed glutathione detoxification pathway (see Chapter 53). Therefore, N-acetylcysteine has a proven track record as an exogenous glutathione analog.

N-Acetylcysteine may prove to be a valuable antioxidant for therapeutic use. It protects the myocardium from ischemic injury, and has been successful in reducing the incidence of reperfusion injury during cardiac catheterization (21). It has also been used with some success in treating critically ill patients with acute respiratory distress syndrome and inflammatory shock syndromes (22,23).

Vitamin E

Vitamin E (a-tocopherol) is a lipid-soluble vitamin that functions primarily as an antioxidant that antagonizes the peroxidative injury of membrane lipids. It is the only antioxidant capable of halting the propagation of lipid peroxidation. The mechanism for this action is shown in Figure 3.4. Vitamin E inhabits the lipophilic interior of cell membranes, where the polyunsaturated fatty acids are also located. When a propagating wave of lipid peroxidation reaches vitamin E, it is oxidized to a free radical, thereby sparing any adjacent polyunsaturated fatty acids from oxidation. The vitamin E radical is poorly reactive, and this halts the propagation of the peroxidation reactions. This action has earned vitamin E the title of a chain-breaking antioxidant. The vitamin E radical is transformed back to vitamin E, and vitamin C can act as the electron donor in this reaction.

Vitamin E deficiency may be common in critically ill patients (24). The normal vitamin E level in plasma is 1 mg/dL, and a level below 0.5 mg/dL is evidence of deficiency (25). Considering the important role of vitamin E as an antioxidant, it seems wise to check the vitamin E status in patients who are at risk for oxidant injury (see Table 3.2).

Vitamin C

Vitamin C (ascorbic acid) is a reducing agent that can donate electrons to free radicals and fill their electron orbitals. It is a water-soluble antioxidant, and operates primarily in the extracellular space. Vitamin C is found in abundance in the lung, where it may play a protective role in inactivating pollutants that enter the airways.

The problem with vitamin C is its tendency to promote (rather than retard) the formation of oxidants in the presence of iron and copper (26-28). Vitamin C reduces iron to the Fe(II) state, and this normally aids in the absorption of iron from the intestinal tract. However, Fe(II) can promote the production of hydroxyl radicals, as described earlier. Thus, vitamin C can function as a pro-oxidant by maintaining iron in its reduced or Fe(II) state. The reactions involved are as follows:

Ascorbate + Fe(III) --» Fe(II) + Dehydroascorbate
(3.10)

Fe(II) + H2O2 --» .OH + OH- + Fe(III)
(3.11)

Several conditions that are common in ICU patients can promote an increase in free iron. Among these are inflammation, blood transfusions, and reductions in binding proteins. The prevalence of these conditions raises serious concerns about the use of vitamin C as an exogenous antioxidant in the ICU patient population.

Plasma Antioxidants

The plasma components with antioxidant activity are listed at the very bottom of Table 3.2. Most of the antioxidant activity in plasma can be traced to two proteins that make up only 4% of total plasma protein pool (27): ceruloplasmin (the copper transport or storage protein) and transferrin. Transferrin binds iron in the Fe(III) state, and ceruloplasmin oxidizes iron from the Fe(II) to Fe(III) state. Therefore, ceruloplasmin helps transferrin to bind iron, and both proteins then act to limit free iron in the plasma. For this reason, iron sequestration has been proposed as the major antioxidant activity in plasma (24). This is consistent with the actions of Fe(II) to promote free radical production, as shown in Figure 3.1.

OXIDANT STRESS

The risk and severity of oxidation-induced tissue injury are determined by the balance between oxidant and antioxidant activities. When oxidant activity exceeds the neutralizing capacity of the antioxidants, the excess or unopposed oxidant activity can promote tissue injury. This condition of unopposed biological oxidation is known as oxidant stress (29).

PREDISPOSING CONDITIONS

Any imbalance in the activities of oxidants and antioxidants can result in unopposed oxidation. The box plots in Figure 3.5 show the effects of two conditions that promote oxidant-antioxidant imbalance on the level of oxidant stress in humans. The index of oxidant stress in this study is the activity of lipid hydroperoxides in urine, measured as spontaneous chemiluminescence and reported in counts per minute (CPM). Healthy, nonsmoking adults (the control group) show the lowest level of oxidant activity. The effects of an increase in oxidant burden is shown in a group of heavy smokers (one puff of a cigarette contains roughly one billion free radicals). The effects of a deficiency in antioxidant protection are shown for a group of patients with human immunodeficiency virus (HIV) infection (glutathione deficiency is common in HIV infections) (30). Each of the predisposing conditions is accompanied by a significant increase in oxidant activity in comparison to the activity in the healthy, control subjects. Note also that the HIV patients have ongoing oxidant stress when they are symptom-free. This supports the notion that oxidant stress is a cause and not a consequence of pathologic organ injury.

CLINICAL DISEASE

As mentioned earlier, oxidants have been implicated in the pathogenesis of more than 100 clinical diseases (9); the ones most likely to be encountered in the ICU are listed in Table 3.2. Unopposed biological oxidation has been documented in each of these clinical conditions (9,10,30-35). This does not establish a causal role for oxidation (this will require evidence that antioxidant therapy can improve outcome), but the tendency for oxidation to cause independent and progressive tissue damage (e.g., in chain reactions) is reason enough to suspect that oxidant-induced injury plays a role in these illnesses.

Inflammation

Most of the clinical conditions in Table 3.2 are accompanied by inflammation, and the conditions with multiorgan involvement are often associated with a progressive, systemic inflammatory response. As a result, inflammation has been proposed as a principal offender in pathologic forms of oxidant injury. The release of free radicals from activated neutrophils and macrophages creates an oxidant-intense environment, and the ability of host cells to withstand this oxidative assault may be the important factor in determining the clinical course of inflammatory conditions. In the desirable world, leukocyte-derived oxidants would annihilate all invading microbes, but would not affect the host cells. In the undesirable world, the inflammatory oxidants would destroy both the invader and the host. This proposed scheme is intuitively appealing, and emphasizes the value of providing antioxidants routinely in inflammatory illnesses.

