Renal Replacement Therapy and Rhabdomyolysis

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Chapter 43 Renal Replacement Therapy and Rhabdomyolysis

Brad W. Butcher, MD , Kathleen D. Liu, MD, PhD, MAS

Renal Replacement Therapy

1 What are the indications for renal replacement therapy (RRT)?

Indications can be grouped by using the AEIOU mnemonic:

A: (Metabolic) Acidosis refractory to bicarbonate administration.

E: Electrolyte imbalances, of which hyperkalemia is the most life threatening.

I: Ingestions. Some drugs and toxins (and their toxic metabolites) can be cleared with dialysis, including aspirin, lithium, methanol, or ethylene glycol.

O: Overload. Ultrafiltration with dialysis can relieve hypoxemia resulting from volume overload, which may be particularly problematic in the setting of oliguria or anuria.

U: Uremia. Symptoms and signs of uremia can range from mild (anorexia, nausea, pruritus) to severe (encephalopathy, asterixis, pericarditis); patients may also have clinical platelet dysfunction (bleeding) due to uremia.

3 What are hybrid therapies?

SLED, SLEDF, EDD, and SCD collectively refer to recently developed hybrid modes of dialysis. Dialysis can be delivered through a variety of conventional IHD machines (an advantage over CRRT), usually with some minor modifications to allow for slower dialysate flow rates compared with IHD. Therapy is delivered intermittently but over a longer time period (6-12 hours per session) than conventional IHD (3-4 hours per session) and often on a daily basis. Thus hybrid therapies have many of the benefits of CRRT without some of the disadvantages (see question 5).

4 In whom should CRRT or hybrid therapy be considered?

CRRT or hybrid therapy should be considered in any critically ill patient with an indication for dialysis. CRRT or hybrid modalities tend to be better tolerated hemodynamically than intermittent dialysis because of slower rates of solute flux and fluid removal. CRRT may also allow for increased net daily ultrafiltration compared with IHD because volume removal occurs continuously, albeit at a slower rate. Furthermore, in highly catabolic, critically ill patients, increased clearance with CRRT or hybrid modalities compared with IHD may allow for better control of azotemia, acidosis, and electrolyte abnormalities, including hyperphosphatemia. Last, patients with elevated intracranial pressure or fulminant hepatic failure may not tolerate IHD because of rapid shifts in solute concentrations. Importantly, IHD is preferable to CRRT in patients with severe, life-threatening hyperkalemia and some types of ingestions because clearance per unit time is slower with CRRT than with IHD.

5 What are some disadvantages of CRRT?

Because of its continuous nature, CRRT requires long-term relative immobilization of the patient, which can increase the risk for venous thromboembolism, pressure ulcers, and persistent deconditioning. Continuous anticoagulation is often necessary to prevent filter clotting and subsequent blood loss, and this may increase the bleeding risk. CRRT frequently results in hypothermia as blood is cooled during transit through the extracorporeal circuit; importantly, this can mask the development of a fever. Last, CRRT is highly labor intensive, typically requiring 1:1 nursing, and therefore costly.

6 Define hemofiltration, hemodialysis, and hemodiafiltration

Hemofiltration: Plasma is forced from the blood space into the effluent via the application of pressure across a highly permeable membrane. This results in convective clearance of small and middle-sized molecules through the physical property of solvent drag. This modality does not significantly change the concentration of serum electrolytes and waste products unless a replacement fluid is infused into the blood, effectively diluting out those solutes the physician wishes to remove (e.g., urea nitrogen and potassium) and increasing the concentration of those solutes in which the patient might be deficient (e.g., bicarbonate in a patient with acidemia).

Hemodialysis: Blood flows on one side of a semipermeable membrane, and the dialysate, which contains various electrolytes and glucose, flows along the other side, usually in the opposite (countercurrent) direction. A concentration gradient drives electrolytes and water-soluble waste products from the plasma compartment into the dialysate. The dialysis machine generates a pressure across the membrane to drive plasma water from the blood side to the dialysate side. Dialysis results in diffusive clearance, preferentially of small molecules.

Hemodiafiltration: This technique makes simultaneous use of hemofiltration and hemodialysis, resulting in both diffusive and convective clearance.

7 List the basic components of a prescription for IHD and for CRRT

IHD:

Dialysis access: Arteriovenous fistula, arteriovenous graft, tunneled dialysis catheter, or temporary dialysis catheter

Treatment duration: For most patients with end-stage renal disease, this ranges between 3 and 4 hours. When a patient with acute renal failure or acute kidney injury (AKI) starts hemodialysis, initial sessions may be as short as 1 to 1.5 hours to decrease the risk of dialysis disequilibrium syndrome.

