Glomerular Filtration Rate

The GFR is the best measure of glomerular function. Normal GFR is approximately 125 mL/min. However, manifestations of reduced GFR are not seen until the GFR has decreased to 50% of normal. When GFR decreases to 30% of normal, a stage of moderate renal insufficiency ensues. Patients remain asymptomatic with only biochemical evidence of a decline in GFR (i.e., an increase in serum concentrations of urea and creatinine). Further workup usually reveals other abnormalities, such as nocturia, anemia, loss of energy, decreasing appetite, and abnormalities in calcium and phosphorus metabolism.

As the GFR decreases further, a stage of severe renal insufficiency begins. This stage is characterized by profound clinical manifestations of uremia and biochemical abnormalities, such as acidemia; volume overload; and neurologic, cardiac, and respiratory manifestations. At the stages of mild and moderate renal insufficiency, intercurrent clinical stress may compromise renal function further and induce signs and symptoms of overt uremia. When the GFR is 5% to 10% of normal, it is called end-stage renal disease (ESRD), and continued survival without renal replacement therapy becomes impossible ( Table 59.3 ).

Blood Urea Nitrogen

The blood urea nitrogen (BUN) concentration is not a direct correlate of reduced GFR. BUN is influenced by nonrenal variables, such as exercise, bleeding, steroids, and massive tissue breakdown. The more important factor is that BUN is not elevated in kidney disease until the GFR is reduced to almost 75% of normal.

Creatinine and Creatinine Clearance

Measurements of creatinine provide valuable information regarding general kidney function. Creatinine in serum results from turnover of muscle tissue and depends on daily dietary intake of protein. Normal values are 0.5 to 1.5 mg/100 mL; values of 0.5 to 1 mg/100 mL are present during pregnancy. Creatinine is freely filtered at the glomerulus, and apart from an almost negligible increase in content because of secretion in the distal nephron, it is neither reabsorbed nor secreted. Serum creatinine measurements reflect glomerular function ( Fig. 59.4 ), and creatinine clearance is a specific measure of GFR. Creatinine clearance can be calculated by the following formula derived by Cockcroft-Gault that accounts for age-related decreases in GFR, body weight, and sex:

Theoretic relationship between blood urea nitrogen and creatinine versus glomerular filtration rate (GFR) .

Redrawn from Kassirer JP. Clinical evaluation of kidney function-glomerular function. N Engl J Med . 1971;285:385.

This value should be multiplied by 0.85 for women because a lower fraction of body weight is composed of muscle.

Because there is such a wide range in normal values, a 50% increase in serum creatinine concentration, indicative of a 50% reduction in GFR, may go undetected unless baseline values are known. In addition, excretion of drugs dependent on glomerular filtration may be significantly decreased despite what might seem to be only slightly elevated serum creatinine values (1.5-2.5 mg/100 mL). The serum creatinine concentration and clearance are better indicators of general kidney function and GFR than are similar measurements of urea nitrogen ( Box 59.1 ). However, there are disease states in which even the serum creatinine can be affected independent of the GFR ( Table 59.4 ). The main limitation of current GFR estimates is the greater inaccuracy in populations without known chronic kidney disease than in those with the disease. Nonetheless, current GFR estimates facilitate detection, evaluation, and management of the disease, and they should result in improved patient care and better clinical outcomes.

Concentration

Urinary specific gravity is an index of the kidney’s concentrating ability, specifically renal tubular function. Determination of urinary osmolality (i.e., measurement of the number of moles of solute [osmoles] per kilogram of solvent) is a similar, more specific test. Excretion of concentrated urine (specific gravity, 1.030; 1050 mOsm/kg) is indicative of excellent tubular function, whereas a urinary osmolality fixed at that of plasma (specific gravity 1.010; 290 mOsm/kg) indicates renal disease. The urinary dilution mechanism persists after concentrating defects are present, so a urinary osmolality of 50 to 100 mOsm/kg still may be consistent with advanced renal disease.

Protein

Patients without renal disease can excrete 150 mg of protein per day; greater amounts may be present after strenuous exercise or after standing for several hours. Massive proteinuria (i.e., >750 mg/day) is always abnormal and usually indicates severe glomerular damage.

Glucose

Glucose is freely filtered at the glomerulus and is subsequently reabsorbed in the proximal tubule. Glycosuria signifies that the ability of the renal tubules to reabsorb glucose has been exceeded by an abnormally heavy glucose load and is usually indicative of diabetes mellitus. Glycosuria also may be present in hospitalized patients without diabetes who are receiving intravenous glucose infusions.

Urinalysis and Appearance

Gross and microscopic observations of urine and its sediment, along with determination of urinary pH, specific gravity, protein content, and glucose content, are two of the most readily available, inexpensive, and informative laboratory tests. The gross appearance of urine may indicate the presence of bleeding or infection in the genitourinary tract. Microscopic examination of urinary sediment may reveal casts, bacteria, and various cell forms, supplying diagnostic information in patients with renal disease.