Antioxidant Therapy

The value of maintaining antioxidant protection is not a debatable issue because loss of antioxidant defenses is a known cause of tissue destruction; the best example of this is the accelerated decay that occurs after death. Therefore, antioxidant supplements should be considered as a routine measure in patients who spend more than a few days in the ICU. In patients with any of the clinical conditions in Table 3.2, it would be wise to monitor some of the endogenous antioxidants (vitamin E, vitamin C, and selenium). A reduced antioxidant level in blood (or any body fluid) may not indicate a deficiency state (it may indicate that the antioxidant is being used), but would certainly be an indication to provide supplements. The real value of antioxidant therapy will be determined by clinical studies, some of which are currently in progress.

METABOLIC SUPPORT

The tendency for aerobic metabolism to generate toxins has significant implications for the approach to metabolic support in critically ill patients. When metabolically-generated oxidants overwhelm the body's antioxidant defenses, the common practice of supporting metabolism by promoting the availability of oxygen and nutrients serves only to generate more toxic metabolites. The proper maneuver here is to support the antioxidant defenses. This approach adds another dimension to the concept of metabolic support by considering the output side of metabolism. Remember that metabolism is an engine (i.e., an energy converter) and like all engines, it has an exhaust that contains noxious byproducts of combustion. The exhaust from an automobile engine adds pollutants to the atmosphere; likewise, the exhaust from a metabolic engine adds pollutants to the "biosphere."

RESPIRATORY GAS TRANSPORT

INTRODUCTION

Respiration is thus a process of combustion, in truth very slow, but otherwise exactly like that of charcoal.
Antoine Lavoisier

One of the basic elements of aerobic life is the combustion reaction, in which oxygen releases the energy stored in organic fuels and carbon dioxide is generated as a chemical byproduct. The business of aerobic metabolism is the combustion of nutrient fuels, and the circulatory system plays a dual role in supporting this process by delivering oxygen to drive the reaction and removing the carbon dioxide that is generated. Because both processes have a common purpose, the transport of oxygen and carbon dioxide in blood has been designated the respiratory function of blood. This chapter describes the basic features of each transport system, and demonstrates the central role of hemoglobin in the transport of both oxygen and carbon dioxide.

OXYGEN TRANSPORT

Oxygen is the most abundant element on the surface of the earth (1), yet because it does not dissolve readily in water, it is unavailable to cells in the interior of the body. Thus, we depend on a steady supply of this element to survive, yet we function as a natural barrier to its movement. A possible explanation for this is the role of oxygen in promoting oxidative damage, discussed in Chapter 3. For now, we will assume that oxygen is a wonderful element.

The transport system for oxygen is separated into four components: blood oxygen content, oxygen delivery in arterial blood, oxygen uptake from the microcirculation, and oxygen extraction ratio.

WHOLE BLOOD O2 CONTENT

The concentration of oxygen in arterial blood (CaO2), often called the oxygen content, is described by Equation 2.1.
CaO2 = (1.34 x Hb x SaO2) + (0.003 x PaO2)
(2.1)

The contribution of hemoglobin is described in the first term of the equation: 1.34 ´ Hb ´ SaO2. This relationship states that each gram of hemoglobin (Hb) will bind 1.34 mL O2 when it is fully saturated with oxygen. The arterial O2 saturation (SaO2) is expressed as a fraction, not a percentage (i.e., 1.0 instead of 100%). One gram of hemoglobin can actually bind 1.39 mL O2 at full saturation (2). However, a small fraction of the circulating hemoglobin is represented by forms that do not readily bind oxygen (i.e., methemoglobin and carboxyhemoglobin), so the lower binding capacity of 1.34 mL/g more accurately describes the behavior of the total pool of circulating hemoglobin. The oxygen bound by hemoglobin at a concentration of 15 g/dL and an O2 saturation of 98% will then be

1.34(mL/g) x 15(g/dL) x 0.98 = 19.7 mL/100mL
(2.2)

Note that because hemoglobin concentration is expressed in g/dL (g/100 mL), the concentration of hemoglobin-bound oxygen is expressed in mL/100 mL (volume %). The contribution of the oxygen dissolved in plasma is defined by the solubility coefficients shown in Table 2.1. At a normal body temperature of 37° C, the solubility of oxygen in plasma is .028 mL/L/mm Hg. To express the concentration in mL/100 mL, the solubility coefficient is divided by 10, creating the second term shown in Equation 2.1: 0.003 ´ PaO2. Thus, at a PaO2 of 100 mm Hg, the expected concentration of dissolved oxygen is
0.03(mL/100mL/mmHg) x 100 mmHg = 0.3 mL/100 mL
(2.3)

The total concentration of oxygen in arterial blood is then 19.7 + 0.3 = 20 mL/100 mL, or 200 mL/L. Repeating this calculation using an O2 saturation of 75% derives the O2 content in mixed venous (pulmonary artery) blood, as shown in Table 2.2.

A comparison of the total and dissolved O2 concentrations in Table 2.2 shows that hemoglobin carries 98.5% of the oxygen in arterial blood and 99.5% in mixed venous blood. If we were forced to rely solely on the 3 mL/L of dissolved oxygen in arterial blood, a cardiac output of 89 L/minute would be necessary to sustain a normal whole-body O2 consumption of 250 mL/minute.

Hemoglobin versus PaO2

To illustrate the relative strength of hemoglobin and PaO2 in determining the O2 content of blood, Table 2.3 shows the relative influence of anemia and hypoxemia on arterial oxygenation. A 50% reduction in hemoglobin (from 15 to 7.5 mg/dL) is fully expressed as a 50% reduction in CaO2. However, a 50% reduction in PaO2 (from 90 to 45 mm Hg) results in only a 20% decrease in CaO2 (which is similar to the 18% decrease in SaO2). These examples emphasize the following points:

Changes in hemoglobin concentration have a larger impact on arterial oxygenation than changes in PaO2.

