Hemoglobin therapy in hemodialysis

Low doses of stroma-free diaspirin cross-linked hemoglobin are administered to patients undergoing hemodialysis, to achieve hemostabilization and avoid hypotensive episodes in susceptible patients. Hemoglobin therapy when implemented prophylactically in hemodialysis also partially obviates the need for further interventions to control circulatory system instability.

BACKGROUND OF THE INVENTION 
Kidney dialysis has been a therapeutic boon to thousands of patients a 
year, who have severely compromised or nonexistent kidney function. 
However, many of these patients experience side effects and complications 
ranging from hypersensitivity to recurrent hypotension. For a general 
discussion of hemodialysis complications, see Levin, et al., 
"Complications During Dialysis", in Nissenson, et al., eds., Dialysis 
Therapy, Hanley & Belfes, Inc., 1986, p. 85. Among the most common of 
complications is hypotension, arising in 20-30 percent of all hemodialysis 
patients. Many of these patients experience chronic hypotension, some so 
severe that they cannot tolerate the procedure at all, and must resort to 
peritoneal dialysis or transplant. The incidence of intradialytic 
hypotension occurs most frequently in older patients and in women. 
The cause of intradialytic hypotension varies depending on whether it 
occurs early or late in the treatment phase. It may result when the rate 
of intravascular volume depletion during ultrafiltration exceeds 
replacement. The diffusion of replacement fluid into the intravascular 
space counteracts the normal compensatory response of increased peripheral 
resistance. Also, hypotension can occur even during volume overload 
because of the time dependency of refilling of the intravascular space. 
Similarly, if the patient's weight is below the "dry weight", volume 
shifts may no longer be adequate to maintain blood pressure. For a 
discussion of the causes of hypotension in hemodialysis, see Schulman, et 
al., "Complications of Hemodialysis", in Principles and Practices of 
Nephrology, Jacobson, et al., eds., B. C. Decker, Inc., 1991, pp. 757-759. 
Other causes of intradialytic hypotension have been described. Shulman, 
infra, p. 759 lists as early hemodialysis hypotension causes: dialyzer 
volume, bioincompatible membranes, various medications, sepsis, and 
pericardial tamponade; listed as late stage hypotension causes, in 
addition to ultrafiltration rate and a too low setting for dry weight: 
excessive weight gain, decline in osmolarity, acetate accumulation, 
arrhythmia, and autonomic neuropathy. It is significant to note that most 
of the common causes of intradialytic hypotension involve fluid volume 
changes for which the body is incapable of fully compensating. 
Treatment of intradialytic hypotension focuses on its suspected cause. If a 
too rapid removal of fluids is the suspected cause, dialysis is 
discontinued and the patient is placed in the Trendelenburg position to 
enhance venous return. (See Kidney Electrolyte Disorders, eds. J. C. M. 
Chan, et al., Churchill Livingstone, 1990). The most common pharmacologic 
intervention for hypotension is administration of isotonic or hypertonic 
saline, to restore fluid balance. Pressor agents are not generally 
recommended, in part because a high percentage of hemodialysis patients 
are older persons with manifest clinical hypertension. In fact, it is 
recommended in designing hemodialysis regimens for these patients, that 
all blood pressure medication be curtailed for at least four hours prior 
to treatment. 
SUMMARY OF THE INVENTION 
Since patients requiring hemodialysis generally must be treated two to 
three times weekly for several hours per treatment, it is medically 
desirable to minimize complications as much as possible to avoid sequelae 
requiring further intervention, and needless traumatization of the 
patient. This is especially desirable for predictably recurrent 
complications in particular patient subgroups, such as those having 
recurrent hypotension. 
It is therefore an object of the present invention to provide a preventive 
therapy in which an agent is administered prophylactically about the time 
dialysis commences, to achieve circulatory stability and maintain blood 
pressure at acceptable levels. From the standpoint of patient well-being 
it is preferable to prevent hypotension from occurring than to treat the 
condition once it is manifest. 
It is a further object of the invention to provide a therapy for 
intradialytic hypotension generally which prevents hypotension arising 
from multiple causes, and not just treating manifest hypotension once a 
suspected cause has been identified. 