Urine and Serum Electrolytes With Blood Gases

Sodium, potassium, chloride, and bicarbonate concentrations should be determined if impairment in renal function is suspected. However, the results of these tests usually remain normal until frank renal failure is present and hyperkalemia does not occur until patients are uremic. Measuring urinary sodium or chloride excretion is especially useful when attempting to differentiate between causes of hyponatremia, as seen in volume contraction (whether a decrease in total circulatory volume or a decrease in effective arterial blood volume), versus conditions associated with increased salt loss, such as the syndrome of inappropriate secretion of antidiuretic hormone, salt-losing nephropathy, or adrenal insufficiency. If significant renal disease is present, patients consuming a diet high in animal protein may develop metabolic acidosis.

Imaging Studies

Hypervolemia

Total body contents of sodium and water are increased in chronic renal failure (CRF), although this increase might not be clinically apparent until the GFR is reduced to very low levels. Weight gain is usually associated with volume expansion and is offset by the concomitant loss of lean body mass. The combination of loop diuretics with metolazone, which acts by inhibiting the Na-Cl cotransporter of the distal convoluted tubule, can overcome diuretic resistance.

Acidemia

Although urine can be acidified normally in most patients with CRF, these patients have a reduced ability to produce ammonia. In the early stages, the accompanying organic anions are excreted in urine, and the metabolic acidosis is of the non–anion gap variety. With advanced renal failure, a fairly large “anion gap” can develop (to approximately 20 mmol/L), however, with a reciprocal decrease in plasma bicarbonate ion (HCO ₃ ) concentration. This acidemia is usually corrected by hemodialysis. Although acidemia is well compensated in moderate CRF, patients can become acidemic and hyperkalemic in the postoperative period ( Table 59.5 ).

Hyperkalemia

The approximate daily filtered load of potassium (K ⁺ ) is 700 mmol. Most of this filtered load is reabsorbed in tubule segments, and most of the K ⁺ excreted in the final urine reflects events governing K ⁺ handling at the level of the cortical collecting tubule and beyond. K ⁺ excretion in the gastrointestinal tract is augmented in patients with CRF. However, hyperkalemia may be precipitated in numerous clinical situations, including protein catabolism, hemolysis, hemorrhage, transfusion of stored red blood cells, metabolic acidosis, and exposure to various medications that inhibit K ⁺ entry into cells or K ⁺ secretion in the distal nephron.

Cardiac and Pulmonary Manifestations

Hypertension is a common complication of CRF and ESRD. Because hypervolemia is the major cause of hypertension in uremia, normotension is usually restored by the use of diuretics in predialysis patients or by dialysis in ESRD patients. However, despite therapy, patients remain hypertensive due to activation of the renin-angiotensin system and autonomic factor. Patients generally have left ventricular hypertrophy and accelerated atherosclerosis (disordered glucose and fat metabolism). Pericarditis can be observed in patients with inadequate dialysis unlike patients with CRF who undergo regular dialysis.

Pulmonary edema and restrictive pulmonary dysfunction are a common feature of patients in renal failure. Hypervolemia, heart failure, decreased serum oncotic pressure, and increased pulmonary capillary permeability contribute to the development of pulmonary edema. Diuretic therapy or dialysis can be effectively used to treat pulmonary congestion and edema due to excess intravascular volume.

Hematologic Manifestations

CRF usually causes a normochromic, normocytic anemia. Anemia is generally observed when the GFR decreases to less than 30 mL/min and is due to insufficient production of erythropoietin by the diseased kidneys. Other factors are iron deficiency, either related to or independent of blood loss from repeated laboratory testing, blood retention in the dialyzer, or gastrointestinal bleeding. Treatment of anemia with iron, darbepoetin alfa, and human recombinant erythropoietin ( Table 59.6 ) restores a normal hematocrit and avoids repetitive red blood cell transfusions, reduces the requirement for hospitalization, and decreases cardiovascular mortality by approximately 30%.

Prolongation of the bleeding time because of decreased activity of platelet factor 3, abnormal platelet aggregation and adhesiveness, and impaired prothrombin consumption contributes to the clotting defects. The abnormality in platelet factor 3 correlates can be corrected with dialysis, although prolongation of the bleeding time can be observed in well-dialyzed patients. Abnormal bleeding times and coagulopathy in patients with renal failure may be managed with desmopressin, cryoprecipitate, conjugated estrogens, blood transfusions, and erythropoietin use.

Opioids

Renal failure has implications of major clinical importance with respect to the metabolism and excretion of morphine and meperidine. For the fentanyl congeners, the clinical importance of renal failure is less marked.

Morphine is an opioid with active metabolites that depend on renal clearance mechanisms for elimination. Morphine is principally metabolized by conjugation in the liver, and the water-soluble glucuronides (morphine-3-glucuronide and morphine-6-glucuronide) are excreted via the kidney. The kidney also plays a role in the conjugation of morphine, accounting for nearly 40% of its metabolism. Patients with renal failure can develop high levels of morphine-6-glucuronide and life-threatening respiratory depression. In view of these changes induced by renal failure, alternatives to morphine should be considered in patients with severely altered renal clearance mechanisms.

The clinical pharmacology of meperidine is also significantly altered by renal failure. Normeperidine, the chief metabolite, has analgesic and central nervous system (CNS) excitatory effects. Because the active metabolites are subject to renal excretion, this potential CNS toxicity secondary to normeperidine accumulation is especially a concern in patients in renal failure.