Hypoxemia (a decrease in PaO2) has a relatively minor impact on arterial oxygenation if the accompanying change in SaO2 is small.

PO2 influences blood oxygenation only to the extent that it influences the saturation of hemoglobin with oxygen. Therefore, SaO2 is a more reliable index of arterial oxygenation than PaO2.

The Hemoglobin Mass

The hemoglobin concentration is traditionally expressed in grams per deciliter rather than in grams per liter, and this tends to create an underappreciation for the size of the hemoglobin pool in blood. For example, a hemoglobin concentration of 15 g/dL means that there are 150 grams of hemoglobin per liter of whole blood. Thus, a normal blood volume of 5.5 liters contains 0.825 kg, or 1.85 lb, of hemoglobin! To place this in perspective, consider that the normal weight of the heart is 0.3 kg, or about one-third the mass of circulating hemoglobin. Therefore, the heart must push three times its weight to move hemoglobin through the circulatory system. This represents a substantial work load for the heart. The reason for the size of hemoglobin pool is not clear because there is much more than needed for oxygen transport. The answer may be that hemoglobin has other functions in addition to oxygen transport, as discussed later in the chapter.

OXYGEN DELIVERY (DO2)

The oxygen transport parameters are shown in Table 2.4. Transport in arterial blood is described by oxygen delivery (DO2), which is defined as the product of the cardiac output (Q) and the arterial oxygen content (CaO2).

DO2 = Q x CaO2 = Q x (1.34 x Hb x SaO2) x 10
(2.4)

Note that the dissolved oxygen component is eliminated. The factor 10 converts the final units to mL/minute. If the cardiac index (cardiac output divided by the body surface area) is used to derive the DO2, the units are expressed as mL/minute/m2. As shown in Table 2.4, the normal range for DO2 is 520 to 570 mL/minute/m2.

OXYGEN UPTAKE (VO2)

The oxygen uptake from the microcirculation is a function of the cardiac output and the difference in oxygen content between arterial and venous blood; that is, VO2 = Q ´ (CaO2 - CVO2). Because CaO2 and CVO2 share the same term for hemoglobin binding (1.34 ´ Hb), this term can be isolated to create Equation 2.5.

VO2 = Q x 13.4 x Hb x (SaO2 - SvO2)
(2.5)

The factor 1.34 has been multiplied by 10 to convert units. This relationship is depicted schematically in Figure 2.1. As indicated in Table 2.4, the normal range for the VO2 is 110 - 160 mL/minute/m2.

OXYGEN EXTRACTION RATIO (O2ER)

The oxygen extraction ratio (O2ER) is the ratio of O2 uptake to O2 delivery (VO2/DO2), and is the fraction of the oxygen delivered to the microcirculation that is taken up into the tissues. The ratio can be multiplied by 100 to generate a percentage.

O2ER = VO2/DO2x100
(2.6)

The normal O2ER is 0.2 to 0.3 (20 to 30%), indicating that 20 to 30% of the oxygen delivered to the capillaries is taken up into the tissues. Thus, only a small fraction of the available oxygen in capillary blood is used to support aerobic metabolism. Oxygen extraction is adjustable, and in conditions where O2 delivery is impaired, the O2ER can increase to 0.5 to 0.6. In trained athletes, the O2ER can be as high as 0.8 during maximal exercise (3). Adjustments in O2 extraction play an important role in maintaining oxygen uptake when oxygen delivery is variable, as described in the next section.

CONTROL OF OXYGEN UPTAKE

The oxygen transport system normally operates to maintain a constant rate of oxygen uptake (VO2) in conditions where O2 delivery (DO2) can vary widely (3). This is accomplished by compensatory adjustments in O2ER in response to changes in DO2. The O2ER describes the relationship between O2 and DO2; that is, O2ER = VO2/DO2, which can be rearranged as shown in Equation 2.7.

VO2 = DO2 x O2ER
(2.7)

According to this relationship, when a decrease in DO2 is accompanied by a proportional increase in O2ER, the VO2 remains constant. However, when the O2ER is fixed, a decrease in DO2 is accompanied by a proportional decrease in VO2. The adjustability of the O2 extraction therefore defines the tendency for VO2 to change in response to variations in O2 delivery. The normal relationship between DO2 and VO2 is described in the next section.

THE DO2-VO2 CURVE

The relationship between O2 delivery and O2 uptake is described by the curve in Figure 2.2, where O2 delivery is the independent variable. As the O2 delivery decreases below normal, the O2ER increases proportionally and the VO2 remains constant. When the O2ER reaches its maximum level (0.5 to 0.6), further decreases in DO2 are accompanied by proportional decreases in VO2. In the linear portion of the curve, the VO2 is supply-dependent and the production of adenosine triphosphate (ATP) is limited by the supply of oxygen. This condition of oxygen-limited energy production is called dysoxia (4).

Critical O2 Delivery

The DO2 at which the VO2 becomes supply-dependent is called the critical oxygen delivery, and is the point at which energy production in cells becomes oxygen-limited (dysoxia). The critical DO2 in anesthetized subjects is in the vicinity of 300 mL/minute/m2, but in critically ill patients, the critical DO2 varies widely, from 150 to 1000 mL/minute/m2 (3). Regardless of the source of this variability, it means that the critical DO2 must be determined for each individual patient in the ICU.

Supply-Dependent VO2

In critically ill patients, the DO2-VO2 relationship can be linear over a wide range, and the supply-dependent VO2 in these patients can be the result of three possible conditions (3-6). One condition is pathologic supply dependency, where ATP production is limited by the supply of oxygen (dysoxia). This condition produces the supply dependency at very low levels of DO2 in Figure 2.2. Another condition is physiologic supply dependency, where VO2 is the independent variable and DO2 changes in response to a primary change in the metabolic rate (6). This condition is responsible for the linear DO2-VO2 relationship seen during exercise, and may be responsible for supply dependency in critically ill patients. Most importantly, it indicates that a linear DO2-VO2 relationship may not be the result of a pathologic process. Finally, supply dependency may be an artifact produced when VO2 is calculated and not directly measured. This latter possibility is discussed in more detail in Chapter 13.

