Drug Criteria & Outcomes: Plasma volume expander formulary
By Andrea Williams, PharmD Written as a PharmD candidate at Auburn University School of Pharmacy, Auburn, AL
Mechanism of action
Albumin 5%, 6% Hetastarch in Lactated Electrolyte Injection (Hextend), and 6% Hetastarch in 0.9% sodium chloride (Hespan), are colloid solutions. They exert an oncotic pressure similar to plasma and help retain water in the vascular system (retention of intravascular fluid).
Indications
Albumin, 6% Hetastarch in Lactated Electrolyte Injection (LEI), and 6% Hetastarch in 0.9% sodium chloride (NaCl) are indicated in the treatment of hypovolemia when plasma volume expansion is desired and to support oncotic pressure. These products are used in patients as an adjunct in shock due to hemorrhage, burns, surgery, sepsis, or trauma. They are not a substitute for blood or plasma.1
Hetastarch LEI is different than the Hetastarch NaCL and albumin in that Hetastarch LEI not only creates on-cotic pressure and permits retention of intravascular fluid; it also provides electrolytes necessary to physiologic functions. Hetastarch LEI has a composition re-sembling that of the principal ionic constituents of normal plasma ( To see Table 1, click here). It also provides lactate, which acts as a source of bicarbonate in patients with unimpaired lactate metabolism.2
Hetastarch NaCl is 6% hetastarch in normal saline (Na = 154 mEq/L and Cl = 154 mEq/L); Hetastarch LEI is 6% hetastarch in lactated electrolyte injection.
Dosage and administration
Hetastarch LEI, Hetastarch NaCl, and albumin are administered by intravenous infusion only. The dosage and rate for acute use in plasma volume expansion depend upon the amount of blood or plasma lost and the resultant hemoconcentration, as well as age, weight, and clinical condition of the patient.
The usual adult dose for Hetastarch LEI is 500-1,000 mL. Doses of 1,500 mL/d usually are not required; however, 1,500 mL has been used during major surgery without needing blood or blood products. Doses larger than 1,500 mL generally warrant the administration of blood and blood products.1
Pharmacokinetics
A single dose of hetastarch results in elimination in the urine of approximately 33% (polymers with a molecular weight of less than 59 kDa — glomerular filtration) of the dose within 24 hours (see Table 2, click here). This is a variable process but usually results in an intravascular hetastarch concentration of less than 10% of the total dose injected by two weeks. Also, the hydroxyethyl group is not cleaved, but remains intact and attached to glucose units when excreted.
Hetastarch also is removed by redistribution, which is the uptake and temporary storage of hetastarch in the tissues. After 24 hours, 23% of the total dose is extravasated into the interstitial space.3
Contraindications
Solutions containing hetastarch are contraindicated in patients with known hypersensitivity, bleeding disorders, or congestive heart failure (CHF) where volume overload is a potential problem. Also, solutions with hetastarch should not be used in renal disease with oliguria or anuria not related to hypovolemia.
Solutions such as Hetastarch LEI, which contain lactate, should not be used if lactic acidosis is present in a patient.
Solutions containing albumin are contraindicated in patients with known hypersensitivity to albumin or patients with severe anemia or cardiac failure.1
Hetastarch LEI, Hetastarch NaCl, and Albumin are rated pregnancy category C.
Interactions
One drug interaction with albumin involves angiotensin-converting enzyme inhibitors (ACEI). The ACEI can increase the risk of atypical reactions (e.g., flushing and hypotension) and should be withheld for at least 24 hours prior to plasma exchange in which large volumes of albumin are administered. Also, albumin can cause an increase in the alkaline phosphatase lab test.3
There are no known drug interactions with hetastarch (Hetastarch NaCl or Hetastarch LEI). However, there are few incompatibilities that are listed in Table 3. To see Table 3, click here.
Adverse effects
Adverse effects are summarized in Table 4. To see Table 4, click here.
Clinical studies
The clinical trials available on Hetastarch LEI are limited. One trial comparing Hetastarch LEI to albumin regarding safety has been completed. There are two studies comparing the base of Hetastarch LEI and Hetastarch NaCl (lactated ringer’s [LR] and normal saline; no hetastarch). Three studies have been completed studying the coagulation profile of Hetastarch LEI. In addition, there have been two comparative trials on Hetastarch LEI vs. Hetastarch NaCl. All of the trials mentioned above have small study populations, which is a major weakness.
One trial of 28 total patients (14 in each group) compared the safety of Hetastarch LEI vs. albumin.5 No statistically significant difference was shown between the two groups in regard to coagulation profiles and postoperative hematocrits or blood product usage. This trial concluded that Hetastarch LEI is a safe and reasonable alternative to albumin, but the sample size was very small.