In the method of the present inventions stroma-free hemoglobin is 
peridialytically administered in a low dose for stabilizing the 
circulatory system in hemodialysis patients susceptible to chronic 
episodes of blood pressure fluctuation, and for treating chronic 
hypotension in susceptible patients undergoing hemodialysis. 
The hemoglobin solution administered is stroma-free hemoglobin and 
preferably diaspirin cross-linked. It is advantageous to administer the 
solution over a period of 10 to 45 minutes after commencement of 
hemodialysis.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT 
While any patient undergoing renal hemodialysis may encounter complications 
because of the frequency and duration of treatment, certain patient 
subgroups appear to be especially prone to complications such as 
hypotension occurring early in the procedure or in the later stages. These 
recurrent hypotensive episodes can be generally of two types, (1) in which 
blood pressure fluctuates, sometimes erratically, or (2) the patient 
experiences a sudden drop in pressure resulting in dizziness and actual 
fainting. These episodes may be accompanied by cardiac arrhythmia, which 
actually contributes to the condition. Such sudden drops in pressure may 
occur more than once in a single dialysis procedure. In general, a 
hypotensive event is said to occur when blood pressure falls either 
suddenly or transiently about 10 minutes after procedure initiation, by 
greater than about 20 mm Hg, or when systolic blood pressure falls below 
100 mm Hg although these criteria will vary and are often interpreted very 
subjectively. 
Patients who experience hypotension or blood pressure fluctuation can be 
identified from their file histories, and may be considered for the 
hemoglobin therapy of the present invention if routine adjustments in the 
dialysis procedure (lowering rate of ultrafiltration, salt concentration 
of the dialysate, etc.) do not produce a remission of the episodes. It 
will largely be a matter for the attending physician or nephrologist to 
ascertain those who qualify for hemoglobin therapy, taking into account 
factors such as the age and condition of the patient, secondary 
pathologies, drug regimens, the frequency and severity of hypotensive 
episodes, etc. 
Administration of hemoglobin suppresses blood pressure fluctuation, and 
largely prevents intradialytic hypotension. One unexpected benefit is to 
minimize and virtually obviate conventional therapeutic intervention, even 
for causes of hypotension classically associated with fluid imbalances. 
Infusions of albumin, iso- and hypertonic saline, are avoided, which 
enhances patient comfort and well-being during the dialysis procedure. 
The hemoglobin therapy of the present invention involves administration of 
hemoglobin in a pharmacologically effective amount, generally, at low 
doses. In the clinical studies set forth in the Example, three dose levels 
of 25, 50 and 100 mg hemoglobin/kg body weight were infused. In other 
studies, and from animal models, pharmacologic efficacy is achieved in 
dose ranges from 10 mg/kg to about 1200 mg/kg. Any dose in this range is 
"low" when defined as an amount of hemoglobin too low to serve as a 
one-for-one oxygen carrying replacement for whole blood in which blood 
loss results in hypotension at least as pronounced as is observed in 
susceptible patients undergoing hemodialysis. 
Response of individual patients to particular doses of hemoglobin will 
vary, as with any drug, and the physician will adjust the dose to achieve 
the optimal effect. In some patients a dose of 15 mg/kg may be adequate, 
but in others a dose towards the high end of the recommended dose range 
(1200 mg/kg) may be required. In the occasional patient a dose in excess 
of 1200 mg/kg may be needed to be pharmacologically effective, and is 
still considered by Applicants to be within the scope of the invention so 
long as the low dose definition set forth herein is met. 
While it is known that the pharmacologic effects of hemoglobin are dose 
dependent up to a certain threshold, the duration of the effects is 
affected by dose, with the effects obtained at a larger dose continuing 
longer. In patients having a history of primarily late stage hypotension, 
larger doses may be indicated so that an adequate level is present at 
later times in the dialysis treatment, when hypotensive episodes are 
anticipated. In some patients, it may be most beneficial to administer the 
hemoglobin in more than one dose, or even in a continuous dose, over the 
course of dialysis. Such variations are within the scope of the present 
invention, so long as administration occurs peridialytically in relation 
to the treatment. 