The relationship between DO2 and VO2 is an important component of oxygen transport monitoring in the ICU, and can be used to identify tissue ischemia (e.g., pathologic supply dependency) or to create a therapeutic strategy (e.g., increasing DO2 when the O2 extraction is maximal). The applications of oxygen transport monitoring in the care of critically ill patients is described in Chapter 13.

CARBON DIOXIDE TRANSPORT

Carbon dioxide is the major end-product of oxidative metabolism (7) and, because it is capable of transforming into carbonic acid when hydrated, it can cause problems if allowed to accumulate. The value of CO2 elimination is apparent in the operation of the ventilatory control system; that is, the ventilatory control system is designed to regulate carbon dioxide and to promote its elimination through the lungs. An increase in PCO2 of 5 mm Hg can result in a twofold increase in minute ventilation. To produce an equivalent increment in ventilation, the arterial PO2 must drop to 55 mm Hg (8). Thus, the ventilatory control system keeps a close eye on CO2, but pays little attention to oxygen (whereas clinicians keep a close eye on oxygen and pay little attention to CO2).

TOTAL BODY CO2

Carbon dioxide is more soluble in water than oxygen, and thus moves more freely in the body fluids. However, the total body content of CO2 is reported as 130 L (9), which seems to be quite a trick, considering that the average adult has no more than 40 to 50 L of water to spare. The explanation for this is that the CO2 enters into a chemical reaction with water. This allows large volumes of CO2 to enter a solution because the reaction with water dissociates CO2 and maintains the gradient that drives the gas into solution. Opening a bottle of warm champagne or a warm beer demonstrates how much CO2 can be present in a solution.

WHOLE BLOOD CO2 CONTENT

Unlike oxygen, the CO2 content of whole blood cannot be derived using simple equations. The reason for this will become apparent as the CO2 transport process is revealed. However, the fraction of CO2 dissolved in plasma can be defined using the solubility coefficients for CO2 shown in Table 2.1. At a normal body temperature of 37° C, the concentration of dissolved CO2 is 0.686 mL/L/mm Hg. At a PCO2 of 40 mm Hg, the dissolved CO2 in arterial blood is (40 ´ .68) 26 mL/L, as shown in Table 2.2. When compared with the total CO2 content, it is apparent that only a small fraction of the CO2 is present in the dissolved form.

TRANSPORT SCHEME

The centerpiece of CO2 transport is the hydration reaction, and Figure 2.3 shows how the reaction participates in the transport process. The first step in the hydration reaction is the formation of carbonic acid (H2CO3). This is normally a slow reaction, and takes about 40 seconds to complete (10). The reaction speeds up considerably in the presence of the enzyme carbonic anhydrase, and takes less than 10 milliseconds to complete (10). Carbonic anhydrase is confined to the red cell, and is not present in plasma. Thus, CO2 is rapidly hydrated only in the red cell, so CO2 is drawn into the red cell.

Carbonic acid dissociates to generate hydrogen and bicarbonate ions. A large fraction of the bicarbonate generated in the red cell is pumped back into the plasma in exchange for chloride. The hydrogen ion generated in the red cell is buffered by the hemoglobin. In this way, the CO2 that enters the red cell is dismantled, and the parts stored (hemoglobin) or discarded (bicarbonate) to create room for more CO2 to enter the red cell. These processes, along with the carbonic anhydrase-facilitated hydration reaction, create a sink for large volumes of CO2 in the red cell.

A small fraction of CO2 in the red cell reacts with free amino groups on hemoglobin. This produces carbamic acids, which dissociate into hydrogen ions and carbamino residues (HbNHCOO-). This reaction is not a major component of CO2 transport.

Unit Conversions

If the values in Figure 2.3 are added up, the total CO2 content is 23 mEq/L in whole blood, with 17 mEq/L in plasma and 6 mEq/L in the red cell. Thus, most of the CO2 appears to be in the plasma, but this is deceiving because much of the plasma component is in the form of bicarbonate that has been expelled from the red blood cell.

Because CO2 is a ready source of ions (hydrogen and bicarbonate), the concentration of CO2 is often expressed in mEq/L. This is the case in Figure 2.3. The conversion is based on the following: 1 mole of CO2 has a volume of 22.3 L (STPD), so 1 mM CO2 is approximately 22.3 mL and 1 mM/L CO2 is approximately 22.3 mL/L or 2.23 mL/100 mL (vol%). Therefore,

CO2(mEq/L) = CO2mL/100mL/2.23
(2.8)

HEMOGLOBIN AS A BUFFER

As mentioned earlier, the mass of hemoglobin in circulating blood is far greater than what is needed to transport oxygen, and moving this excess hemoglobin represents a considerable work load for the heart. This would make the circulatory system an energy-inefficient system unless the excess hemoglobin is required for some other vital function. As shown in Figure 2.3, hemoglobin has an important role in the transport of carbon dioxide. Considering the large volume of CO2 in the blood, the large size of the hemoglobin pool becomes more understandable.

The function of hemoglobin in CO2 transport is to act as a buffer for the hydrogen ions that are produced by the hydration of CO2 in the red blood cell. The ability of hemoglobin to act as a buffer has been recognized since the 1930s, but this property of hemoglobin receives little attention. The buffer capacity of hemoglobin is shown in Table 2.5 (11). Note that the total buffering capacity of hemoglobin is six times as great as the buffering capacity of all the plasma proteins combined. A small part of this difference is due to the enhanced buffer capacity of the hemoglobin molecule, but most of the difference is due to the enormous size of the circulating hemoglobin pool.