The clinical pharmacology of the fentanyl congeners is not grossly altered by renal failure, although a decrease in plasma protein binding potentially can alter the free fraction of the fentanyl class of opioids. As with fentanyl, sufentanil pharmacokinetics are not altered in any consistent fashion by renal disease, although greater variability exists in the clearance and elimination half-life of sufentanil when patients have impaired renal function. An increased clinical effect is likely with alfentanil in renal failure because of a decreased initial volume of distribution and an increased free fraction of alfentanil. However, no delay in recovery after alfentanil administration should be expected. Neither the pharmacokinetics nor the pharmacodynamics of remifentanil are altered by impaired renal function.

Hydromorphone, as the parent drug, does not substantially accumulate in hemodialysis patients. Conversely, an active metabolite, hydromorphone-3-glucuronide, quickly accumulates between dialysis treatments but seems to be effectively removed during hemodialysis. With careful monitoring, hydromorphone can be used safely in patients who require dialysis. However, it should be used with caution in patients with a GFR less than 30 mL/min and who have yet to start dialysis or who have withdrawn from dialysis.

Inhaled Anesthetics

All inhaled anesthetics are biotransformed to some extent, with the nonvolatile products of metabolism eliminated almost entirely by the kidney. Reversal of the CNS effects of inhaled anesthetics depends on pulmonary excretion; therefore impaired kidney function would not alter the response to these anesthetics. From the viewpoint of selecting an anesthetic that would not be harmful to patients with mild or moderate impairment of renal function, all of the modern potent inhaled vapor anesthetics are acceptable. Fluoride levels after isoflurane increase by only 3 to 5 μM and by only 1 to 2 μM after halothane ; therefore these anesthetics have no nephrotoxic potential.

Desflurane and sevoflurane, two newer inhaled anesthetics, are remarkably different from each other with respect to their molecular stability and biotransformation. Desflurane is highly stable and resists degradation by soda lime and the liver. The mean inorganic fluoride concentration after 1 minimum alveolar concentration (MAC)-hour exposure to desflurane was less than 1 μM. The safety of desflurane in renal failure patients has been confirmed. In addition, more sensitive indices of renal function—urine retinol-binding protein and β- N -acetylglucosaminidase—showed no evidence of renal damage. Prolonged exposure to desflurane (7 MAC-hours) has been associated with normal renal function.

Sevoflurane is not very stable. Soda lime causes it to decompose, and it is biotransformed by the liver. Plasma inorganic fluoride concentrations approaching nephrotoxic levels (50 μmol/L) have been reported after prolonged inhalation of sevoflurane. However, no evidence of gross changes in renal function has been found in humans. Data also suggest that sevoflurane can safely be delivered at fresh gas flows as low as 1 L/min without significant production of a breakdown product named compound A (fluoromethyl-2,2-difluoro-1-[trifluoromethyl] vinyl ether), which is considered potentially nephrotoxic.

Inhaled anesthetics cause a transient reversible depression in renal function. GFR, renal blood flow, urine output, and urinary excretion of sodium are decreased ( Table 59.8 ). Probable mechanisms include loss of renal autoregulation, activation of neurohumoral factors (e.g., antidiuretic hormone, vasopressin, renin), and neuroendocrine responses. Although most inhaled anesthetics have been shown to reduce GFR and urinary excretion of sodium, studies examining their effects on renal blood flow have yielded conflicting results, which can be explained by differences in experimental methodology. Data suggest that renal blood flow is maintained with halothane, isoflurane, and desflurane but that it is decreased with sevoflurane.

Intravenous Anesthetics

Reversal of CNS effects after the administration of ultrashort-acting barbiturates such as thiopental and methohexital occurs as a result of redistribution, and hepatic metabolism is the sole route of elimination of these drugs. Thiopental is 75% to 85% bound to albumin, the concentration of which may be markedly reduced in uremia. Because it is a highly bound drug, reduced binding permits a greater proportion of an administered dose of thiopental to reach receptor sites. In addition, thiopental is a weak acid, with its pK _a in the physiologic range; acidosis results in more un-ionized, nonbound, active thiopental. In combination, these changes produce an increase in the free fraction of thiopental from 15% in normal patients to 28% in patients with CRF. With thiopental metabolism essentially unchanged in renal disease, the dose to produce and maintain anesthesia should be reduced. The same considerations are true for methohexital, although metabolism plays a slightly greater part in the termination of its therapeutic effect.

Propofol does not adversely affect renal function as reflected by measurements of creatinine concentration. Prolonged infusions of propofol may result in the excretion of green urine because of the presence of phenolic metabolites in the urine. This discoloration does not affect renal function. Urate excretion is increased after the administration of propofol and is usually manifested as cloudy urine when urate crystallizes under conditions of low pH and temperature.

There are no reports of the disposition of narcotics and tranquilizers when used in large dosage for anesthesia in uremic patients. These drugs are extensively metabolized before excretion; therefore they should not have a particularly prolonged effect. The benzodiazepines, especially diazepam, have a long half-life and tend to accumulate. Because of the greater ease of reversibility of the potent inhaled anesthetics versus intravenous drugs, inhaled anesthetics may offer some advantages for the induction of general anesthesia in uremic patients.

