RENAL DiSEASE AND ANESTHESiA
A good number of patients with chronic kidney disease undergo surgeries for reasons that may or may not be related to kidney disease; therefore, understanding the pathophysiology and the clinical management of these patients is highly important for the anesthesiologist. Preoperative management of patients with chronic kidney disease can be challenging. A number of factors, including preoperative assessment, fluid and electrolyte issues, bleeding, and dialysis issues, must be considered simultaneously to decrease morbidity and mortality related to surgery. Further, additional morbidity is contributed by the organ dysfunctions and the coexisting diseases commonly met in these patients.
Definition and Classification of stages of Chronic Kidney Disease
In 2002, the National Kidney Foundation Kidney Disease Outcomes Quality Initiative published the first consensus definition of CKD in adults. In the following years, epidemiologic data demonstrated a substantial increase in the risk of general complications, mortality and progression to end-stage renal failure with worsening glomerular filtration rate (GFR). Moreover, it could be proven that the cause of CKD fundamentally affected patients’ outcome. Therefore, the Kidney Disease: Improving Global Outcomes (KDIGO) workgroup arrived in 2012 at a new definition of CKD.
According to KDIGO 2012, CKD is classified based on cause, GFR, and albuminuria category if these are present for more than 3 months (if symptoms do not last longer than 3 months, the diagnosis of CKD is not established and tests should be repeated). These guidelines divide CKD into five groups depending on the presence or absence of kidney damage and the level of kidney function (Fig. 1).
Stage 1 and 2 include kidney damage with normal/increased GFR (90 ml/min) and mildly reduced GFR (60 – 89 ml/ min), respectively. Moderate or clinically significant CKD refers to CKD stages 3 (GFR 30 – 59 ml/min), 4 (GFR 15–29ml/min), and 5 (GFR<15ml/min).
Kidney Disease: Improving Global Outcomes classification for chronic kidney disease. Green, low risk (if no other markers of kidney disease, no chronic kidney disease); orange, high risk; red, very high risk; yellow, moderately increased risk.
The dispiriting term end-stage renal disease represents a stage of CKD where the accumulation of toxins, fluid, and electrolytes normally excreted by the kidneys results in the uremic syndrome. This syndrome leads to death unless the toxins are removed by renal replacement therapy, using dialysis or kidney transplantation.
The normal annual mean decline in GFR with age from the peak GFR (~120 ml/min per 1.73 m2) attained during the third decade of life is ~1 ml/min per year per 1.73 m2, reaching a mean value of 70 ml/min per 1.73 m2 at age 70. The mean GFR is lower in women than in men. For example, a woman in her 80s with a normal serum creatinine may have a GFR of just 50 ml/min per 1.73 m2.
Measurement of albuminuria is helpful for monitoring nephron injury and the response to therapy in many forms of CKD, especially chronic glomerular diseases. While an accurate 24-hour urine collection is the “gold standard” for measurement of albuminuria, the measurement of albumin-to-creatinine ratio in a spot first-morning urine sample is often more practical to obtain and correlates well, but not perfectly, with 24-hour urine collections. Persistence in the urine of >17 mg of albumin per gram of creatinine in adult males and 25 mg albumin per gram of creatinine in adult females usually signifies chronic renal damage. Microalbuminuria refers to the excretion of amounts of albumin too small to detect by urinary dipstick or conventional measures of urine protein. It is a good screening test for early detection of renal disease, in particular, and may be a marker for the presence of microvascular disease in general. If a patient has a large amount of excreted albumin, there is no reason to perform an assay for microalbuminuria.
Stages 1 and 2 CKD are usually not associated with any symptoms arising from the decrement in GFR. However, there may be symptoms from the underlying renal disease itself, such as edema in patients with nephrotic syndrome or signs of hypertension secondary to the renal parenchymal disease in patients with polycystic kidney disease, some forms of glomerulonephritis, and many other parenchymal and vascular renal diseases, even with well-preserved GFR. If the decline in GFR progresses to stages 3 and 4, clinical and laboratory complications of CKD become more prominent. Virtually all organ systems are affected, but the most evident complications include anemia and associated easy fatigability; decreasing appetite with progressive malnutrition, abnormalities in calcium, phosphorus, and mineral-regulating hormones, such as 1,25-dihydroxycholecalciferol (calcitriol) and parathyroid hormone (PTH); and abnormalities in sodium, potassium, water, and acid-base homeostasis. If the patient progresses to stage 5 CKD, toxins accumulate such that patients usually experience a marked disturbance in their activities of daily living, well-being, nutritional status, and water and electrolyte homeostasis, eventuating in the uremic syndrome. As discussed above, this state will culminate in death unless renal replacement therapy (dialysis or transplantation) is instituted.
Etiology of chronic kidney disease
Table 1 gives an overview of the common causes of CKD.
