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Hemolysis During Hemodialysis
Abstract
Low-grade chronic hemolysis is common in uremia, as red blood cell life span is clearly decreased with reduced renal function. Using isotope red cell tagging, it has been shown that red cell life span averages about 1/2 to 1/3 of normal in uremia. In addition, uremic erythrocytes have been found to be less deformable and osmotically more fragile when compared to their normal counterparts. Transfusion of uremic erythrocytes into an individual with normal renal function will restore the life span of those cells to normal. On the other hand, normal erythrocytes transfused into a uremic individual will have shortened survival. In the past, chronic hemolysis in maintenance dialysis patients may have manifested as increased blood transfusion requirements. However, these days such hemolysis probably more often presents itself as erythropoietin resistance (larger erythropoietin doses being required for a given therapeutic response). A variety of abnormalities (such as impairment of red cell enzymatic activities and reduced synthesis of Na + -K + pump units by uremic reticulocytes) have been suggested to be the causes for the heightened predisposition of uremic erythrocytes to hemolysis.
Uncommonly, patients on dialysis can have severe (at times life-threatening) hemolysis. These patients fi t into either of two categories, depending on whether hemolysis involves all or the majority of the patients being dialyzed under similar circumstances in a given dialysis center or whether the hemolysis is patient specifi c. Hemolysis in the former is often the result of water-borne toxins, centralized dialysis equipment failure, or blood tubing defects-whereas in the latter it results from medication or possibly inadequate dialytic therapy. Use of constricted blood tubing systems and of hypo-osmolal or abnormally warm dialysate results in intravascular hemolysis, whereas drug-induced hemolysis is usually extravascular.
The signs and symptoms of hemolysis are largely nonspecifi c, but certain fi ndings are suggestive. Blood undergoing intravascular hemolysis can show color changes from cherry red to port wine. A sudden deepening of skin pigmentation during or shortly after dialysis can also be a consequence of severe intravascular hemolysis. It is highly likely that these blood and skin color changes are all related to the release of hemoglobin and methemoglobin from erythrocytes, as well as the generation of methemalbumin and a complex containing hemopexin and heme. In slowly developing hemolysis, the patient may not notice any symptoms at all.
In severe acute or subacute hemolysis, the most common presenting symptoms are anorexia, nausea, vomiting, abdominal pain, diarrhea, and back pain. Patients with hemolysis can also present with headache, lethargy, malaise, chills, diaphoresis, hypotension, hypertension, dyspnea, chest pain, palpitation, leg cramps, cyanosis, dark urine (and death can be associated). Pancreatitis can also occur. Laboratory fi ndings include a low hemoglobin concentration, an elevated serum bilirubin level, reticulocytosis, the presence of Heinz bodies, the presence of methemalbumin in the serum, and an elevated serum lactic dehydrogenase value.
Other laboratory evidences of hemolysis comprise low haptoglobin levels, a reduced Cr 15 erythrocyte survival with splenic sequestration, and an abnormal Coomb's test. The onset of clinical manifestations varies, depending on the cause of hemolysis. Occurrence of symptoms within 2 hours of starting dialysis (e.g., hemolysis due to defective blood tubing) and 8 to 24 hours after the onset of dialysis (e.g., copper-induced hemolysis) has been reported.
Refer to Table 30 .1 in regard to this section.
Chloramine Chlorine is the most commonly used antiseptic agent for water supplies in the United States. Unfortunately, chlorine can react with other compounds in water to form undesirable byproducts (such as trihalomethanes). A growing practice is to combine chlorine and ammonia to form chloramine (a compound con-taining NCl groups and produced by the attachment of chlorine to nitrogen) and to use this chemical as an alternative bactericidal compound. Despite being much less reactive than chlorine, chloramine has been found to cause hemolysis outbreaks among dialysis patients in various parts of the world. Most recently, in a dialysis unit in Brazil 16 patients who developed hemolysis after having been exposed to high concentrations of chlorine and chloramine in product water were described.