The buffering actions of hemoglobin are caused by the histidine residues on the molecule. The imidazole group in histidine is responsible for the buffering actions, and is most effective at a pH of 7.0 (the dissociation constant of imidazole has a pK = 7.0, and buffers are most effective within 1 pH unit on either side of the pK). This means that hemoglobin is an effective buffer in the usual pH range of blood. In fact, hemoglobin should be more effective as a buffer than bicarbonate because the pK of carbonic acid is 6.1, which is outside the usual pH range of blood.

Thus, hemoglobin is the focal point of CO2 transport because it can bind the acid equivalence of CO2. The binding of hydrogen ions by hemoglobin creates a sink that maintains CO2 flux into the red cell. Only because of its large mass can hemoglobin accomplish this.

Haldane Effect

Hemoglobin has a greater buffer capacity when it is in the desaturated form, and blood that is fully desaturated can bind an additional 60 mL/L CO2. The increase in CO2 content that occurs when blood is desaturated is known as the Haldane effect. The graph in Figure 2.4 shows that the Haldane effect is responsible for a significant portion of the change in CO2 content between arterial and venous blood. This reaffirms the important role played by hemoglobin in CO2 transport.

CO2 ELIMINATION (VCO2)

Although CO2 is dismantled for transport in the peripheral venous blood, it is reconstituted when the blood reaches the lungs. The next step is elimination through the lungs, and this process is described in Figure 2.5. The elimination of CO2 (VCO2) is a Fick relationship, like VO2, but with the arterial and venous components reversed. Because there are no simple derivative equations for CO2 content in blood, VCO2 is usually measured directly. When VCO2 is expressed as volume/time, the normal value is about 80% of the VO2 (Table 2.4). The ratio VCO2/

VO2 is thus 0.8 normally. This ratio is known as the respiratory quotient (RQ), and it varies according to the type of nutrient being metabolized. (See Chapter 46 for more information on the RQ.)

Acid Excretion

When VCO2 is expressed in mEq/L, it describes the rate of volatile acid excretion. As shown in Figure 2.5, this rate is normally 10 mEq/minute, or 14,400 mEq/24 hours. During exercise, the excretion of volatile acids via the lungs can increase to 40,000 mEq/24 hours. Considering that the kidneys excrete only 40 to 80 mEq acid/24 hours, the major organ of acid excretion in the human body is the lungs, not the kidneys. This method of describing CO2 elimination emphasizes the acid burden of metabolism. This emphasis on the production side of metabolism is an important addition to the current supply-dominant approach to metabolic support.

CIRCULATORY BLOOD FLOW

INTRODUCTION

When is a piece of matter said to be alive? When it goes on "doing something," moving, exchanging material with its environment.
Erwin Schrodinger

The adult human being has an estimated 100 trillion cells that must go on exchanging material with the external environment to stay alive. To accomplish this, the circulatory system includes a vascular network that stretches more than 60,000 miles (more than twice the circumference of the Earth), and an average of 8000 liters of blood is pumped through this vascular network every day (1). This chapter describes the flow of blood through the circulatory system, and includes a description of flow through the heart (cardiac output) and flow through distant regions of the vascular circuit (peripheral blood flow). Most of these concepts are old friends from the physiology classroom, but this chapter applies them to actual practice at the bedside.

CARDIAC OUTPUT

Circulatory flow originates in the muscular contractions of the heart. Because blood is an incompressible fluid that flows through a closed hydraulic loop, the volume of blood ejected by the left side of the heart (in a given time period) must equal the volume of blood returning to the right side of the heart (over the same period of time). This reflection of the conservation of mass (volume) in a closed hydraulic system is known as the principle of continuity (2). It predicts that the volume flow of blood (volumetric flow rate), which is determined by the stroke output of the heart, will be the same at all points along the circulatory system. Therefore, the forces that determine cardiac stroke output also determine volumetric blood flow. The determinants of cardiac stroke output that can be measured or derived in a clinical setting are shown in Table 1.1. Each of these is described briefly in the paragraphs that follow.

PRELOAD

When a weight is attached to one end of a resting muscle, the muscle stretches to a new length. The weight in this situation represents a force called the preload, that is, the load imposed on a muscle before the onset of contraction. The preload force acts indirectly to augment the force of muscle contraction. That is, the preload force stretches the muscle to a new resting length and (according to the length-tension relationship of muscle) the increase in muscle length then leads to a more forceful muscle contraction.

Pressure-Volume Curves

In the intact heart, the stretch imposed on the cardiac muscle at rest is a function of the volume in the ventricles at the end of diastole. Therefore, ventricular end-diastolic volume (EDV) is used as a reflection of the preload force for the intact heart (3). The pressure-volume curves in Figure 1.1 describe the influence of preload on the mechanical performance of the left ventricle during diastole (lower curves) and systole (upper curves). The solid curves represent the normal pressure-volume relationships for diastole and systole. Note that the uppermost curve in the figure has a rapid ascent, indicating that small changes in diastolic volume are associated with large changes in systolic pressure. The normal relationship between diastolic volume (preload) and the strength of ventricular contraction was described independently by Otto Frank and Ernest Starling, and is commonly known as the Frank-Starling phenomenon (3). This relationship can be restated as follows:

In the normal heart, the diastolic volume (preload) is the principal force that governs the strength of ventricular contraction.

This indicates that the stroke output of the normal heart is primarily a reflection of the diastolic volume. Therefore, the most effective measure for preserving the cardiac output is to maintain an adequate diastolic volume. This emphasizes the value of avoiding hypovolemia and correcting volume deficits when they exist.

Ventricular Function Curves

Ventricular end-diastolic volume is not easily measured at the bedside, and the ventricular end-diastolic pressure (EDP) is more commonly used as a reflection of ventricular preload in clinical practice (see Chapter 11 for more information on end-diastolic pressure). The relationship between end-diastolic pressure (preload) and stroke volume (systolic performance) is used to monitor the Frank-Starling relationship in the clinical setting. The curves that define this relationship, known as ventricular function curves (4), are shown in Figure 1.2. Unfortunately, the interpretation of ventricular function curves can be misleading, as is demonstrated in the sections that follow.