A normal kidney contains approximately 1 million nephrons, each of which contributes to the total glomerular filtration rate (GFR). In the face of renal injury (regardless of the etiology), the kidney has an innate ability to maintain GFR, despite progressive destruction of nephrons, as the remaining healthy nephrons manifest hyperfiltration and compensatory hypertrophy. This nephron adaptability allows for continued normal clearance of plasma solutes. Plasma levels of substances such as urea and creatinine start to show measurable increases only after total GFR has decreased 50%.
The plasma creatinine value will approximately double with a 50% reduction in GFR. For example, a rise in plasma creatinine from a baseline value of 0.6 mg/dL to 1.2 mg/dL in a patient, although still within the adult reference range, actually represents a loss of 50% of functioning nephron mass.
The hyperfiltration and hypertrophy of residual nephrons, although beneficial for the reasons noted, has been hypothesized to represent a major cause of progressive renal dysfunction. The increased glomerular capillary pressure may damage the capillaries, leading initially to secondary focal and segmental glomerulosclerosis (FSGS) and eventually to global glomerulosclerosis. This hypothesis is supported by studies of five-sixths nephrectomized rats, which develop lesions identical to those observed in humans with chronic kidney disease (CKD).
2 broad sets of mechanisms of damage leading to CKD are described:
1)A set of progressive mechanisms, involving hyperfiltration and hypertrophy of the remaining viable nephrons, that are a common consequence following long-term reduction of renal mass, irrespective of underlying etiology.
2) Initiating mechanisms specific to the underlying etiology (e.g. immune complexes and mediators of inflammation in certain types of glomerulonephritis, or toxin exposure in certain diseases of the renal tubules and interstitium).
The responses to reduction in nephron number are mediated by vasoactive hormones, cytokines, and growth factors. Eventually, these short-term adaptations of hypertrophy and hyperfiltration become maladaptive as the increased pressure and flow predisposes to sclerosis and dropout of the remaining nephrons.
Clinical and laboratory manifestations of Chronic Kidney Disease and Uremia
In CKD, the sodium and water handling capabilities are limited. Hence, in most cases total body contents of water and sodium are increased. 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 fluid subsequently enters the interstitial tissues from the overloaded intravascular compartment; the process is potentiated by hypoproteinemia.
Hypertension is a common complication of CKD and ESRD. In spite of diuretic therapy/dialysis, patients remain hypertensive due to activation of the renin-angiotensin system and autonomic factor. Hyperreninemic states and exogenous erythropoietin administration can also exacerbate hypertension. Patients generally have left ventricular hypertrophy and accelerated atherosclerosis.
Hypertension is often resistant to drug therapy and the patient may be taking two or more antihypertensives. The patient with renal dysfunction occasionally suffers from hypertension due to renal artery stenosis, especially if the patient has had a renal transplant. Hypertension from this cause is particularly difficult to treat with drug therapy. The difficulty in controlling the very high and labile blood pressure leads to a significant risk of a cerebrovascular accident during the perioperative period.
Peripheral vascular disease is also more common, and occurs at an earlier age,in patients with renal dysfunction.
Patients with CKD experience greater morbidity and mor tality from cardiovascular disease (CVD) in comparison to the general population. Roughly 80% of patients with CKD die, primarily of CVD, before reaching the need for dialysis. Of those undergoing dialysis, 45% will die of a cardiovascular cause.
Coronary Artery Disease
Patients with CKD are at higher risk for death from CVD than the general population. Traditional modifiable risk factors for CVD, such as hypertension, tobacco use, and hyperlipidemia, should be aggressively treated in patients with CKD. Uremic vascular calcification involving disordered phosphorus homeostasis and other mediators may also be a cardiovascular risk factor in these patients.
Myocardial infarction is 10 times more common in the renal transplant patient than in the general population of the same age and sex. Episodes of angina are frequent, and intercurrent anemia is usually a contributory cause. Myocardial arrhythmias may also follow and may be exacerbated by metabolic problems such as hyper- and hypokalemia and hypocalcemia.
Pulmonary edema and restrictive pulmonary dysfunction
Pulmonary edema and restrictive pulmonary dysfunction are commonly seen in patients with 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.
The pulmonary congestion and edema may occur even in the absence of volume overload and is associated with normal or mildly elevated intracardiac and pulmonary capillary wedge pressure. This entity, characterized radiologically by peripheral vascular congestion giving rise to a “butterfly wing” distribution, is due to increased permeability of alveolar capillary membranes. This “low-pressure” pulmonary edema, as well as the cardiopulmonary abnormalities associated with circulatory overload, usually responds promptly to vigorous dialysis.
Chronic metabolic acidosis may be responsible, in part, for the hyperventilation seen in patients with ESRD, but increased lung water and poor pulmonary compliance also stimulate ventilation.
Acute pulmonary edema may develop as a consequence of a myocardial infarction or myocardial ischemia, which are frequent incidents during the perioperative period in the renal patient. More than half of renal failure patients presenting for transplantation are also in congestive (right) heart failure.