Deionization tanks can only remove undesirable ions in exchange for hydrogen or hydroxyl ones but cannot remove nonionic substances such as chloramine. Similarly, reverse osmosis removes 99% of ionic contaminants, 100% of colloidal material, and 100% of microorganisms-but cannot remove chloramine. Chloramine is ordinarily removed by passage through carbon fi lters. Often such passage is adequate to prevent chloramineinduced hemolysis. However, if the chloramine-contaminated water is pumped through a carbon fi lter too forcefully the elevated water pressure generated can create artifi cial channels within the device-thus allowing the passage of chloraminecontaminated water into the dialysate. In addition, traditional carbon fi lters may not have enough capacity to prevent hemolysis when tap water chloramine concentrations are inordinately high-as in the case of drought. An alternative method of removing chloramine from dialysate is to enrich the latter with ascorbic acid. However, serum ascorbic acid levels should be monitored to prevent hypervitaminosis C and secondary hyperoxalosis. This ascorbic acid approach has not been widely adopted.
Chloramine concentrations are determined indirectly by subtracting free chlorine levels from total chloramine values. The Association for the Advancement of Medical Instrumentation (AAMI) has set a level of 0.1 mg/L as the maximum concentration of chloramine allowed in a dialysate. Chloramine levels as low as 0.25 mg/L have been reported to bring about shortened erythrocyte life span, manifested by an increased erythropoietin requirement. Chloramine-induced hemolysis can present as methemoglobinemia, Heinz body anemia, or acute intravascular hemolysis (if chloramine levels are markedly elevated).
In the early days of hemodialysis, an often-reported cause of hemolysis was copper poisoning. The leakage of copper from copper-containing dialysis equipments leads to hemolysis, especially in the face of exhausted deionizers whose effective ion-binding sites are too depleted to be able to remove the metal adequately. More recently, the use of copper in dialysis equipment has dramatically lessened. Less frequently, zinc-contaminated dialysate has been reported to induce hemolysis in dialysis patients.
These compounds have engendered hemolysis in home hemodialysis patients who used nitrate-and nitrite-rich well water as their water supply to generate a dialysate.
Formaldehyde is used as a sterilant for reprocessing used dialyzers and for the disinfection of the dialysate circuit of certain dialysis machines. The chemical has also been found in the fi lters used in a water fi ltration system. If faulty rinsing procedures are employed or formaldehyde-tainted water fi ltration fi lters are used, formaldehyde can inadvertently be introduced into the blood. Formaldehyde in the blood may lead to the development of auto-antibodies against erythrocytes in the form of anti-N-like antibodies that can result in hemolysis. These anti-N-like antibodies are cold agglutinins and show a preference for agglutinating erythrocytes with the NN blood type.
In addition to its other myriad detrimental effects on the body, formaldehyde is a reducing agent and capable of converting NAD to NADH-thus bringing about an inhibition of glycolysis at the level of glyceraldehyde 3-phosphate dehydrogenase and a resultant decline in ATP stores. This reduction in ATP availability (as well as the sterilant's other harmful effects) can foster hemolysis. Other sterilizing agents that have been implicated in inducing hemolysis are glutaraldehyde, sodium hypochlorite, and a mixture of acetic acid, peracetic acid, and hydrogen peroxide. A recent report describes an outbreak of hemolysis in 19 children in a pediatric dialysis unit as a result of disinfecting the water treatment system with a concentrated solution of hydrogen peroxide. There was a mean reduction in hemoglobin levels of 12%.
A reduction of serum osmolality to 260 mmoles/kg does not seem to affect erythrocyte mechanical fragility. However, if osmolality is lowered further a signifi cant degree of hemolysis may occur. Hemodilution can be caused by misadventures such as administering hypo-osmolal plasma expanders. It can also result from dialyzing against hypo-osmolal dialysates, as a result of using a faulty conductivity-measuring device. For instance, in 1994 (in a dialysis center) human error caused a central dialysate delivery machine to be switched to the "rinse and water" mode instead of being directed to the "dialysate" mode. As a consequence, several patients were inadvertently dialyzed with a hypo-osmolal dialysate. The affl icted patients developed symptoms within only 3 minutes of initiating dialysis. One of these patients died as a result.