Muscle Relaxants and Their Antagonists

Succinylcholine has been used without difficulty in patients with decreased or absent renal function. Its metabolism is catalyzed by pseudocholinesterase to yield the nontoxic end products succinic acid and choline. The metabolic precursor of these two compounds, succinylmonocholine, is excreted by the kidneys. Large doses of succinylcholine, which might result from prolonged infusion, should be avoided in patients with renal failure. Although pseudocholinesterase levels are reduced in uremia, these reductions are insufficient and cause a prolonged block. Hemodialysis has been reported to have no effect on cholinesterase levels.

Administration of succinylcholine causes a rapid, transient increase of 0.5 mEq/L in the serum potassium concentration. In traumatized, burned, or neurologically injured patients, the increase may be 5 to 7 mEq/L, probably as a consequence of denervation supersensitivity of the muscle membrane to succinylcholine and to acetylcholine, which can result in cardiovascular collapse. Likewise, an exaggerated increase in serum potassium could be particularly dangerous in uremic patients with hyperkalemia; therefore the use of succinylcholine is inadvisable, unless the patient has undergone dialysis within 24 hours before surgery. If the patient has recently undergone dialysis or has normal serum potassium, the use of succinylcholine is safe in the absence of other contraindications to the medication.

The disposition of nondepolarizing muscle relaxants has been well studied. Renal failure influences the pharmacology of nondepolarizing muscle relaxants by producing either decreased elimination of the drug or its metabolites by the kidney or decreased activity of enzymes that metabolize the drug, such as in the case of mivacurium ( Table 59.9 ). Consequently, the duration of action of muscle relaxants may be prolonged in patients with renal failure.

Approximately 40% to 50% of a long-acting nondepolarizing muscle relaxant, pancuronium, is excreted in urine. A portion of this excretion occurs after biotransformation to the less active metabolite 3-hydroxypancuronium. Pancuronium has a prolonged terminal elimination half-life in patients with reduced renal function (see Table 59.9 ) ; therefore it should be administered cautiously, particularly when several doses are required.

Two nondepolarizing muscle relaxants, atracurium and vecuronium, were introduced into clinical practice during the early 1980s. Atracurium is degraded by enzymatic ester hydrolysis and nonenzymatic alkaline degradation (Hofmann elimination) to inactive products that are not dependent on renal excretion for termination of action. Predictably, their terminal elimination half-life and indices of neuromuscular blockade (onset, duration, and recovery) are the same in patients with normal and absent renal function.

Approximately 30% of a dose of vecuronium is eliminated by the kidneys. Lynam and colleagues found that the duration of neuromuscular blockade after the administration of vecuronium was longer in patients with renal failure than in patients with normal renal function (99 vs. 54 minutes) because of a longer elimination half-life (83 vs. 52 minutes) and lower plasma clearance (3.1 mL/kg/min vs. 5.3 mL/kg/min). In a related area, an interaction between the solvent of cyclosporine (Kolliphor EL) with atracurium and vecuronium has been reported, with the action of these muscle relaxants potentiated in cats, but it is unknown whether such potentiation also occurs in human renal transplant recipients.

Cisatracurium is the single cis isomer of atracurium. Organ-independent mechanisms (Hofmann elimination) account for 77% of the total clearance of cisatracurium. Because renal excretion accounts for only 16% of the elimination of cisatracurium, renal failure should have little effect on its duration of action.

The short-acting drug mivacurium is metabolized by plasma pseudocholinesterase. Its effect has been shown to be lengthened by 10 to 15 minutes in patients with ESRD, most likely because of a decrease in plasma cholinesterase activity in these patients associated with uremia or hemodialysis and there is a decrease in the mivacurium requirement by infusion in anephric patients.

Rocuronium is an aminosteroid nondepolarizing muscle relaxant. The elimination half-life of rocuronium is increased in renal failure because of an increase in the volume of distribution with no change in clearance. This explanation might account for a longer duration of action in anephric patients, although its clinical significance is uncertain.

Pharmacokinetics data for the cholinesterase inhibitors neostigmine, pyridostigmine, and edrophonium for normal, anephric, and renal transplant patients are presented in Table 59.10 ; there are no major differences among the three drugs. Renal excretion is of major importance for the elimination of all three reversal drugs, with approximately 50% of neostigmine and 70% of pyridostigmine and edrophonium excreted in urine. Excretion of all the cholinesterase inhibitors is delayed in patients with impaired renal function to the same or perhaps to a slightly greater extent than is elimination of muscle relaxants. Reappearance of neuromuscular blockade after pharmacologic reversal of neuromuscular blockade in a patient with renal failure is, in most cases, due to some other cause. Table 59.10 contains data indicating that the pharmacokinetics of all the cholinesterase inhibitors is similar in healthy patients and in patients with well-functioning newly transplanted kidneys.