Filter size and type: Biocompatible dialysis membranes are now routinely used.

Blood flow rate: Blood flow rates of up to 400 to 450 mL/min can be achieved with an arteriovenous fistula or graft and up to 350 mL/min with a tunneled or temporary catheter. Generally, the faster the flow, the more efficient the dialysis.

Dialysate flow rate: Typical flow rates range from 500 mL/min to 800 mL/min.

Dialysate bath: Concentrations of potassium, sodium, calcium, and bicarbonate can be customized on the basis of the patient’s laboratory studies.

Ultrafiltration goal: This is the amount of fluid to be removed from the patient over the course of the session; determined by clinical assessment of the patient’s volume status.

Anticoagulation: Clotting within the dialysis circuit can result in significant blood loss; heparin is typically used unless the patient has a contraindication.

CRRT:

As in IHD, the prescription includes dialysis access, filter size and type, hourly fluid balance, and anticoagulation. An alternative to heparin anticoagulation often used with CRRT is regional citrate anticoagulation, in which citrate is administered to chelate calcium, a critical cofactor in the clotting cascade. Arteriovenous fistular and grafts are not used for CART.

Blood flow rates are typically slower than in intermittent dialysis (150-200 mL/min).

Mode of therapy: CVVH, CVVHD, or CVVHDF

Dialysate or replacement fluid: The specific fluid is based on the metabolic parameters of the patient, including the patient’s acid-base status and serum potassium concentration.

Dialysate or replacement fluid flow rate: Dosing is weight based and is typically prescribed at a dose ranging from 20 mL/kg/hr to 35 mL/kg/hr, based on the patient’s weight. Studies have shown no mortality difference between patients with renal replacement therapy administered at these two rates.

8 What kinds of laboratory tests should be ordered regularly for patients receiving CRRT?

Sodium, potassium, bicarbonate, calcium, and phosphate levels can change rapidly during CRRT. Hyperphosphatemia frequently occurs in IHD because of inefficient clearance of phosphate, but hypophosphatemia is more common during CRRT given the continuous clearance of phosphate. Hypocalcemia and hypomagnesemia are also seen, especially when these cations are complexed with citrate (e.g., when citrate is used as an anticoagulant) or when a replacement fluid without these cations is infused into the patient (e.g., during CVVH). Patients with impaired lactate metabolism (e.g., because of severe sepsis or hepatic failure) may have high systemic lactate levels if the dialysate or replacement fluid contains lactate as a base equivalent. In these cases, high lactate levels or worsening acidosis should prompt the use of a bicarbonate-based dialysate or replacement fluid. Blood gas levels should be checked to monitor the patient’s acid-base status.

9 What are nutrition considerations for patients with AKI receiving RRT?

Amino acids are lost in both IHD and CRRT. Critically ill patients with AKI are often highly catabolic; many patients receiving CRRT will require at least 1.5 to 2 g/kg/day of protein or amino acids.

Vitamins:

Water-soluble vitamins are lost in both IHD and CRRT. Replacement of these vitamins can be achieved with the daily administration of a vitamin complex specifically designed for patients receiving RRT.

Fat-soluble vitamins are protein or lipoprotein-bound and are therefore not significantly cleared by CRRT or IHD.

Trace minerals, such as zinc, may be dialyzed with IHD or CRRT; the benefit of supplementation in this situation remains unproved. Aluminum-containing products, which were used in the past as phosphorus binders, should be avoided because of central nervous system toxicity.

10 What are the complications of CRRT?

Among the most important risks of CRRT are the risks inherent in obtaining central venous access. In general, subclavian venous access should be avoided, given the risk of subclavian stenosis with an indwelling catheter, particularly among patients who might require long-term hemodialysis. Electrolyte abnormalities or hypovolemia may also develop with CRRT. Patients may have hypothermia because of heat loss, which may mask a febrile response to infection.

Rhabdomyolysis

11 What causes rhabdomyolysis?

Muscle ischemia, damage, and eventual necrosis lead to rhabdomyolysis. The various causes are grouped into physical and nonphysical causes in Box 43-1. Both groups of causes probably share a common pathway in which increased demand on muscle cells and their mitochondria, because of intrinsic deficiencies or extrinsic forces (i.e., decreased oxygen delivery or increased metabolic demands), leads to ischemia and eventual damage.