A dialysate temperature in excess of 42ºC has been associated with hemolysis that may last for days or even weeks.
When blood is forced to fl ow through a narrow orifi ce or channel, the formed elements are subjected to substantial turbulence and immense shearing strain. As a result, red blood cells can become damaged and fragmented-a phenomenon known as the red cell fragmentation syndrome. Such damaged cells, often shaped like triangles or helmets (for example), are very susceptible to lysis. In 1998, an outbreak of hemolysis took place in three different states-affecting a total of 30 patients. The hemolysis was attributed to the use of defective blood tubing sets containing abnormally narrow apertures.
Of the 25 patients affected in Nebraska and Maryland alone, more than 90% required hospitalization. Of the admitted patients, 32% required intensive unit care-and 36% had to be given blood transfusions. Other causes of obstruction in the vascular circuit that can foster hemolysis include partial occlusion of a vascular catheter (e.g., at its tip, by a thrombus, development of a thrombus at a dialyzer blood port, wide disproportion between the caliber of a dialysis needle or of a cannula (both being too small) and the blood fl ow rate (being too high), malocclusion of a roller pump with its consequent constricting effect on the blood path within the pump segment of an "arterial" blood tubing, impingement of the bevel of an "arterial" needle against the wall of a vascular access, and kinking of a blood tubing.
The abutting of an "arterial" needle against the wall of a vascular access can obstruct the needle's bevel and reduce the caliber of the blood path. If the blood pump now keeps on pumping at the original speed, a vacuum can be created that can lead to "arterial" tubing collapse as well as a highly turbulent and often to-and-fro movement of the blood within that tubing. This scenario most often occurs when the delivery of blood through the "arterial" needle is inadequate, as in the case of access stenosis. Kinking can be the result of the improper manner in which blood tubing is routed over a hard and narrow support, especially if easily collapsible tubing is used. Hemolysis associated with blood path problems is mainly intravascular in nature. However, milder stimuli may lead to less signifi cant damage to red blood cells-causing them to be removed subsequently by the reticuloendothelial system (extravascular hemolysis).
It has been found that the smaller the diameter of a hemodialysis blood cannula the higher the hemolytic effect. Moreover, the position of the apical and lateral holes of a cannula determines the magnitude of blood damage. Even with catheters that are available commercially today, if the blood fl ow is 500 mL/min or higher there is a higher risk of erythrocyte damage. Thus, when high blood fl ows are required larger-size cannulas should be used. Single-needle dialysis is also a risk factor for hemolysis.
Whether a high ultrafi ltraion rate can foster hemolysis is controversial. Dialysis with a negative arterial chamber pressure greater than -350 mmHg, has been found to cause a mild hemolysis. The latter is not severe enough to lead to an increased requirement for erythropoietin dosage. However, one study found that during ultrafi ltration even at negative pressures as high as -710 mmHg on the blood side of the ultrafi ltering membrane no measurable hemolysis was discerned. A recent report describes a patient with mechanical hemolysis secondary to a traumatic carotid-jugular arteriovenous fi stula that manifested as hyporesponsiveness to erythropoietin therapy. The hemolysis resolved after surgical correction of the fi stula. Most commonly, low-grade hemolysis is seen with prosthetic or calcifi ed cardiac valves.
Patients on hemodialysis are more prone to develop hemolysis than patients with normal renal function when exposed to the same offending agents. In one study, the combination of uremia and bacteremia led to signifi cantly more hemolysis than either uremia or bacteremia alone. It has been suggested that there may be an increased susceptibility of uremic erythrocytes to lysis as a result of the presence of noxious agents or of oxidative stress. Lipid peroxidation of the red blood cell membrane (caused by increased free radical formation that occurs in uremia alone and by exposure of polymorphonuclear leucocytes to artifi cial materials in the extracorporeal circuit during hemodialysis), along with the consequent lack of cell deformability and the presence of splenic sequestration, may be an underlying mechanism.