Timing of hemoglobin administration is preferably coincident with the 
commencement of dialysis, and continues by intravenous infusion over a 10 
to 45 minute period. Although hemoglobin administration may be efficacious 
as a palliative during acute episodes of hypotension, the principal 
embodiment of the invention is to administer the hemoglobin 
prophylactically in advance of such episodes so as to prevent hypotensive 
episodes from occurring. 
The hemoglobin utilized in the treatment of this invention is stroma-free, 
substantially free of endotoxin, and sterile. While unmodified stroma-free 
hemoglobin is pharmacologically effective, it tends to dissociate readily 
into its subunits giving it a much reduced half-life in the bloodstream. 
Renal toxicity has also been reported. It is therefore preferable to 
utilize a cross-linked, or crosslinked polymerized hemoglobin manufactured 
according to a number of methods in the art, for example, as described in 
U.S. Pat. Nos. 4,826,811, 4,001,401, 4,412,989, and 5,084,558. Most 
preferred is diaspirin cross-linked hemoglobin made as disclosed in U.S. 
Pat. Nos. 4,600,531 and RE34,271 hereby incorporated by reference. The 
hemoglobin is further purified and sterilized as disclosed in U.S. Pat. 
Nos. 4,831,012, 4,861,867, and 5,128,452. 
Further advantages of the present invention will be apparent from the 
Example which follows: 
EXAMPLE 
Diaspirin cross-linked hemoglobin (DCLHb) in a 10 percent solution was 
infused into patients undergoing hemodialysis according to the randomized, 
single-blinded, cross-over protocol illustrated in FIG. 1. Approximately 
equal numbers of patients (n=3) for a test group and a control group 
receiving normal saline, for each of 3 treatment groups (25, 50, and 100 
mg hemoglobin/kg of body weight) were infused on day 1 with either saline 
or DCLHb. At day 7 the groups were reversed and then infused with the 
opposite of either saline or DCLHb than they received on day 1. Since one 
patient received only the control solution and did not cross-over, an 
extra patient was added to the control group, bringing the total to 19. 
Patients were unaware of which treatment was received. Various physiologic 
parameters were monitored, including blood pressure and the incidence of 
conventional intervention for hypotension. 
FIGS. 2a and 2b depict the data for systolic and diastolic pressures. It is 
evident that the test and control groups at each dosage level do not 
differ at the commencement of dialysis, but thereafter out to about 210 
minutes there is a significant elevation in both systolic and diastolic 
pressures. Thereafter, the groups once again become indistinguishable. 
Table 1 summarizes the combined systolic blood pressure data. Blood 
pressure increases are dose dependent averaging 2 mm Hg for 25 mg/kg dose 
and 29 mm Hg for the 100 mg/kg group. 
TABLE 1 
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25 50 100 
Blood Pressure Change 
mg/kg mg/kg mg/kg 
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Change in BPs DCLHb 
2 .+-. 12* 15 .+-. 29* 
29 .+-. 8* 
Change in BPs placebo 
-1 .+-. 9 4 .+-. 10 
-4 .+-. 12 
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*p &lt; 0.05 vs. placebo; MANOVA 
Correspondingly, the control groups generally demonstrated a reduction in 
systolic blood pressure. 
The results in Table 2 indicate an increase in hypotensive events as 
indicated by increased administration of hypertonic saline. The frequency 
of hypertonic saline interventions were significantly less in the DCLHb 
groups. 
The stabilization of blood pressure as indicated by the number of 
hypertonic saline interventions (Table 2) indicates 1 hypotensive episode 
in one of 18 patients receiving DCLHb compared to 20 episodes in 9 of 19 
patients while receiving the control solution. Thus, low dose hemoglobin 
administration incident to hemodialysis stabilizes blood pressure and 
significantly reduces the need for conventional hypotensive interventions. 
TABLE 2 
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Frequency of 23.4% NaCl IVP for Treatment or Prevention of 
Hypotension 
Normal Saline 
DCLHb # interventions 
# interventions (# patients) 
(# patients) 
______________________________________ 
25 mg/kg 1(1) 3(2) 
50 mg/kg 0(0) 9(5) 
100 mg/kg 0(0) 8(2) 
Total Interventions 
1(1) 20(9) 
(Total Patients) 
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