CASE 30-1, QUESTION 4: Can low-molecular-weight heparins (LMWH) be used for hemodialysis?
Enoxaparin, dalteparin, and tinzaparin are LMWH that are commercially available
but not yet approved by the US Food and Drug Administration (FDA) for
hemodialysis. In a meta-analysis of 11 randomized trials, LMWH was compared
with unfractionated heparin in ESRD patients undergoing either hemodialysis or
hemofiltration. LMWH did not significantly affect the number of bleeding events
(relative risk [RR], 0.96; 95% confidence interval [CI], 0.27–3.43) or
extracorporeal circuit thrombosis (RR, 1.15; 95% CI, 0.70–1.91) compared with
In a randomized, crossover study comparing the safety and
efficacy of enoxaparin with standard heparin, a dose of 1.0 mg/kg body weight of
enoxaparin produced less minor fibrin or clot formation in the dialyzer but more
frequent minor hemorrhage between dialyses. Dosage reduction of enoxaparin to 0.7
mg/kg body weight resulted in similar efficacy and eliminated the minor
17 Dalteparin administered as a single bolus dose of 60 high-flux was
effective in preventing clotting of the hemodialysis circuit with no reports of
18 Tinzaparin has also been shown to be effective as an anticoagulant during
HD, using a weight-based IV dose of 75 international units/kg or a fixed IV dose of
2,500 international units just before dialysis.
Although LMWH can be used to prevent clotting during HD, several factors need
to be taken into account when considering LMWH for prevention and treatment of
venous thromboembolism in HD patients. Because LMWH undergoes renal
elimination, dose adjustments are necessary in patients with ESRD, accompanied by
careful patient monitoring. Although LMWH inhibits factor Xa
kallikrein, measurement of antifactor Xa activity is the only available laboratory
monitoring parameter for these factors; because active heparin metabolites that are
not detected by the factor Xa assay can accumulate in dialysis patients, the clinical
utility of this test is unclear.
Another concern with LMWH is that patients on dialysis exhibit greater sensitivity
to its effect than healthy volunteers.
patients with stage 4 and 5 CKD. In a case series of patients on HD treated with
LMWH for acute coronary syndrome, two patients who received as few as two to
three doses of LMWH exhibited dialysis–access site bleeding, hematuria, and
massive melena. Another subject who received 10 doses experienced hemorrhagic
pericardial effusion, resulting in death. Only one patient in the series, who received a
total of five doses, did not have hemorrhagic complications.
findings, it is recommended that unfractionated heparin, rather than LMWH, be used
in patients on dialysis for prophylaxis and treatment of thromboembolic disease.
CASE 30-1, QUESTION 5: Which agents can be used for anticoagulation during hemodialysis in patients
with heparin-induced thrombocytopenia (HIT)?
HIT is reported to occur in 0% to 12% of patients on HD receiving heparin for
anticoagulation. All forms of heparin, including “heparin-free” dialysis and LMWH
must be stopped in patients with HIT. Another class of agents with potential use in
patients requiring anticoagulation during HD is the direct thrombin inhibitors,
argatroban and lepirudin. The place in therapy for these agents is in individuals who
experience HIT. Argatroban is a synthetic derivative of L-arginine, which is
approved by the FDA for use in patients susceptible to thrombosis who also have a
history of HIT. Most dosage regimens for argatroban consist of an initial bolus dose
at the start of HD followed by a continuous infusion during dialysis.
eliminated by non-renal routes, argatroban dosing in patients with renal failure is the
same as for patients with normal kidney function.
28 However, dose adjustments are
required in hepatic impairment. Murray et al.
29 evaluated three argatroban regimens
in patients having high-flux hemodialysis. Anticoagulation was more consistently
achieved (ACT > 140% of baseline) when a continuous infusion of 2 mcg/kg/minute
with or without a bolus of 250 mcg/kg was used. The infusion was discontinued 1
hour before the end of the HD session. Approximately 20% of argatroban was
removed during HD. Argatroban therapy provided adequate, safe anticoagulation
throughout HD. No thrombosis, bleeding, or other serious adverse events occurred.