Pericarditis is not uncommon in patients with renal dysfunction and is sometimes accompanied by a pericardial effusion. Such problems are more common in the poorly controlled patient, who is overloaded with fluid, and can occur in the absence of infection. Development of a significant effusion may result in pulsus paradoxus, an enlarged cardiac silhouette on chest radiograph, and low QRS voltage and electrical alternans on ECG. The effusion is generally hemorrhagic, and anticoagulants should be avoided if this diagnosis is suspected. Cardiac tamponade can occur; therefore, uremic pericarditis is a mandatory indication for hospitalization and initiation of hemodialysis. Such clinical signs must be taken seriously and anesthesia should, if possible, be delayed until the causal condition has been treated because of the risk of severe myocardial depression intra- and postoperatively.
The anemia of CKD is primarily due to decreased erythropoietin production, which often becomes clinically significant during stage 3 CKD. The possible causes of anemia in CKD include:
Relative deficiency of erythropoietin
Diminished red blood cell survival (uremia)
Iron deficiency, impaired GI iron absorption
Hyperparathyroidism/bone marrow fibrosis
Acute and chronic inflammation with impaired iron utilization (“anemia of chronic disease”)
Folate or vitamin B12 deficiency
Either related to or independent of blood loss from repeated laboratory testing
Blood retention in the dialyzer
Comorbid conditions: Hemoglobinopathy, hypo/ hyperthyroidism, pregnancy, HIV-associated disease, autoimmune disease, immunosuppressive drugs
The anemia in CKD is of the normochromic, normocytic type and is unresponsive to oral iron therapy.
The adverse pathophysiologic consequences in anemia of CKD include:
decreased tissue oxygen delivery and utilization,
increased cardiac output,
ventricular dilatation, and
Clinical manifestations include:
low exercise ability,
decreased cognition and mental acuity, and
impaired host defense against infection.
Most of these manifestations improve if anemia is corrected by erythropoietin administration.
The usual compensatory responses for anemia in CKD include:
rise in 2,3-DPG and acidosis (shift in oxygen dissociation curve to right, thus increasing oxygen delivery);
compensatory increase in cardiac output and lowered viscosity (increasing tissue perfusion).
Hence, evaluation of effort tolerance gives a better idea of the physiological reserve than hemoglobin value. When anemia is present, its severity generally parallels the degree of uremia; chronically uremic patients seem to adapt well to anemia.
Treatment of anemia with iron, darbepoetin alfa, and human recombinant erythropoietin restores a normal hematocrit and avoids repetitive red blood cell transfusions, reduces the requirement for hospitalization, and decreases cardiovascular mortality by approximately 30%.
Note: ESAs should be used with great caution, if at all, in CKD patients with active malignancy, a history of malignancy, or prior history of stroke. (KDIGO 2012)
The preliminary investigation of anemia in any CKD patient should also include assessment of thyroid function tests, and serum vitamin B12 testing prior to initiating therapy with an Erythropoiesis-stimulating agent (ESA).
Note: Anemia can increase the rate of induction and emergence of inhaled anesthetics due to the reduced BGPC (Blood-Gas Partition Coefficient).
Note: Avoid administering IV iron to patients with active systemic infections.
Perioperative Hb correction Guidelines (KDIGO 2012)
Perioperative transfusions are generally not recommended when the Hb is >10 g/dl in otherwise healthy subjects, but should be given when the Hb is less than 7 g/dl in CKD patients.
When Hb concentration is less than 7 g/dl and the patient is otherwise stable, 2 units of red cells should be transfused and the patient’s clinical status and circulating Hb should be reassessed.
High-risk patients (>65 years and/or those with cardiovascular or respiratory disease) may tolerate anemia poorly, and may be transfused when Hb concentration is less than 8 g/dl.
For Hb concentration between 7 and 10 g/dl (70 and 100 g/l), the correct strategy is unclear.
Given the progressive loss of red cell viability which occurs during storage, the ‘‘freshest-available’’ units should be selected in order to maximize post-transfusion survival.
The decision to transfuse a CKD patient with non-acute anemia should not be based on any arbitrary Hb threshold, but should be determined by the occurrence of symptoms caused by anemia.
In patients eligible for organ transplantation, KIDGO specifically recommend avoiding, when possible, red cell transfusions to minimize the risk of allosensitization.
Ref: Kidney International Supplements (2012) 2, 311–316; doi:10.1038/kisup.2012.36
The red blood corpuscles of patients with renal disease have a shorter half-life than those of a healthy person; thus, if the cells of a patient with renal failure were to be given to a healthy patient, their half-life would increase. The increased hemolysis potentiates the normochromic anemia and depletes iron stores further.
Other hematological dysfunctions
Although the platelet count may be normal in the uremic patient, platelet dysfunction may occur (thrombasthenia), prolonging bleeding times and thus increasing the risk of hemorrhage during surgery, especially in the patient who has not been adequately dialyzed. Severe anemia may also contribute to bleeding diathesis.
Patients with later stages of CKD may have a prolonged bleeding time, decreased activity of platelet factor III, abnormal platelet aggregation and adhesiveness, and impaired prothrombin consumption. Clinical manifestations include an increased tendency to bleeding and bruising, prolonged bleeding from surgical incisions, menorrhagia, and spontaneous GI bleeding.