Whether antioxidants that reduce free radical production can prevent red blood cell damage in uremic patients is at present unknown. Many trials have evaluated the effectiveness of vitamin E-coating of the dialyzer membrane and glutathione and vitamin C infusion on both oxidative damage to red blood cells and hemolysis. Although most studies have found a benefi t, the fi ndings were not yet extensive enough to warrant universal implementation. Recently, the use of electrolyzed-reduced water that contains active hydrogen and possesses a lower redox potential (to prepare dialysates for hemodialysis) has been suggested to reduce hemodialysis-enhanced production of reactive oxygen species and proinfl ammatory cytokines, peroxidation of erythrocytes, and hemolysis.
The benefi cial effects on erythrocytes (including that of the reduction of erythropoietin dosage because of the amelioration of hemolysis) are believed to be related to the scavenging of reactive oxygen species by the electrolyzed-reduced water used to prepare the dialysate. Electrolyzed-reduced water is generated by passing compressed water into a compartment of electrolysis through a solenoid valve. Treatment with erythropoietin may not only augment red cell generation but reduce hemolysis in patients with uremia. Withdrawal of erythropoietin has been found to lead to neocytolysis (selective hemolysis of the youngest red cells).
Insuffi cient dialysis may also lead to hemolysis, as revealed by the U.S. National Cooperative Dialysis Study. In this study, the hematocrit value in the group with a mid-week blood urea nitrogen (BUN) level of 105 to 115 mg/dL was signifi cantly lower than the value in the group with a corresponding BUN value of 76 mg/dL. Although this difference in hematocrit may partly be due to reduced red cell production or more occult bleeding, some investigators have observed an inverse relationship between BUN concentrations and red cell life span. Others have shown that the osmotic resistance of the red cells to hemolysis is impaired with uremia and is improved after dialysis.
Other causes of hemolysis include medications, co-existing illnesses, and electrolyte abnormalities. Medications are a wellknown cause of hemolysis in dialysis patients, especially in those with glucose-6-dehydrogenase defi ciency. Some common offending agents include aspirin, penicillins, cephalosporins (especially cefotetan), sulfonamides, sulfones, nitrofurantoin, phenacetin, primaquine, quinidine, hydralazine and some vitamin K derivatives. One case report describes massive hemolysis after intramuscular injection of diclofenac. Another report reviewed a patient with severe acute respiratory syndrome on long-term dialysis who developed hemolysis after being treated with ribavirin.
Systemic disease states such as systemic lupus erythematosus, scleroderma, periarteritis nodosa, thrombotic thrombocytopenic purpura, the hemolytic uremic syndrome, malignant hypertension, and certain malignant tumors all predispose to the occurrence of microangiopathic hemolytic anemia. Hyperslenism due to causes such as chronic hepatitis, transfusion hemosiderosis, marrow fi brosis, and silicone deposition is well documented to cause hemolytic anemia. A low serum phosphorus concentration from any cause may lead to a predisposition to hemolysis.
With severe hemolysis, a profound anemia may occur that may require blood transfusions. However, the more immediate danger in end-stage renal disease patients is that of hyperkalemia. This problem is exacerbated if hemolysis occurs after blood has passed through the dialyzer.
After the diagnosis of hemolysis is confi rmed, one needs to fi nd and then remove the cause. Obviously, discontinuation of dialysis is important if intradialytic acute hemolysis is suspected. The blood present in the dialyzer and in the blood tubing should not be returned to the patient, as this blood may contain excessive amounts of potassium. In addition, it is imperative to monitor the electrocardiogram frequently in these patients so that hyperkalemia can be detected promptly. Further management should follow available guidelines intended for the treatment of hyperkalemia (if present) and for that of severe anemia.
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