Ventricular Compliance

The stretch imposed on cardiac muscle is determined not only by the volume of blood in the ventricular chambers, but also by the tendency of the ventricular wall to distend or stretch at any given chamber volume. This latter property is described as the compliance (distensibility) of the ventricle. Compliance is defined by the following relationship between changes in EDP and volume (EDV) (5):

Compliance= change EDV/change EDP

(1.1)

The lower curves in Figure 1.1 show the end-diastolic pressure-volume relationships for the normal ventricle and a noncompliant (stiff) ventricle. As the ventricle becomes less compliant (e.g., when the ventricle hypertrophies), there is less of a change in diastolic volume relative to the change in diastolic pressure. Early in this process, the EDV remains normal, but the EDP increases above normal. As the compliance decreases further, the increase in EDP eventually reduces venous inflow into the heart, thereby causing a reduction in EDV. The decrease in EDV then leads to a decrease in the force of ventricular contraction. This illustrates how changes in ventricular compliance can lead to changes in cardiac stroke output, and how changes in cardiac stroke output can be independent of changes in systolic function.

The decrease in stroke output that accompanies a decrease in ventricular compliance is known as diastolic heart failure (6). The difference between heart failure caused by systolic and diastolic dysfunction is presented in Chapter 16.

The Preload Measurement

Changes in ventricular compliance also influence the reliability of EDP as a reflection of EDV. For example, a decrease in ventricular compliance results in a higher-than-expected EDP at any given EDV. Therefore, the EDP overestimates the actual preload (EDV) when the ventricle is noncompliant. The following points are important to remember when EDP is used as an index of ventricular preload:

EDP provides an accurate reflection of preload only when ventricular compliance is normal. Changes in EDP provide an accurate reflection of changes in preload only when ventricular compliance is constant.

The influence of ventricular compliance on the assessment of preload surfaces again in Chapter 11. Chapter 16 describes the importance of an accurate preload measurement in distinguishing systolic from diastolic forms of heart failure.

AFTERLOAD

When a weight is attached to one end of a contracting muscle, the force of muscle contraction must overcome the opposing force of the weight before the muscle begins to shorten its length. The weight in this situation represents a force called the afterload, the load imposed on the muscle after the onset of contraction. The afterload is an opposing force that determines the force of muscle contraction needed to initiate muscle shortening (i.e., isotonic muscle contraction). In the intact heart, the afterload force is equivalent to the tension developed across the wall of the ventricles during systole (3).

The determinants of ventricular wall tension are derived from observations on soap bubbles made by the Marquis de Laplace in 1820. These observations were the basis for the law of Laplace, which states that the tension across a thin-walled sphere is directly related to the internal pressure and radius of the sphere: T = Pr. Because the ventricles are not thin-walled spheres, the Laplace relationship for the intact heart incorporates a factor that reflects the average thickness of the ventricular wall (5). The law of Laplace applied to the intact heart is then expressed as T = Pr/t, where T represents the tension across the wall of the ventricle during systole, P represents the transmural pressure across the ventricle at the end of systole, r represents the chamber radius at the end of diastole, and t represents the average thickness of the ventricular wall. The forces that contribute to ventricular wall tension are shown in Figure 1.3.

Pleural Pressures

Because afterload is a transmural force, it is influenced by the pleural pressures at the outer surface of heart. Negative pleural pressures increase transmural pressure and increase ventricular afterload, whereas positive pleural pressures have the opposite effect. Negative pressures surrounding the heart can impede ventricular emptying by opposing the inward displacement of the ventricular wall during systole (7). This action is responsible for the decrease in systolic blood pressure (reflecting a decrease in stroke volume) that occurs during the inspiratory phase of spontaneous breathing. When this inspiratory-related drop in pressure is greater than 15 mm Hg, the condition is called pulsus paradoxus (which is a misnomer, because the response is not paradoxical, but is an exaggerated version of the normal response).

Positive pleural pressures can promote ventricular emptying by facilitating the inward displacement of the ventricular wall during systole (7). Rapid and forceful rises in positive pressure surrounding the heart might also produce a massagelike action to expel blood from the heart and great vessels in the thorax. This is the proposed explanation for the success of cough CPR, which uses forceful coughing to maintain circulatory flow in patients with ventricular tachycardia (8). In fact, positive pleural pressure swings may be responsible for the hemodynamic effects of closed chest cardiac massage, as discussed in Chapter 18 (8).

Impedance versus Resistance

A major component of afterload is the resistance to ventricular outflow in the aorta and large, proximal arteries. The total hydraulic force that opposes pulsatile flow is known as impedance (9). This force is a combination of two forces: (a) a force that opposes the rate of change in flow, known as compliance, and (b) a force that opposes mean or volumetric flow, known as resistance. Vascular compliance is not easily measured at the bedside (10). On the other hand, vascular resistance is derived by assuming that hydraulic resistance is analogous to electrical resistance. That is, Ohm's law predicts that resistance to flow of an electric current (R) is directly proportional to the voltage drop across a circuit (E) and inversely proportional to the flow of current (I); R = E/I. The hydraulic analogy then states that resistance to the flow of fluid through a tube is directly proportional to the pressure drop along a tube (Pin - Pout), and inversely proportional to the flow of volume (Q):

R=Pin-Pout/
(1.2)

This relationship is applied to the systemic and pulmonary circulations, creating the following derivations:

SVR=(MAP-CVP)/C
(1.3)
Pulmonary vacular resistance (PVR) = (MAP - LAP)/C
(1.4)

where MABP is mean arterial blood pressure, CVP is central venous pressure, MPAP is mean pulmonary artery pressure, LAP is left-atrial pressure, and CO is the cardiac output. Vascular resistance is expressed in units of pressure and flow. Because the pressures are measured in mm Hg, the units would be mm Hg per mL/second. However, the dislike for expressing pressures in mm Hg has led to the common practice of expressing vascular resistance in CGS (centimeter-gram-second) units, or dynes ´ second/cm5. The conversion is dynes second/cm5 = 1333 ´ mm Hg/mL/second.