Sugammadex, a newer reversal drug, is a cyclodextrin molecule that inactivates aminosteroidal neuromuscular blockers, such as vecuronium and rocuronium, by selectively binding to them. The resultant sugammadex-neuromuscular blocker complex is excreted by the kidney. In patients with severe renal impairment, these cyclodextrin complexes can accumulate. Although sugammadex can effectively reverse neuromuscular blockade in these patients, the effect of prolonged exposure to sugammadex is unclear. There are insufficient data at this time to recommend the routine administration to patients with severe renal impairment. There are also data to suggest that sugammadex complexes can be effectively dialyzed using high-flux hemodialysis.

Vasopressors and Antihypertensive Drugs

Patients with severe renal disease are frequently given antihypertensive and other cardiovascular medications. More than 90% of the thiazides and 70% of furosemide are excreted by the kidneys, and they have prolonged durations of action in patients with abnormal or absent renal function. Propranolol is almost completely metabolized in the liver, and esmolol is biodegraded by esterases in the cytosol of red blood cells ; therefore their effects are not prolonged in patients with abnormal or absent renal function. The calcium channel–blocking agents nifedipine, verapamil, and diltiazem are extensively metabolized in the liver to pharmacologically inert products; they can be administered in usual doses to patients with renal insufficiency. Nitroglycerin can be useful because it is metabolized rapidly, with less than 1% excreted unchanged in urine.

Sodium nitroprusside has had a resurgence in use since its initial introduction as a hypotensive drug in the 1920s. Cyanide is an intermediate in the metabolism of sodium nitroprusside, with thiocyanate being the final metabolic product. Although cyanide toxicity as a complication of sodium nitroprusside therapy is well described, it is less well appreciated that thiocyanate is also potentially toxic. The half-life of thiocyanate is normally more than 4 days, and it is prolonged in patients with renal failure. Hypoxia, nausea, tinnitus, muscle spasm, disorientation, and psychosis have been reported when thiocyanate levels are more than 10 mg/100 mL. Sodium nitroprusside is less desirable for prolonged administration than either trimethaphan or nitroglycerin.

Hydralazine is slower acting than the other three drugs discussed previously. Its action is terminated by hydroxylation and subsequent glucuronidation in the liver, with approximately 15% excreted unchanged in urine. The elimination half-life of hydralazine is prolonged in patients with uremia; therefore caution is required when it is administered. After a single intravenous dose of 0.5 mg/kg of labetalol, the volume of distribution, clearance, and elimination half-life were similar in patients with ESRD and in healthy volunteers.

If administration of a vasopressor is necessary, a direct α-adrenergic–stimulating drug such as phenylephrine would be effective. This type of vasopressor causes the greatest interference with renal circulation. Although β-adrenergic–stimulating drugs such as isoproterenol maintain heart and brain perfusion without renal vasoconstriction, they also increase myocardial irritability. When possible, it is best to substitute simple measures such as blood volume expansion for drug therapy. If these measures are inadequate, β-adrenergic–stimulating drugs or dopamine should be used.

Dialysis

Dialysis may not decrease perioperative AKI; however, it can treat the associated acidosis, hyperkalemia, and hypervolemia. For certain surgeries, such as aortic, dialysis actually reduces 30-day mortality rates in patients who develop loss of renal function. As many as 75% of these survivors regain kidney function and become independent of dialysis.

Nondialytic Management

Optimal therapy for renal dysfunction has not been established, and it is not clear whether interventions such as ACE-I therapy or diuretic therapy prevent decline in kidney function around the time of surgery.

Normal hemodynamic variables probably should be preserved during the operative period in an attempt to prevent AKI. In addition, scavengers of oxygen free radicals such as mannitol and N -acetylcysteine have been given to prevent ischemia-reperfusion injury. However, studies implementing these strategies have failed to show benefit in reduction of AKI in cardiac surgery patients. For years, mannitol was administered before aortic clamping, especially prior to the application of a suprarenal cross-clamp during abdominal aortic aneurysm. Clinical trials thus far have failed to demonstrate that this approach reduces the incidence of renal failure in this population of patients.

Both dopamine and atrial natriuretic peptide initially showed promise in the prevention of AKI because of their vasoactive effects leading to increased renal blood flow. Studies have shown neither dopamine nor atrial natriuretic peptide to be associated with improved mortality. Use of fenoldopam, a selective renal dopamine receptor agonist, has been shown to reduce postoperative AKI; however, it has not been associated with a reduction in the need for renal replacement therapy or hospital mortality.

Pathophysiology of Prostate Hyperplasia

The prostatic gland is often described as a walnut-sized organ at the base of the bladder. There are three major areas—the fibromuscular stroma that surrounds the gland and two glandular zones termed central and peripheral. There is also a smaller, approximately 5% of the normal prostate, glandular region that surrounds the prostatic urethra designated as the transition zone; which is the primary site of benign prostatic hyperplasia (BPH). Nodular expansion of this area causes compression of the urethra along with the associated partial bladder outlet obstruction in men. The prostate is rich in blood supply with vessels penetrating the prostatic capsule and branching within the gland. There are also large venous sinuses adjacent to the capsule. The prevalence of BPH increases precipitously from the fourth decade of life, peaking at 88% of men in their 80s.