Interestingly, CKD patients also have a greater susceptibility to thromboembolism, especially if they have renal disease that includes nephrotic-range proteinuria. The latter condition results in hypoalbuminemia and renal loss of anticoagulant factors, which can lead to a thrombophilic state.
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.
Potassium balance generally remains intact in chronic renal failure until the GFR is less than 10–20 ml/min. Inability to excrete potassium by the distal tubule results in accumulation of this electrolyte. Patients with CKD usually tolerate significant hyperkalemia, partly due to increased intestinal excretion. However a sudden increase in potassium load can trigger rapid increases in serum potassium and cause life-threatening arrhythmias.
Endogenous causes include:
any type of cellular destruction such as protein catabolism, hemolysis, hemorrhage,
transfusion of stored red blood cells
hyporeninemic hypoaldosteronism (renal tubular acidosis type IV, seen particularly in diabetes mellitus), and
acidemic states (0.6 mEq/l elevation in K+ for each 0.1 unit decrease in pH).
Exogenous causes include:
diet (e.g. citrus fruits and salt substitutes containing potassium) and
drugs that decrease K+ secretion (amiloride, triamterene, spironolactone, NSAIDs, ACE inhibitors) or block cellular uptake (β-blockers).
*There is no clear correlation between levels of potassium and the likelihood of an arrhythmia; however, arrhythmia is more likely if the increase in potassium is rapid.
Tall T waves and small P waves
Prolonged PR interval Broad, bizarre QRS complexes — these merge with both the preceding P wave and subsequent T wave. Peaked T waves
Huge peaked T waves. Sine wave appearance.
Tall T waves and small P waves
Hypokalemia is not common in CKD and usually reflects markedly reduced dietary potassium intake, especially in association with excessive diuretic therapy or concurrent GI losses. However, even with these conditions, as the GFR declines, the tendency to hypokalemia diminishes and hyperkalemia may supervene. Therefore, the use of potassium supplements and potassium-sparing diuretics should be constantly reevaluated as GFR declines.
Patients with renal failure develop a metabolic acidosis that is initially associated with hyperchloremia and normal anion gap. When renal failure becomes severe, inability to excrete titrable acids (1 mEq/kg/d, generated by metabolism of dietary proteins) causes an increased anion gap. The resultant metabolic acidosis is primarily due to loss of renal mass. This limits production of ammonia (NH3) and limits buffering of H+ in the urine. (Other causes include decreased filtration of titratable acids such as sulfates and phosphates, decreased proximal tubular bicarbonate resorption, and decreased renal tubular hydrogen ion secretion.) Although patients with chronic renal failure are in positive hydrogen ion balance, the arterial blood pH is maintained at 7.33–7.37 and serum bicarbonate concentration rarely falls below 15 mEq/L. The excess hydrogen ions are buffered by the large calcium carbonate and calcium phosphate stores in bone. This contributes to the renal osteodystrophy of chronic renal failure described below.
If chronic metabolic acidosis is present (T CO2 < 20 m Eq/L) during IPPV (intermittent positive pressure ventilation) under anesthesia, minute ventilation should be increased above normal to continue respiratory compensation during anesthesia.
Changes in Sodium
Sodium is mainly an extracellular cation, in contrast with potassium. The serum level is therefore a more accurate estimate of the total body content. With proper dietary control of intake, and appropriate diuretic and dialysis therapy if necessary, the serum sodium can be managed easily. A rise in serum sodium is usually an indication of dehydration, rather than an excess of sodium ions; a fall is usually due to fluid retention, caused by excessive fluid intake and/or inadequate dialysis.
The decreased excretion of glucose by the diseased kidney makes control of blood glucose difficult, especially in the insulin-dependent diabetic patient in renal failure or in the patient receiving drugs which increase blood glucose, e.g. corticosteroid therapy. Hyperglycemia increases the risk of infection in the postoperative patient. This is in part the reason why, before the advent of the immunosuppressant drug cyclosporine (cyclosporin A), when steroid therapy was commonplace, renal transplantation was less successful in the diabetic patient. A rise in blood sugar may be accompanied by a rise in serum potassium, making cardiac arrhythmias more likely.
Type 2 diabetes is the leading cause of end-stage renal disease in developed countries.
Factors leading to Increased risk of hypoglycemia:
Decreasing renal mass leads to impaired gluconeogenesis and glycenolysis
Decreased renal clearance of insulin
Decreased clearance of hypoglycemic drugs
Comorbidity and co-medication
Factors increasing impaired glucose tolerance in advanced CKD:
Peripheral insulin resistance in CKD from counter-regulatory hormones, electrolyte abnormalities, uremic acidosis, and accumulation of uremic toxins
Plasma albumin levelsare often reduced in patients with renal disease. This may be due to hemodilution, to impaired synthesis if the patient is catabolic or malnourished, to an increased loss of protein through the diseased nephron, or to combinations of these factors. Alterations in plasma albumin may alter the degree of binding of many drugs. This is particularly relevant with drugs that are highly protein bound (98% or more), such as warfarin, diazepam, and phenytoin. Here, only 2% or less of the drug in the plasma is unbound, and thus free to have an effect. A small decrease in plasma albumin, and thus drug binding, can cause a significant increase in free drug available. An increase in unbound drug from 2% to 3% represents a 50% increase, and therefore markedly potentiates the drug effect.