Clinical Monitoring

Although afterload is a combination of several forces that oppose ventricular emptying, most of the component forces of afterload cannot be measured easily or reliably at the bedside. As a result, the vascular resistance, derived as shown above, is often used as the sole measure of ventricular afterload. However, as might be expected, vascular resistance is not an accurate measure of total ventricular afterload (11).

A shift in the height and slope of the ventricular function curve could be an indirect marker of changes in afterload, as shown in Figure 1.2. However, shifts in the ventricular function curve can also be caused by changes in the contractile state of the myocardium, and because it is not possible to determine whether myocardial contractility is constant using bedside measurements, a shift in the position of ventricular function curves cannot be used as a marker of changes in afterload.

CONTRACTILITY

The contraction of striated muscle is attributed to interactions between contractile proteins arranged in parallel rows in the sarcomere. The number of bridges formed between adjacent rows of contractile elements determines the contractile state or contractility of the muscle fiber. The contractile state of a muscle is reflected by the force and velocity of muscle contraction (3).

The contractile state of cardiac muscle in the intact heart is reflected in the systolic performance of the ventricles. This is demonstrated in the upper curves in Figure 1.1. The systolic pressures in this figure reflect isovolumetric contraction (i.e., the pressures are generated before the aortic valve opens), which eliminates the influence of outflow impedance (afterload) on systolic pressure. Therefore, the changes in systolic pressure at any given diastolic volume (preload constant) reflect changes in the contractile state of the myocardium.

Clinical Monitoring

Changes in myocardial contractility alter the height and slope of the ventricular function curve, as demonstrated in Figure 1.2. However, as just mentioned, changes in the position of ventricular function curves can also be the result of changes in ventricular afterload. Therefore, because it is not possible to monitor afterload to determine whether it is constant, a shift in the ventricular functions curve is not a reliable method for detecting changes in myocardial contractility (4).

PERIPHERAL BLOOD FLOW

The cardiac stroke output travels through a vast array of vascular channels that can differ markedly in size. The focus of the remainder of the chapter is the factors that govern flow through these vascular channels.

Caution: The determinants of flow through vascular conduits are derived from idealized hydraulic models that differ considerably from the conditions that exist in the intact circulatory system. For example, the flow in small tubes usually is steady or nonpulsatile flow, and does not represent the continually changing pulsatile pattern of flow that occurs in many regions of the native circulation. Because of discrepancies like this, the description of blood flow that follows should be used more as a qualitative than quantitative description of the hydraulics of vascular flow.

FLOW IN RIGID TUBES

The hydraulic analogy of Ohm's law, as mentioned previously, states that steady volumetric flow (Q) through a rigid tube is proportional to the pressure gradient between the inlet and outlet of the tube (Pin - Pout), and the constant of proportionality is the hydraulic resistance to flow (R):

Q=(Pin-Pout) x 1/
(1.5)

The flow of fluids through small tubes was described independently by a German engineer (G. Hagen) and a French physician (J. Poiseuille), and their observations are combined in the equation shown below, called the Hagen-Poiseuille equation (12,13).

Q=(Pin-Pout) x (PiR4/8uL
(1.6)

This equation identifies the components of hydraulic resistance as the inner radius (r) and length of the tube (L), and the viscosity of the fluid (u). Because the final term in the Hagen-Poiseuille equation is the reciprocal of resistance (i.e., 1/R), the hydraulic resistance to steady, volumetric flow is expressed as

R=8uL/Pir
(1.7)

The components of the Hagen-Poisseuille equation are shown in the diagram in Figure 1.4. Note that flow varies according to the fourth power of the inner radius of the tube.

Thus, a twofold increase in the inner radius of the tube will result in a sixteenfold increase in flow: (2r)4 = 16 r. Flow varies much less with the other determinants of resistance; that is, a twofold increase in the length of the tube or the viscosity of the fluid results in a 50% decrease in flow rate. The influence of tube dimensions on flow rate has more practical applications as determinants of flow through vascular catheters, as presented in Chapter 4.

FLOW IN TUBES OF VARYING DIAMETER

The Hagen-Poisseuille equation predicts that as blood moves away from the heart and encounters vessels of decreasing diameter, the resistance to flow should increase and flow rate should decrease. However, the principle of continuity described earlier predicts that blood flow will be the same at all points along the vascular circuit. This apparent dilemma can be resolved by considering the relationship between flow velocity and cross-sectional area of a tube. For a rigid tube of varying diameter, the velocity of flow (v) at any point along the tube is directly proportional to the volumetric flow rate (Q) and inversely proportional to the cross-sectional area of the tube (A). These relationships are described below (2).

v=Q/
(1.8)

If flow is constant, a decrease in the cross-sectional area of a tube results in an increase in the velocity of flow. This is how the nozzle on a garden hose works, and is the rationale for jet ventilation.

Equation 1.8 can be rearranged to yield the relationship Q = v ´ A. This relationship indicates that proportional changes in velocity and cross-sectional area in opposite directions result in a constant volume flow rate. This means that blood flow can remain unchanged in blood vessels of diminishing diameter if there are equal and opposite changes in the velocity of flow and the cross-sectional area of the vessels. The trick here is to use the total cross-sectional area of the vessels in a region rather than the cross-sectional area of individual vessels. This resolves the discrepancy between the principle of continuity and the Hagen-Poiseuille relationships.

Circulatory Design

The graph in Figure 1.5 shows the changes in flow velocity and cross-sectional area in different regions of the circulation (13). As expected, when blood moves toward the periphery, there are proportionate and reciprocal changes in cross-sectional area and velocity of flow. The high velocity of flow in the proximal arteries seems well suited for delivering blood quickly to the microcirculation, to allow more time for diffusional exchange with the tissues. The low velocity and large cross-sectional area in the capillaries are also well-suited for diffusional exchange. These features show a rational design in the circulatory system.