Surgical Procedures

TURP has long been considered the “gold standard” for the surgical treatment of BPH. Over the past several decades, the number of monopolar TURP (M-TURP) procedures performed annually in the United States has steadily declined secondary to advances in medical management, α-blockers, and 5-α reductase inhibitors; the introduction of newer surgical treatment modalities, bipolar TURP (B-TURP), laser TURP (L-TURP), microwave ablation, and aquablation; and the development of patient care guidelines.

The TURP procedure is performed by inserting a resectoscope through the urethra and resecting or vaporizing prostatic tissue in an orderly fashion. This can be accomplished using one of several techniques: M-TURP or B-TURP using an electrically powered cutting-coagulating metal loop, Holmium laser enucleation of the prostate (HoLEP), bipolar plasma vaporization, or laser-vaporization. A recently introduced novel technique is aquablation, a minimally invasive water ablation technique combining image guidance and robotics with a high-velocity saline stream for targeted and heat-free removal of prostatic tissue. During resection, care must be taken not to violate the prostatic capsule. If the capsule is violated, large amounts of irrigation fluid may be absorbed into the circulation via the periprostatic or retroperitoneal spaces. If perforation is suspected, the procedure should be quickly terminated and hemostasis should be established.

Bleeding during M-TURP is common but is usually easily controlled. Arterial bleeding is controlled by electrocoagulation; however, when large venous sinuses are opened, hemostasis becomes difficult. If bleeding becomes uncontrollable, the procedure should be terminated as quickly as possible, and a Foley catheter should be passed into the bladder and traction applied. Excessive bleeding requiring transfusion occurs in approximately 2.5% of M-TURP procedures.

Irrigation Solutions

Ideally, an irrigation solution for use during TURP should be isotonic, nonhemolytic, electrically inert, transparent, nonmetabolized, nontoxic, rapidly excreted, easily sterilized, and inexpensive. Such a solution does not exist. Initially, the solution of choice for M-TURP was distilled water because it is electrically inert, transparent, and inexpensive, but it is extremely hypotonic. When absorbed into the circulation, it causes massive hemolysis, hyponatremia, renal failure, and CNS symptoms. Solutions of normal saline or Ringer lactate are isosmotic and are tolerated if absorbed into the circulation but are highly ionized and would cause dispersion of the high-frequency current from the M-TURP resecting loop. These issues led to the use of nearly isotonic irrigation solutions, such as glycine, Cytal (a combination of 2.7% sorbitol and 0.54% mannitol), sorbital, mannitol, glucose, and urea ( Table 59.12 ). These solutions allow for electrocautery and are moderately hypotonic to maintain transparency.

Although these irrigation solutions cause no significant hemolysis, excessive absorption can lead to several perioperative complications, such as circulatory overload, pulmonary edema, and hyponatremia. In addition, the solutes can have adverse effects: glycine can cause cardiac, neurologic, and retinal effects; mannitol rapidly expands the blood volume and can cause pulmonary edema in cardiac compromised patients; sorbital is metabolized to fructose and lactate, and may cause hyperglycemia and/or lactic acidosis; and glucose can cause severe hyperglycemia in diabetic patients.

Replacement of distilled water with nearly isosmotic solutions has eliminated hemolysis and its sequelae as a complication of M-TURP. The incidence of severe CNS symptoms associated with severe hyponatremia, such as seizures and coma, has been reduced. However, the other major complication associated with the absorption of large volumes of irrigation solutions, overhydration, still is present. The use of normal saline as the bladder irrigation solution with the newer surgical techniques has eliminated the risks of dilutional hyponatremia and TURP syndrome.

Anesthetic Considerations for Transurethral Resection of the Prostate

Spinal anesthesia is considered the anesthetic technique of choice when traditional M-TURP is performed. Spinal anesthesia provides adequate anesthesia for the patient with relaxation of the pelvic floor and perineum for the surgeon. Cardiac morbidity and mortality after M-TURP were similar for general or regional ; however, spinal anesthesia has the advantage of allowing the patient to remain awake and enables the anesthesiologist to recognize the early signs and symptoms (e.g., mental status changes) of TURP syndrome or the extravasation of irrigating solution. Restlessness and confusion are early signs of hyponatremia and/or serum hypoosmolality and generally not signs of inadequate anesthesia. The continued administration of sedatives or the induction of general anesthesia might mask severe complications of TURP syndrome and even lead to death.

A sensory level of T10 provides satisfactory regional anesthesia for TURP by achieving an anesthetic block level that interrupts sensory transmission from the prostate and bladder neck; in addition, this sensory level eliminates the uncomfortable sensation of bladder distention. Higher sensory levels might mask the symptoms (abdominal or shoulder pain and/or nausea and vomiting) of accidental perforation of the bladder or prostatic capsule in the awake patient.

Spinal anesthesia has a few advantages over epidural anesthesia for TURP. It is considered to be technically easier to perform in elderly patients. The incomplete block of the sacral nerves, which provide sensory innervation to the prostate, bladder neck, and penis, occasionally occurs with epidural anesthesia and is usually avoided with spinal anesthesia. However, if a regional technique cannot be performed because of technical difficulty, concerns of sacral nerve coverage, coagulation status, and/or patient refusal, then general anesthesia will be required.