Box 43-1 Major Causes of Rhabdomyolysis

Physical Causes

Trauma and compression

Occlusion or hypoperfusion of the muscular vessels

Excessive muscle strain: exercise, seizure, tetanus, delirium tremens

Electrical current

Hyperthermia: exercise, sepsis, neuroleptic malignant syndrome, malignant hyperthermia

Nonphysical Causes

Metabolic myopathies, including McArdle disease, mitochondrial respiratory chain enzyme deficiencies, carnitine palmitoyl transferase deficiency, phosphofructokinase deficiency

Endocrinopathies, including hypothyroidism and diabetic ketoacidosis (due to electrolyte abnormalities)

Drugs and toxins, including medications (antimalarials, colchicine, corticosteroids, fibrates, HMG-CoA reductase inhibitors, isoniazid, zidovudine), drugs of abuse (alcohol, heroin), and toxins (insect and snake venoms)

Infections (either local or systemic)

Electrolyte abnormalities: hyperosmotic conditions, hypokalemia, hypophosphatemia, hyponatremia, or hypernatremia

Autoimmune diseases: polymyositis or dermatomyositis

12 Discuss the symptoms and signs of rhabdomyolysis

The classic presentation of rhabdomyolysis, consisting of myalgias, weakness, and dark urine, is rare, and often only one or two of these symptoms are present. A history suggestive of muscle compression, a physical examination demonstrating muscle tenderness, and laboratory tests confirming muscle damage lead to a strong presumptive diagnosis.

13 What laboratory tests should be ordered to diagnose rhabdomyolysis?

Creatine phosphokinase activity is the most sensitive indicator of muscle damage; it may continue to increase for several days after the original insult. Hyperkalemia, hyperuricemia, and hyperphosphatemia also occur, as these substances are released from the damaged muscle cells. Hypocalcemia develops as calcium is chelated and deposited in the damaged muscle tissue. Lactic acidosis and an anion gap metabolic acidosis can result from release of other organic acids from cells.

14 What are the complications of rhabdomyolysis?

The most immediate concern is hyperkalemia due to cell necrosis, particularly in the setting of AKI, which occurs through several mechanisms. Damaged myocytes release myoglobin and its metabolites, which precipitate with other cellular debris to form pigmented casts in renal tubules, obstructing urinary flow. Third-spacing of fluids, particularly at the site of muscle injury, can lead to both intravascular hypovolemia with impaired renal perfusion and compartment syndrome. Furthermore, precipitation of myoglobin in the kidney can initiate a cytokine cascade that leads to renal vasoconstriction, further exacerbating acute renal failure.

Although patients usually have hypocalcemia, they rarely have symptoms. Caution should be exercised when treating hypocalcemia because patients often have rebound hypercalcemia during the recovery phase. Symptoms of hypocalcemia, such as tetany, Chvostek or Trousseau signs, or cardiac arrhythmias, should be treated promptly. Other immediate concerns include hypovolemia, particularly in the setting of crush injuries or other causes of compression injury.

15 What treatment options are available?

Supportive care, with intravascular volume repletion and prevention of continued renal insult, is the main strategy. In general, fluids should be instilled at a rate sufficient to result in an hourly urine output of 200 to 300 mL. Although limited clinical evidence supports this strategy, using sodium bicarbonate–based crystalloids to alkalinize the urine is thought to improve the solubility of myoglobin and decrease its direct tubular toxicity. Mannitol can be used to promote an osmotic diuresis, and both thiazide and loop diuretics can also be used to augment urine flow once it is clear that the patient is intravascularly volume replete. Allopurinol, dosed for the degree of renal impairment, reduces the production of uric acid, which can crystallize in the tubules along with myoglobin. Control of hyperkalemia, which may require the provision of dialysis, and treatment of symptomatic hypocalcemia are important parts of the treatment regimen.

16 What kind of prophylactic management options are possible?

Guidelines for the treatment of catastrophic crush injuries (developed in response to natural disasters including earthquakes) recommend the initiation of volume resuscitation with crystalloid even before extrication. In the first 24 hours, up to 10 L of intravascular volume may be lost as sequestrated fluid in the affected limb. Administration of up to 10 to 12 L of fluid may be required during this period, with careful monitoring of urine output.

17 What drugs need to be avoided in patients with rhabdomyolysis?

Succinylcholine, a drug used for rapid muscle paralysis to achieve airway control, causes generalized depolarization of neuromuscular junctions and can cause hyperkalemia if the patient has abnormal proliferations of the motor end plates. Patients with rhabdomyolysis often have hyperkalemia, and therefore succinylcholine should generally be avoided, given the often lethal nature of these hyperkalemic events. In addition, medications that are known to be associated with rhabdomyolysis (e.g., 3-hydroxy-3-methylglutaryl–coenzyme A [HMG-CoA] reductase inhibitors) should be avoided, if possible.