FLOW IN COLLAPSIBLE TUBES

The hydraulic relationships described above apply to flow through rigid tubes, but blood vessels are not rigid tubes. The determinants of flow in collapsible tubes are explained with the aid of the apparatus shown in Figure 1.6 (14). The apparatus shows a tube with collapsible walls passing through a fluid reservoir. The height of the fluid in the reservoir can be adjusted to vary the external pressure on the tube. As mentioned earlier, flow in a rigid tube is proportional to the pressure difference between the inlet and outlet of the tube (Pin - Pout). This is also the case in collapsible tubes as long as the external pressure is not high enough to compress the tube. However, as shown in Figure 1.6, when the external pressure exceeds the outlet pressure (Pext > Pout) and compresses the tube, the driving force for flow is pressure difference between the inlet pressure and the external pressure (Pin - Pext). In this situation, the driving pressure for flow is independent of the pressure gradient along the tube.

The Pulmonary Circulation

Vascular compression has been demonstrated in the cerebral, pulmonary, and systemic circulations. Extravascular compression is a particular concern in patients who require positive-pressure mechanical ventilation (14). In this situation, pressures in the alveoli can exceed pressures in the underlying pulmonary capillaries, and the resultant capillary compression changes the driving force for flow across the lungs, as illustrated in Figure 1.6. Thus, whereas the normal driving pressure for flow across the lungs is the difference between the mean pulmonary artery pressure and the left-atrial pressure (PAP - LAP), the driving pressure for flow when pulmonary capillaries are compressed is the difference between the pulmonary artery pressure and the alveolar pressure (PAP - Palv). The pulmonary vascular resistance (PVR) will then differ as follows:

Normal: PVR=PAP-LAP/C
(1.9)
when Palv>LAP: PVR=PAP-Palv/C
(1.10)

The problems created by vascular compression in the lungs are discussed in Chapters 11 and 26.

VISCOSITY

Solids resist being deformed (changing shape), whereas fluids deform continuously (i.e., flow) but resist changes in the rate of deformation (i.e., the flow rate). The inherent resistance of a fluid to changes in flow rate is expressed as the viscosity of the fluid (12,15). When a force is applied that changes flow rate (i.e., a shear force), the change in flow rate varies inversely with the viscosity of the fluid. Thus, as the viscosity of a fluid increases, the fluid flows less rapidly in response to a shear force. The influence of viscosity is easily demonstrated by comparing the flow of molasses (high viscosity) and the flow of water (low viscosity) when the force of gravity is applied (i.e., when both are spilled).

Blood Viscosity

The viscosity of whole blood is determined by the number and strength of interactions between plasma fibrinogen and the circulating erythrocytes (15,16). The concentration of circulating erythrocytes (i.e., the hematocrit) is the principal determinant of whole blood viscosity. The relationship between hematocrit and blood viscosity is shown in Table 1.2. Note that viscosity is expressed in absolute units (centipoise) and also as a relative value (the ratio of blood viscosity to the viscosity of water). Whole blood with a normal hematocrit (i.e., 40%) has a viscosity that is three to four times higher than that of water. Thus, to move whole blood with a normal hematocrit, the circulatory system must generate a pressure that is three to four times higher than the pressure needed to move water the same distance. The acellular blood (zero hematocrit) in Table 1.2 is equivalent to plasma, and has a viscosity that more closely approximates the viscosity of water. Thus, moving plasma does not require nearly the work involved in moving whole blood. This difference in work load can have significant implications in the patient with coronary disease or limited cardiac reserve.

Other factors that influence viscosity are body temperature and the flow rate (16). Viscosity rises in response to decreases in temperature and flow rate. The increase in blood viscosity in low flow states might represent an adaptive response aimed at promoting coagulation at sites of hemorrhage (15). However, the rise in viscosity can also serve to further reduce blood flow and thereby provoke ischemic injury. The tendency of viscosity to increase with decreases in blood flow is a potential problem in the ICU patient population, and deserves further study.

Hemodynamic Effects

The Hagen-Poisseuille equation predicts that (all other variables constant) blood flow will change in the same proportion as the change in blood viscosity; that is, if viscosity is reduced by one-half, blood flow will double (15).

The graph in Figure 1.7 demonstrates the hemodynamic effects of a progressive decrease in blood viscosity. In this case, the subject was an elderly male with secondary polycythemia, and the reduction in viscosity was achieved by progressive (isovolemic) hemodilution. As shown in the graph, the progressive reduction in hematocrit was associated with a progressive rise in cardiac output. The disproportionate improvement in cardiac output may be caused by the fact that low flow rates can increase viscosity, and thus an increase in flow could itself produce a further increase in flow. The ability to modulate blood flow by manipulating the hematocrit is presented in more detail in Chapter 44.

Clinical Monitoring

Viscosity is measured by placing a fluid sample between two parallel plates that are sliding past each other, and recording the resistance or "stickiness" in the movement of the plates. The instrument that performs this task is called a viscometer. The units of measurement for viscosity are the poise (or dyne ´ second/cm2) in the CGS system, and the pascal second (Pa s) in the SI system. To convert units, use the relationship 1 poise = 0.1 Pa s. Viscosity is also expressed in relative terms (relative to the viscosity of water), a method that may be preferred for its simplicity.

The major drawback in monitoring viscosity is the tendency of viscosity to vary with changes in temperature, hematocrit, and flow rate. As a result, local conditions in the microcirculation can produce changes in blood viscosity that will go undetected in the in vitro (viscometer) measurement of viscosity. In states of adequate blood flow, the measurement is considered to be reasonably accurate. However, for the critically ill patient with suspected low flow who might benefit from measurements of blood viscosity, the reliability of the measurement is likely to be uncertain. A more feasible application of the viscosity measurement would be to monitor the effects of packed cell transfusions on blood viscosity to determine the point at which hemoconcentration can be counterproductive in individual patients.