Most anesthetic agents are not predominantly bound to plasma albumin: neuromuscular blocking drugs are mainly bound to plasma globulins, although not to a significant degree.
Uremic encephalopathy does not occur until GFR falls below 10–15 ml/min. Encephalopathy may be due to tertiary hyperparathyroidism, where an elevated PTH level or, rarely, hypercalcemia, can be the culprit. PTH may be one of the uremic toxins. Symptoms begin with difficulty in concentrating and can progress to lethargy, confusion, and coma. Physical findings include nystagmus, weakness, asterixis, and hyperreflexia. These symptoms and signs may improve after initiation of dialysis.
Peripheral neuropathies manifest themselves as sensorimotor polyneuropathies (stocking and glove distribution) and isolated or multiple isolated monone- uropathies. Patients can have restless legs, loss of deep tendon reflexes, and distal pain. The earlier initiation of dialysis may prevent peripheral neuropathies, and the response to dialysis is variable.
Other neuropathies result in impotence and autonomic dysfunction.
Bone Manifestations of CKD
The metabolic bone disease of CKD refers to the complex disturbances of calcium and phosphorus metabolism, parathyroid hormone (PTH), active vitamin D, and fibroblast growth factor-23 (FGF-23) homeostasis. Decline in glomerular filtration rate (GFR) and loss of renal mass lead directly to increased serum phosphorus and hypovitaminosis D. Both of these abnormalities result in hypocalcemia and hyper parathyroidism. Many CKD patients also have nutritional 25 (OH) vitamin D deficiency.
The disorders of calcium, phosphorus, and bone are referred to as renal osteodystrophy. The most common disorder is osteitis fibrosa cystica — the bony changes of secondary hyperparathyroidism. This affects ~ 50% of patients nearing ESRD. As GFR decreases below 25% of normal, phosphorus excretion is impaired. Hyperphosphatemia leads to hypocalcemia, stimulating secretion of PTH, which has a phosphaturic effect and normalizes serum phosphorus. This continuous process leads to markedly elevated PTH levels and high bone turnover with osteoclastic bone resorption and subperiosteal lesions. Metastatic calcifications, such as tumoral calcinosis, can occur. Radiographically, lesions are most prominent in the phalanges and lateral ends of the clavicles.
Osteomalacia is a form of renal osteodystrophy with low bone turnover (affecting 10% of patients nearing ESRD). With worsening renal function, there is decreased renal conversion of 25-hydroxycholecalciferol to the 1,25-dihydroxy form. Gut absorption of calcium is diminished, leading to hypocalcemia and abnormal bone mineralization. Deposition of aluminium in bone can also lead to osteomalacia.
Adynamic bone disease is a disorder of low bone turnover. More than 25% of patients nearing ESRD show evidence of minimal osteoid and decreased or absent bone remodeling. Its frequency is increasing because of increased use of active vitamin D analogs, which suppress PTH production.
All of the above entities can cause bony pain and proximal muscle weakness. Spontaneous bone fractures can occur that are slow to heal. When the calcium-phosphorus product (serum calcium [mg/dl] x serum phosphate [mg/ dl]) is above 60–70, metastatic calcifications are commonly seen.
Other endocrine system effects
Decreased libido and erectile dysfunction are common in advanced CKD. Men have decreased testosterone levels; women are often anovulatory. Women with serum creati nine less than 1 .4 mg/dL are not at increased risk for poor outcomes in pregnancy; however, those with serum creati nine greater than 1 .4 mg/dL may experience faster progres sion of CKD with pregnancy. Fetal survival is not compromised, however, unless CKD is advanced. Despite a high degree of infertility in patients with ESRD, pregnancy can occur in this setting; however, fetal mortality approaches 50%, and babies who survive are often prema ture. In female patients with ESRD, renal transplantation with a well-functioning allograft affords the best chances for a successful pregnancy.
CKD patients commonly experience gastrointestinal symptoms including dysgeusia, anorexia, dyspepsia, hiccups, nausea, and vomiting. Gastrointestinal hemorrhage occurs frequently and may originate from peptic ulcer disease, vascular ectasia or diverticulosis, with uremic bleeding diathesis, ulcerogenic medications, and infections contributing to this increased bleeding tendency. Lower gastrointestinal tract symptoms include constipation and diarrhea. CKD also affects gastric motility, the pancreas, and the gall bladder.
Uremic fetor is a urine-like odor on the breath of persons with uremia. The odor occurs from the smell of ammonia, which is created in the saliva as a breakdown product of urea. Uremic fetor is usually associated with an unpleasant metallic taste (dysgeusia) and can be a symptom of chronic kidney disease.