Controversy exists on whether regional or general anesthetic techniques influence blood loss during TURP. Some studies have reported decreased bleeding under regional anesthesia, whereas others found no significant difference between the techniques. Taking into consideration the studies that observed decreased bleeding with regional anesthesia, the authors have postulated that regional anesthesia reduces blood loss not only by decreasing systemic blood loss but also by decreasing central and peripheral venous pressures. However, spinal anesthesia, by reducing central venous pressure (CVP), may allow for greater absorption of irrigating solution compared to general anesthesia. Additional factors that influence blood loss during TURP are the vascularity and size of the gland, the duration of the procedure, the number of sinuses opened during resection, and the presence of infection and prostatic inflammation from repeated or recent catheterizations.

Anesthetic considerations for TURP should also include positioning. TURP is usually performed in the lithotomy position with a slight Trendelenburg tilt. This positioning results in changes in pulmonary blood volume; a decrease in pulmonary compliance; a cephalad shift of the diaphragm; and a decrease in lung volumes such as residual volume, functional residual volume, tidal volume, and vital capacity. Cardiac preload may also increase. Nerve injuries to the common peroneal, sciatic, and femoral nerves may occur.

Morbidity and Mortality After Transurethral Resection of the Prostate

Patients presenting for TURP are often elderly and tend to have coexisting diseases. With a reported 30-day mortality rate associated with M-TURP to be between 0.2% and 0.8%, the common causes of death include pulmonary edema, renal failure, and myocardial infarction. Mortality rates are similar in patients receiving regional anesthesia or general anesthesia. In one study the postoperative morbidity rate was noted to be 18%, with increased postoperative morbidity seen in patients with acute urinary retention, gland size greater than 45 g, resection exceeding 90 minutes, and age older than 80 years.

The most concerning complication of M-TURP is TURP syndrome. This syndrome has a multifactorial pathophysiologic presentation and is essentially an iatrogenic form of water intoxication caused by a combination of excessive absorption of irrigating solution and the resulting hyponatremia. Large studies have reported an incidence rate of mild to moderate TURP syndrome of between 0.78% and 1.4%. However, a mortality rate as high as 25% has been reported for severe TURP syndrome (serum sodium concentration <120 mEq/L).

Another concern, because many of the patients for TURP are elderly, is the incidence of postoperative cognitive dysfunction. In a small prospective study comparing spinal anesthesia with intravenous sedation to general anesthesia in elderly TURP patients, significant reduction in cognitive function was noted in both groups after 6 hours, with no difference in perioperative mental function between the groups at any time or even after 30 days.

Absorption of Irrigating Solution

In almost every TURP procedure, irrigating solution is absorbed through opened prostatic venous sinuses. Several factors govern the amount and rate of absorption: (1) the height of the irrigating solution above the surgical table, which affects hydrostatic pressure; (2) the amount of distension of the bladder; (3) the extent of opened venous sinuses; and (4) the length of surgical resection time. On average, 10 to 30 mL of fluid is absorbed per minute of resection time, with the possibility of 6 to 8 L absorbed in procedures lasting up to 2 hours. Whether patients experience complications as a consequence of absorption of irrigating solution depends on the amount and type of fluid absorbed.

Excessive Circulatory Volume, Hyponatremia, and Hypoosmolarity

The rapid volume expansion that occurs with excessive absorption of irrigation fluid leads to circulatory overload. Initially, hypertension and bradycardia may be observed, and in patients with compromised cardiac function, this could progress to pulmonary edema and eventually cardiac arrest. After the initial hypertensive stage, a period of prolonged hypotension may follow. One suggested mechanism is the combination of hypertension and hyponatremia, which causes a net water flux along osmotic and hydrostatic pressure gradients out of the intravascular space into the pulmonary interstitium, causing pulmonary edema and hypovolemic shock. In addition, the release of endotoxins into the circulation with the associated metabolic acidosis also causes hypotension. Whether symptoms of circulatory overload occur in a given patient depends on the patient’s cardiovascular status, the amount and rapidity of absorption of irrigating fluid, and the extent of surgical blood loss.

The severity of symptoms of hyponatremia correlate with the rate by which serum sodium concentration falls. Acute changes in serum sodium levels are more concerning than chronic hyponatremia. In addition, it is often impossible to separate symptoms of cardiovascular compromise caused by hyponatremia from those secondary to circulatory overload. CNS symptoms and cardiovascular effects are observed with acute decreases in serum sodium levels to less than 120 mEq/L. At first, one may observe restlessness and confusion, and with continuing decreases in serum sodium levels this may progress to loss of consciousness and seizures (<110 mEq/L). Hypotension, pulmonary edema, and congestive heart failure may also occur at serum sodium levels of less than 120 mEq/L, along with electrocardiogram changes (widened QRS complexes, ventricular ectopy, and ST segment increases) observed at levels less than 115 mEq/L. Eventually at levels near 100 mEq/L, respiratory and cardiac arrest may occur.