Acid-base interpretation

18 Identify the normal extracellular pH, and define acidosis and alkalosis

The range for the normal extracellular pH in arterial blood is considered to be 7.37 to 7.43. Of note, the normal pH in venous blood is slightly lower (by 0.05 pH units on average); the lower venous pH results from the uptake of metabolically produced carbon dioxide in the capillary circulation. Acidemia is defined as an increase in the hydrogen ion concentration of the blood, resulting in a decrease in pH, and alkalemia is defined as a decrease in the hydrogen ion concentration in the blood, resulting in an increase in pH. Acidosis and alkalosis refer to processes that lower or raise the pH, respectively. These processes can be either metabolic or respiratory in origin and, occasionally, a combination of both.

19 What information is necessary to properly interpret a patient’s acid-base status?

To accurately interpret a patient’s acid-base status, an arterial blood gas analysis, serum electrolyte concentrations, and the serum albumin concentration are needed.

20 What is the anion gap, how is it calculated, and why is it important in understanding a patient’s acid-base status?

The anion gap is defined as the difference between the plasma concentrations of the major cation (sodium) and the major measured anions (chloride and bicarbonate), expressed mathematically by the following equation:

A normal anion gap is generally considered to be 8 to 12 in a patient with a normal serum albumin concentration of 4.0 g/dL. In patients with hypoalbuminemia, the anion gap should be “corrected” by adding 2.5 to the calculated anion gap for every 1 g/dL decrease in albumin concentration. The anion gap is elevated in processes that result in an increase in the plasma concentration of anions that are not routinely measured in conventional chemistry panels, including lactate, phosphates, sulfates, and other organic anions (such as the degradation products of commonly ingested alcohols). Calculating the anion gap is critical when assessing a patient’s acid-base status because an elevated anion gap may alert the physician to the presence of a metabolic acidosis that might not be apparent on first glance of the arterial blood gas values. Accordingly, the anion gap should always be calculated when assessing a patient’s acid-base status. Furthermore, the different diagnosis of a metabolic acidosis is largely influenced by the presence or absence of an elevated anion gap (see later).

21 Describe an approach to a comprehensive interpretation of a patient’s acid-base status using the arterial blood gas and the serum chemistry values

Identify whether the patient has acidemia or alkalemia: If the pH is less than 7.37, the patient has acidemia, and, if the pH is greater than 7.43, the patient has alkalemia. Importantly, a pH between 7.37 and 7.43 does not imply that the patient does not have an acid-base disturbance; rather it suggests the presence of a mixed acid-base disorder.

Determine whether the primary disturbance is respiratory or metabolic: If the patient has acidemia and the PCO₂ is greater than 40 mm Hg, then the primary process is respiratory; if the patient has acidemia and the serum bicarbonate concentration is less than 24 mEq/L, then the primary process is metabolic. If the patient has alkalemia and the PCO₂ is less than 40 mm Hg, then the primary process is respiratory; if the patient has alkalemia and the serum bicarbonate concentration is greater than 24 mEq/L, then the primary process is metabolic.

Determine whether appropriate compensation for the primary disorder is present: To determine how the kidneys compensate for a primary respiratory process and vice versa, see Table 43-1. If the compensation is less than or greater than predicted, then another primary acid-base disturbance might be present. For example, in presence of a metabolic acidosis, if the PCO₂ is lower than expected a concomitant primary respiratory alkalosis is present, whereas if the PCO₂ is higher than expected a concomitant primary respiratory acidosis is present.

Calculate the anion gap to look for the presence of an anion gap metabolic acidosis.

Calculate the delta-delta: In the presence of an isolated anion gap metabolic acidosis, the serum bicarbonate concentration should fall by an amount that equals the degree to which the anion gap is raised. If this is not the case, another metabolic disorder (either a non–anion gap metabolic acidosis or a metabolic alkalosis) is present. This can be determined by calculating the delta-delta, which is mathematically expressed as follows:

^{Table 43-1} Appropriate Compensation for Primary Acid-Base Disturbances and Their Common Causes

Primary acid-base disturbance	Subtype	Expected compensation
Metabolic acidosis	Anion gap	Decrease in PCO₂ = 1.2 × ΔHCO₃ or PCO₂ = (1.5 × HCO₃) + 8 ± 2
	Non–anion gap
Metabolic alkalosis		Increase in PCO₂ = 0.7 × ΔHCO₃
Respiratory acidosis	Acute	Increase in HCO₃ = 0.1 × ΔPCO₂
	Chronic	Increase in HCO₃ = 0.35 × ΔPCO₂
Respiratory alkalosis	Acute	Decrease in HCO₃ = 0.2 × ΔPCO₂
	Chronic	Decrease in HCO₃ = 0.4 × ΔPCO₂