Uremia delays gastric emptying. The patient with renal disease, espe- cially if not well managed preoperatively, should be considered to have a full stomach. The use of a rapid-sequence induction should be consid- ered at the beginning of anesthesia, although the use of succinylcholine must be balanced against the rise in serum potassium which this drug will produce.
Anesthetic agents in Renal Failure
Drugs excreted unchanged by the kidney
Degree of protein binding (albumin concentration may be markedly reduced in uremia)
Increase in volume of distribution (prolong elimination half-life)
Metabolic acidosis (more un-ionized, non-bound, active form of weakly acidic drugs)
Nephrotoxicity of drugs used
Induction agents & Sedatives
Propofol undergoes extensive, rapid hepatic biotransformation to inactive metabolites that are excreted by the kidneys. Its pharmacokinetics appear to be unchanged in patients with renal failure, and there are no reports of prolongation of its effects in ESRD.
Propofol is likely to cause a greater fall in blood pressure than thiopental in all patients, but this decrease does not appear to be greater in patients with renal failure." After a bolus dose, the plasma levels of propofol are similar in renal patients and healthy patients, as are the pharmacokinetic parameters.
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 metabo- lites 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.
Barbiturates are more potent in renal disease, in part because of the pre-existing myocardial problems. Reversal of CNS effects occurs a s a result of redistribution. Hepatic metabolism is the sole route of elimination. Thiopental is 75–85% bound to albumin. Hence greater proportion of free drug reach the receptor sites. Thiopental is a weak acid. Acidosis will result in more un-ionized, unbound, active thiopental. This accounts for the exaggerated clinical effects of thiopental in these patients and explains the need for a decreased induction dose in uremic patients compared with normal patients.
Ketamine is less extensively protein bound than thiopental, and renal failure appears to have minimal influence on its free fraction. Redistribution and hepatic metabolism are largely responsible for termination of the anesthetic effects, with <3% of the drug excreted unchanged in the urine. Nor-ketamine, the major metabolite, has one-third the pharmacologic activity of the parent drug and is further metabolized before it is excreted by the kidney. Poor renal function is not known to alter the pharmacokinetics or clinical profile of ketamine. Major disadvantage is that its sympathomimetic action may worsen preexisting tachycardia and hypertension.
Etomidate, although only 75% protein bound in normal patients, has a larger free fraction in ESRD. The decrease in protein binding does not seem to alter the clinical effects of an etomidate anesthetic induction in patients with renal failure.
Benzodiazepines and Tranquillisers
Patients with CKD are actually more sensitive to sedative effects than normal persons. The benzodiazepines, as a group, are extensively protein bound. CKD increases the free fraction of benzodiazepines in plasma, which may potentiate their clinical effect. Certain benzodiazepine metabolites are pharmacologically active and have the potential to accumulate with repeated administration of the parent drug to anephric patients. For example, 60 to 80% of midazolam is excreted as its (active) α-hydroxy metabolite, which accumulates during long-term infusions in patients with renal failure. Acute renal failure (ARF) appears to slow the plasma clearance of midazolam, whereas repeated diazepam or lorazepam administration in CKD may carry a risk of active metabolite induced sedation. Alprazolam is also found to be more sedative due to decreased protein binding and increased free fraction.
Single-dose of morphine pharmacokinetics in renal failure demonstrate no alteration in its disposition. However, chronic administration results in accumulation of its 6-glucuronide metabolite, which has potent analgesic and sedative effects. There is also a decrease in protein binding of morphine in CKD, which mandates a reduction in its initial dose.
Meperidine (Pethidine) is remarkable for its neurotoxic, (CNS excitability, convulsions) renally excreted metabolite (normeperidine) and is not recommended for use in patients with poor renal function.
Fentanyl appears to be an excellent opioid for use in CKD because of its lack of active metabolites, unchanged free fraction, and short redistribution phase. Small to moderate doses, titrated to effect, are well tolerated by uremic patients.
Alfentanil has been shown to have reduced protein binding but no change in its elimination half-life or clearance in CKD, and is extensively metabolized to inactive compounds. Therefore, caution should be exercised in administering a loading dose, but the total dose and infusion dose should be similar to those for patients with normal renal function.
The free fraction of sufentanil is unchanged in CKD; however, its pharmacokinetics are variable, and it has been reported to cause prolonged narcosis.
Remifentanil has unaltered pharmacokinetic and dynamic effects in patients with chronic renal failure compared with healthy controls. Remifentanil is rapidly metabolized by nonspecific esterases to a weakly active (about 4,600 times less potent as μ-opioid agonist), renally excreted metabolite, and remifentanil acid. Renal failure has no effect on clearance of remifentanil, but elimination of the principal metabolite, remifentanil acid, is markedly reduced. However, the clinical implications of this metabolite are limited.
Buprenorphine, which is also metabolized mainly in the liver, does not appear to cumulate in renal failure, although the inactive metabolites do
Dexmedetomidine is a relatively new sedative agent primarily metabolized in the liver. The most likely explanation for its longer-lasting sedative effect is that less protein binding of dexmedetomidine occurs in subjects with renal dysfunction.