Another antithrombin product, lepirudin, is produced through recombinant DNA
technology. It is biologically similar to hirudin, which is isolated from the saliva of
leeches. Unlike argatroban, lepirudin is significantly cleared by the kidneys and by
30 The loading dose for intermittent hemodialysis in patients
with HIT, who need anticoagulation to prevent clotting during dialysis, is 0.2 to 0.5
mg/kg (5–30 mg) with individualized dosage adjustment based on residual renal
14,31 An activated partial thromboplastin time ratio (APTTr) measured
prior to the next dialysis session targeting an APTTr < 1.5 and, where available, a
lepirudan assay targeting a therapeutic range of 0.5 to 0.8 mcg/mL are used to guide
14 An antidote is not available; however, fresh frozen plasma or
factor VIIa concentrates can be used if major bleeding occurs. Bivalirudin is a
potential alternative for anticoagulation in patients with HIT, who are at risk for
major bleeding. Among the direct thrombin inhibitors, it has the shortest half-life of
25 minutes (in patients without renal dysfunction). Dosing is still being elucidated. A
retrospective cohort study of 24 ICU patients undergoing intermittent hemodialysis
found that an average dose of 0.07 mg/kg/hour achieved an APTT goal of 1.5 to 2.5
32 while bivaluridin infused at a lower rate 1.0 to 2.5 mg/hour
(0.009–0.023 mg/kg/hour) targeting an APTTr of approximately 1.5 was reported for
patency of the hemodialysis circuitry.
Two heparinoids, danaparoid and fondaparinux, have been evaluated for
anticoagulation in hemodialysis patients with HIT; however, danaparoid was
withdrawn from the United States, and fondaparinux is currently not approved for
hemodialysis. A preliminary study found that fondaparinux can be used as an
anticoagulant only in patients using low-flux polysulfone dialyzers.
risk of thrombosis occurred with high-flux dialyzers attributed to increased removal
of fondaparinux, resulting in inadequate anticoagulation. Further studies are
necessary to define the role of this agent in patients on chronic HD.
weight was 69.9 kg. What are the possible etiologies for his hypotension?
In addition to solute removal, the artificial kidney must be used to maintain fluid
balance in the patient without renal function. Most patients will become anuric once
stabilized on HD, requiring control of ingested fluids between treatment sessions.
Fluid removal during dialysis is then necessary to achieve the “dry weight,” or
weight below which the patient could become symptomatic from volume depletion.
Achieving the dry weight is accomplished by ultrafiltration, through adjustment of the
transmembrane pressure. The dry weight for R.W. has been set at 69.1 kg. Below this
weight, R.W. exhibited symptoms of orthostasis.
Intradialytic hypotension (IDH) can produce a variety of clinical signs and
symptoms, including nausea and vomiting, dizziness, muscle cramps, and headache.
The reported incidence of hypotension is 10% to 30%, and even higher in patients
with specific risk factors, such as autonomic dysfunction associated with diabetes
and cardiac disease. It primarily is caused by excessive fluid removal from the
vascular compartment at a rate exceeding mobilization of fluid from the interstitial
space. As a consequence, patients with an inadequate hemodynamic response to
intravascular volume depletion will exhibit a decrease in blood pressure and other
symptoms. An ultrafiltration rate greater than 10 mL/hour/kg was found to be
associated with higher odds of IDH (odds ratio = 1.30; p = 0.045) and a higher risk
of mortality (RR, 1.02; p = 0.02).
It may be necessary to adjust the dry weight
upward if the patient is volume-depleted and symptomatic after dialysis.
Other causes of hypotension relate to rises in core body temperature. Sympathetic
nervous system activity increases in response to ultrafiltration, leading to
vasoconstriction of the dermal circulation and impaired heat dissipation. Increased
central heat production can occur during the dialysis procedure. The increase in core
body temperature can overcome peripheral vasoconstriction, resulting in
hypotension. Excessive heating of dialysate can also produce vasodilation. Cooling
of the dialysate to slightly below body temperature may correct this problem,
although many patients are uncomfortable and do not tolerate the cooling effect.