The classic CNS signs of TURP syndrome are thought to be not caused by hyponatremia itself but are due to the acute serum hypoosmolality that allows the shift of intravascular fluid into the brain and consequent cerebral edema. With the advent of modern nonelectrolyte irrigating solutions, the incidence of severe CNS complications has been reduced; however, CNS disturbances can still occur secondary to severe hyponatremia.

Glycine Toxicity

Glycine is a nonessential amino acid and when absorbed in significant amounts may cause neurologic and cardiac effects. Glycine has been implicated as the probable cause of transient blindness in TURP patients. Centrally acting mechanisms, such as cerebral edema, may also cause visual impairment, but normal pupillary light reflexes are retained. In TURP patients with transient blindness, the pupils are sluggish or nonreactive, suggesting a retinal effect. Glycine is an inhibitory neurotransmitter of the retina, and in one investigation, prolongation of visual evoked potentials along with deterioration of vision was observed after absorption of a few hundred milliliters of 1.5% glycine irrigation. Glycine has also been shown to have subacute effects on the myocardium with the appearance of T-wave depressions or inversions on electrocardiography; and CK-MB isoenzymes may be elevated in some patients, without meeting criteria for myocardial infarction, for up 24 hours after surgery.

Ammonia Toxicity

Because glycine is metabolized in the liver into ammonia, absorption of glycine may result in CNS toxicity. The early signs of ammonia toxicity, nausea and vomiting, usually occur within 1 hour after surgery. CNS signs and symptoms are observed when serum concentrations of ammonia are greater than 100 μmol/L. With higher levels, patients may lapse into a coma lasting from 10 to 12 hours and awaken after levels decrease to less than 150 μmol/L.

Bladder Perforation

Inadvertent perforation of the bladder during TURP is another common complication, with a reported incidence of approximately 1% and with most perforations occurring retroperitoneally. The usual cause is surgical instrumentation or overextension of the bladder with irrigating solution. An early sign of perforation, often overlooked, is a decrease in the return of irrigating solution. Eventually, a significant volume of fluid accumulates in the abdomen causing distension; conscious patients with a regional anesthetic may complain of abdominal pain and/or experience nausea and vomiting. With intraperitoneal perforations, symptoms are similar and develop sooner, and a patient may complain of severe shoulder pain secondary to diaphragmatic irritation. Intraperitoneal perforations are treated with either open surgical repair or percutaneous drainage of the abdomen.

Transient Bacteremia and Septicemia

The prostate harbors a variety of bacteria, which can be a source of perioperative bacteremia via opened prostatic venous sinuses. The presence of an indwelling catheter will further increase this risk. Therefore the prophylactic administration of antibiotics in patients is recommended for TURP procedures. The bacteremia is usually transient, symptomless, and easily treated with common antibiotic combinations; however, 6% to 7% of these patients may develop septicemia.

Hypothermia

Using room temperature irrigating solutions may cause shivering and hypothermia in patients undergoing TURP procedures. This may be especially noticeable in older populations who have a reduced thermoregulatory capacity. Warming the irrigation solutions will decrease heat loss and shivering. Concerns that these warmed solutions may cause increased bleeding secondary to vasodilation has not been shown to be clinically significant.

Bleeding and Coagulopathy

Estimates of blood loss during TURP are frequently inaccurate secondary to the mixing of blood with large volumes of irrigating solution. Blood loss during M-TURP has been estimated to range from 2 to 4 mL/min of resection time or 20 to 50 mL/g of resected prostatic tissue ; however, these guidelines are rough estimates, and the careful monitoring of the patient’s vital signs and serial hematocrits should be used to assess blood loss and the need for transfusion.

Abnormal bleeding after TURP occurs in less than 1% of cases. Possible causes include dilution of platelets (dilutional thrombocytopenia) and coagulation factors secondary to the absorption of large volumes of irrigating solutions, as well as systemic coagulopathy. In these patients, systemic coagulopathy is caused by either primary fibrinolysis or disseminated intravascular coagulopathy. In primary fibrinolysis, the prostate releases a plasminogen activator that converts plasminogen into plasmin, which then increases bleeding via fibrinolysis. If primary fibrinolysis is suspected, treatment is with epsilon aminocaproic acid given intravenously in a dose of 4 to 5 g during the first hour, followed by an infusion of 1 g/h. Some clinicians believe that the systemic absorption of resected prostatic tissue, which is rich in thromboplastin, will trigger the onset of disseminated intravascular coagulopathy. Treatment is supportive with administration of intravenous fluid and blood products as required.

Treatment of Transurethral Resection of Prostate Syndrome

TURP syndrome may occur as early as a few minutes after the start of the procedure and as late as several hours after completion. A high index of awareness of the signs and symptoms ( Table 59.13 ) must be present among the surgical team. Initially, based on the patient’s symptomatology, supplemental oxygenation, ventilation, and cardiovascular support should be provided; concomitantly, other treatable conditions such as hypercarbia, hypoglycemia and diabetic coma, or drug interactions should be considered. If TURP syndrome is suspected, blood samples should be drawn for analysis of electrolytes, glucose, and arterial blood gases and a 12-lead electrocardiogram should be obtained. Furthermore, the surgeon should terminate the procedure as rapidly as possible.

Table 59.13

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