Muscle relaxants are the most likely group of drugs used in anesthetic practice to produce prolonged effects in ESRD because of their reliance on renal excretion. Only succinylcholine, atracurium, cisatracurium, and mivacurium appear to have minimal renal excretion of the unchanged parent compound. Although the following discussion focuses on the pharmacology of individual muscle relaxants, coexisting acidosis and electrolyte disturbances, as well as drug therapy (e.g. aminoglycosides, diuretics, immunosuppressants, magnesium-containing antacids), may alter the pharmacodynamics of muscle relaxants in patients with renal failure.
Succinylcholine has been used without difficulty in patients with decreased or absent renal function. Use of a continuous infusion of succinylcholine, however, is more problematic because the major metabolite, succinylmonocholine, is weakly active and excreted by the kidney. It has been reported that pseudocholinesterase levels are reduced in uremia. However, values are rarely so low that they cause a prolonged block. Hemodialysis has been reported to have no effect on cholinesterase levels.
Concern about the increase in serum potassium levels after succinylcholine administration (0.5 mEq/l in normal subjects) implies that the serum potassium should be normalized to the extent possible in patients with renal failure. An exaggerated rise in serum potassium could be particularly dangerous in uremic patients with elevated potassium levels, so the use of succinylcholine is inadvisable unless the patient has undergone dialysis within 24 hours before surgery and serum potassium <5.5mEq/L.
Pancuronium has an increased half-life when creatinine clearance in lower than 50ml/min and therefore its prolonged or repeated administration should be avoided. Usually pancuronium is avoided in patients with renal dysfunction.
About 30% of a dose of vecuronium is eliminated by the kidneys. The duration of neuromuscular blockade after the administration of vecuronium is longer in patients with renal failure because of a longer elimination half-life and lower plasma clearance. In addition, the active metabolite, 3-desmethylvecuronium, was shown to accumulate in anephric patients receiving a continuous vecuronium infusion who subsequently had prolonged neuromuscular blockade. An intubating dose would be expected to last ~50% longer in patients with ESRD.
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 may account for a somewhat longer duration of action in anephric patients, although its clinical significance is uncertain.
Atracurium and its derivative, cisatracurium, undergo enzymatic ester hydrolysis and spontaneous non-enzymatic (Hoffman) degradation (38% and 77 % respectively) with minimal renal excretion of the parent compound. Their elimination half-life, clearance, and duration of action are not affected by renal failure, nor have they been reported to cause prolonged clinical effects in CKD. These characteristics strongly recommend the use of atracurium and cisatracurium in patients with renal disease.
One potential concern is that an atracurium metabolite, laudanosine, causes seizures in experimental animals and may accumulate with repeated dosing or continuous infusion. Consistent with its greater potency and lower dosing requirements, cisatracurium metabolism results in lower laudanosine blood levels than does atracurium in CKD patients.
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.
The pharmacokinetics of clinically available anticholinesterases are affected by renal failure. They have a prolonged duration of action in ESRD because of their heavy reliance on renal excretion, 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. Thus, “recurarization” after reversal of neuromuscular blockade in a patient with renal failure is, in most cases, due to some other cause, such as an interaction of the residual muscle relaxant with an antibiotic or a diuretic.
Pharmacokinetics data in normal and anephric patients
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.
All inhaled anesthetics are biotransformed to some extent, with the nonvolatile products of metabolism eliminated almost entirely by the kidney. However, reversal of the CNS effects of inhaled anesthetics is dependent on pulmonary excretion, so impaired kidney function will not alter the response to these anesthetics.
Inhaled anesthetics cause a transient reversible depression in renal function. GFR, renal blood flow, urine output, and urinary excretion of sodium are decreased. Probable mechanisms include reduced renal blood flow, loss of renal autoregulation, neurohumoral factors (e.g. antidiuretic hormone, vasopressin, renin), and neuroendocrine responses.
Both methoxyflurane and enflurane have been shown to cause impairment in urine concentrating ability and antidiuretic hormone (ADH)-resistent polyuria. Renal injury from anesthetic gases is related to liberation of inorganic fluoride.
Halothane is not significantly defluorinated under normal clinical conditions and is not nephrotoxic. Although halothane potentiates the bradycardia produced by beta- blocking drugs, it will not alter renal perfusion unless the patient is hypotensive, hypovolemic, or hypercarbic, when renal blood flow will decrease further.
Isoflurane, an isomer of enflurane, is defluorinated much less than enflurane. Peak serum fluoride concentration after 6 hours of isoflurane anesthesia was only 4.4 μmol/l. Isoflurane should not be associated with fluoride-associated nephrotoxicity. many authors suggest isoflurane as the inhalational agent of choice in these patients, despite the risk of coronary artery steal in the presence of coronary artery disease.