Eating during dialysis can also cause a fall in blood pressure because of vasodilation
of the splanchnic vessels. While food is usually prohibited during dialysis, patients
prone to IDH should avoid eating just before dialysis. Antihypertensive therapy
before dialysis may exacerbate hypotensive episodes as well; in some patients, these
drugs may need to be withheld until after the dialysis session has ended. Immediate
treatment of the hypotensive episode can be accomplished by reclining the patient,
administering a small (100 mL) bolus of normal saline into the venous blood line,
and reducing the ultrafiltration rate.
Several pharmacologic agents have been proposed for the management of IDH,
including ephedrine, fludrocortisone, caffeine, vasopressin, L-carnitine, sertraline,
reviewed these agents for their potential use in the
treatment of IDH and concluded that only midodrine, sertraline, and L-carnitine show
potential benefit in patients. Midodrine is an oral prodrug that is converted to
desglymidodrine, a selective α1
-agonist. Doses of 10 to 20 mg, 30 minutes before
dialysis are effective for most patients, but the presence of active myocardial
ischemia is a major contraindication.
36 Sertraline is a selective serotonin reuptake
inhibitor that has shown promise in IDH at daily doses of 50 to 100 mg/day. The
mechanism is proposed to be improvement of autonomic function. However, neither
midodrine or sertraline have shown additive effects to that of using cool
37,38 L-Carnitine has also been tried for treatment of IDH with IV doses of
20 mg/kg at dialysis. Its mechanism of action is not known, but it may be related to
improvements in vascular smooth muscle and cardiac functioning.
meta-analysis of five studies examining the role of L-carnitine supplementation for
IDH failed to confirm a benefit.
An accurate assessment of R.W.’s dry weight is essential. R.W. reports gaining a
few extra pounds. If weight gain is related to increased volume, then sodium
restriction is needed to minimize weight gain because of fluid retention between
dialysis sessions. Another consideration is a change in his lean mass. When
questioned about his diet, R.W. reports an improvement in his appetite. It is
important to consider “real” weight changes when assessing the dry weight and
volume status. Without appropriately increasing the dry weight goal to compensate
for his real weight gain, R.W. became volume depleted and hypotensive. His dry
weight should be adjusted upward to the point at which he no longer is symptomatic
CASE 30-1, QUESTION 7: What other hemodialysis-related complications must be watched for and how
Perhaps also related to fluid shifts, muscle cramps experienced during dialysis may
be induced by excessive ultrafiltration, resulting in altered perfusion of the affected
tissues. Several treatments have been attempted, including reduced ultrafiltration, and
infusion of hypertonic saline or glucose (in nondiabetic patients) for cramps
occurring near the end of dialysis.
40 Exercise and stretching of the affected limbs may
also be beneficial. Short-term daily administration of vitamin E 400 IU alone or in
combination with vitamin C has been found to reduce episodes of cramping.
Vitamin E can cause bleeding and potentiate bleeding with warfarin. Vitamin C
therapy is known to produce hyperoxaluria, oxalate-containing urinary stones, and
renal damage; therefore, vitamin C supplementation is limited to 60 to 100 mg daily.
The long-term effects of vitamin E and vitamin C administration in hemodialysis
Dialysis disequilibrium is a syndrome that has been recognized since the initiation of
HD more than 30 years ago. Its etiology is related to cerebral edema, and patients
new to HD are at a greater risk because of the accumulation of urea.
of urea from the extracellular space lowers plasma osmolality, thereby leading to a
shift of free water into the brain. Lowering of intracellular pH, as can occur during
dialysis, has also been suggested as a cause. Clinical manifestations occur during or
shortly after dialysis and include central nervous system effects, such as headache,
nausea, altered vision, and in some cases, seizures and coma. Treatment is aimed at
prevention by initiating dialysis gradually by using shorter treatment times at lower
blood flow rates in new patients. Direct therapy can be provided in the form of IV
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