Sevoflurane is defluorinated through oxidative metabolism to approximately the same extent as that of enflurane. Clinical studies show that serum fluoride concentrations often peak above 50 μmol/L, even when sevoflurane is administered during surgery of average duration. Because of sevoflurane’s low blood-to-gas solubility and its rapid elimination, fluoride concentrations fall very quickly after surgery, and renal toxicities are not expected from sevoflurane administration. The recent finding that methoxyflurane, and not sevoflurane, undergoes significant microsomal biotransformation in the kidney, with resulting higher intraparenchymal fluoride concentrations, may explain why actual renal injury does not seem related to serum fluoride concentrations. Carbon dioxide absorents (sodalime, baralyme) react with sevoflurane and eliminate HF from its isopropyl moiety to form breakdown products like compound A [fluoromethyl 2,2-difluoro 1- (trifluoromethyl) vinyl ether] particularly when baralyme absorbers of smaller size are used. Toxic blood levels of compound A may induce nephrotoxicity in humans undergoing low flow sevoflurane anesthesia. US FDA (food and drug administration) warns against the use of sevoflurane at fresh gas flows less than 2L/min. The concern that sevoflurane might exacerbate preexisting renal disease has also been raised. However, renal toxicity has not been detected when sevoflurane was administered in patients with renal insufficiency with a relatively high flow of 4 l/min.
Clinical studies performed with desflurane show no evidence of nephrotoxicity. Desflurane is extremely resistant to defluorination, and serum fluoride concentrations in surgical patients after exposure to desflurane are not increased above background concentrations. Therefore, desflurane should be appropriate as a maintenance agent during anesthesia for patients with chronic renal failure.
Nonsteroidal anti-inflammatory drugs (NSAIDs)
Nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided in patients with CKD. NSAIDs inhibit the production of renal prostaglandins PGE2 and PGI2, which are responsible for maintaining renal blood flow during hypovolemia and in the presence of vasoconstrictors, and could precipitate acute renal failure.
Local anesthetic drugs
Local anesthetics are valuable agents for perioperative pain control in CKD, but their duration of action is reduced secondary to acidosis. Maximum doses of local anesthetics should also be reduced by 25% because of reduced protein binding and a lower CNS seizure threshold.
Regional anesthesia in patients with Renal Dysfunction
Regional anesthesia is commonly chosen for peripheral procedures such as creation of arteriovenous fistulas, for which brachial blocks are a popular choice.
The concerns while opting for regional blockade include:
Platelet dysfunction occurs both as result of intrinsic platelet abnormalities and impaired platelet–vessel wall interaction. The normal platelet activation, recruitment, adhesion and aggregation is defective in advanced renal failure.
Dialysis may partially correct these defects, but cannot totally eliminate them. The hemodialysis process itself may in fact contribute to bleeding. Hemodialysis is also associated with thrombosis as a result of chronic platelet activation due to contact with artificial surfaces during dialysis.
Renal clearance is the primary mode of elimination for several anticoagulants, including LMWH (low molecular weight heparin), fondaparinux, and the new oral factor Xa and IIa inhibitors. Therefore, with reduced renal function, these drugs may accumulate and may increase the risk of bleeding, particularly in elderly patients and those at high risk for bleeding.
As acidosis decreases the central nervous system threshold to the toxic effects of local anaesthestics, the total of anaesthetic should be decreased by approximately 25 per cent in the acidotic patient.
Acidemia and hyperkalemia decrease the protein binding of bupivacaine, thereby increasing the free fraction and the risk of toxicity.
Patients with uremia may have higher plasma levels of local anesthetic following peripheral nerve block.
The use of regional anaesthesia in patients with uremic neuropathy is controversial. Neuropathy is a common complication of end-stage renal disease (ESRD), typically presenting as a distal symmetrical process with greater lower-limb than upper-limb involvement. Neuropathy generally only develops at glomerular filtration rates of less than 12 ml/min. The most frequent clinical features reflect large-fiber involvement, with paresthesias, reduction in deep tendon reflexes, impaired vibration sense, muscle wasting, and weakness.
Renal patients are prone to hemodynamic instability and hypotension when sympathetic blockade is superimposed to preexisting autonomic dysfunction.
Coagulopathy in uremia may lead to epidural hematoma, particularly when patient is not or inadequately dialysed.
Increased risk of arrhythmias, if epinephrine is added to local anesthetics
Increased risk of catheter site infection
Bleeding time >15 minutes is a contraindication for neuraxial block. (Platelet dysfunction may be present even in the face of normal platelet count, PT, aPTT and TT).
Patients undergoing hemodialysis require intermittent anticoagulation and may present to the operating room with an unclear coagulation status.
Postoperatively sensory level should be carefully evaluated.
Several studies have compared anesthetic techniques for the creation of arteriovenous fistulae, a procedure that is common in patients with end-stage renal disease and is well suited to brachial plexus block. Some investigators have concluded that little difference exists in outcome among general, local, and brachial plexus anesthesia for this operation. Mouquet and colleagues specifically studied the effects of these three techniques on brachial artery blood flow and concluded that both general anesthesia and brachial plexus block improved blood flow through the fistula during surgery, whereas local infiltration did not. Several subsequent studies have shown increased vein diameter, increased rates of native fistula formation, increased fistula blood flow, and shorter maturation time when regional anesthesia is used, compared to either general or local anesthesia. (NYSORA)