There have been several studies comparing intravenous lactated ringer’s solution with 0.9% sodium chloride (just the base of Hetastarch LEI or Hetastarch NaCl; no hetastarch) in surgery patients and in healthy patients. One trial that compared LR with normal saline (without the hetastarch) indicated that the normal saline group developed hyperchloremic acidosis and therefore received more bicarbonate therapy (30 mL) during the operative period than the LR group (4 mL).6 However, there was no difference in bicarbonate therapy in the postoperative period. Also, patients in the normal saline group received a larger volume of platelet transfusion (478 mL) than the LR group (223 mL; P value = 0.02). This study also examined patient complications, ventilation time, intensive care unit time, and length of hospital stay; with regard to these four outcomes, there was no difference between the two groups. One limitation of this study is that the sample size (66 patients total) chosen for the multiple outcome endpoints might be inadequate to detect any true difference in one of the endpoints (not enough power).
Another study comparing the bases examined the effect of LR or normal saline on osmolality and time to first urination in healthy human volunteers.7 This study only included 18 patients, which is a weakness for this trial. The results of this study concluded that the normal saline group had a significant delay in time to first urination compared to LR group (106 min vs. 75 min, respectively; P value < 0.001). The effects of hyperchloremia on the kidney seem to be the cause of the delayed urination.
Hyperchloremia can produce a progressive renal vasoconstriction and a decrease in glomerular filtration rate. Furthermore, changes in renal blood flow correlate with plasma chloride. In this study, the observer was not blinded, which could have caused some bias in the results. Another weakness in this trial is that the patients were healthy volunteers who did not have surgery.
There are several studies focusing on coagulation parameters of Hetastarch LEI and Hetastarch NaCl. One study compared Hetastarch LEI, Hetastarch NaCl, and LR using thromboelasto-graphy (TEG) as a measure of coagulation.8 TEG parameters are r time (clot onset time or time until the first significant level of detectable clot formation), k time (clot formation rate or time from beginning of clot formation to a fixed level of clot firmness), and maximum amplitude (total clot strength). There were 90 patients in this trial (30 in each group). A statistically significant difference was shown for all three endpoints with Hetastarch LEI having the most favorable outcome. (To see Table 5, click here.)
This study was only available as an abstract; therefore, limitations could not be assessed. The conclusion of this study indicated that Hetastarch LEI showed less of an effect on the coagulation profile than Hetastarch NaCl, which exhibited a hypocoagulation profile, and LR, which had a hypercoagulable profile.
Another study focusing on coagulation studied Hetastarch LEI diluted in platelet-free plasma samples.9 Prothrombin times and aPTT was assessed. Hetastarch LEI was found to have no adverse effects on prothrombin times or aPTT. The results of this study revealed no changes in hemostasis compatible with disseminated intravascular coagulation (DIC) or any activation of the procoagulant system. This study, however, was not conducted in human subjects, which is a major limitation.
One trial comparing Hetastarch LEI to Hetastarch NaCl is a prospective, randomized, double-blinded, controlled clinical trial.10 This trial examined acid-base, electrolyte status and gastric perfusion in elderly patients. Forty-seven elderly patients undergoing major surgery were randomly allocated to one of the two groups (23 patients in the Hetastarch LEI group and 24 in the Hetastarch NaCl group). Only 42 were analyzed (21 in each group) due to several withdrawals not related to the medication. During the surgery, each patient received 500 mL of either Hetastarch LEI or Hetastarch NaCl at the induction of general anesthesia. Further IV fluids were given according to a clinical algorithm. The total volume of Hetastarch LEI given was 4,232 ± 2,196 mL; the total volume of Hetastarch NaCl given was 4,616 ± 2,575 mL. (To see Table 6, click here.)
The mean increase in chloride levels from baseline to the postoperative sample was significantly larger in the Hetastarch NaCl group than in the Hetastarch LEI group.
Also, 14 patients in the Hetastarch NaCl group experienced hyperchloremic metabolic acidosis compared with none in the Hetastarch LEI group. Hyperchloremic metabolic acidosis may impair end organ perfusion and interfere with cellular ex-change mechanisms. Hyperchloremia alone has a negative effect on renal blood flow and glomerular filtration rate. This study was stopped due to the possibility that hyperchloremic metabolic acidosis, which occurred in 67% of the Hetastarch NaCl patients, might be associated with an increased incidence of patient adverse events. One weakness of this study is that the trial was conducted in the United Kingdom, and the population may differ from that in the United States. Another weakness of this trial is that the sample size is very small.
The conclusion of this trial shows that the use of Hetastarch LEI can avoid the development of hyperchloremic metabolic acidosis and is associated with better indices of gastric mucosal perfusion than Hetastarch NaCl in elderly surgical patients.
Another trial compared Hetastarch LEI and Hetastarch NaCl as a plasma expander for large volume use in patients undergoing major surgery.11 The trial was a prospective, randomized, two-center study including 120 patients (60 in each group), which was calculated to have at least 80% power to detect a difference in means of 30%. The main outcome for this trial was efficacy of Hetastarch LEI compared to Hetastarch NaCl. Patients in each group received similar amounts of the study drugs (1,596 mL of Hetastarch LEI and 1,428 mL of Hetastarch NaCl).
Six patients in the Hetastarch NaCl group received parenteral calcium compared to only one in the Hetastarch LEI group (to see Table 7, click here). Also, three patients in the Hetastarch NaCl group experienced massive blood loss compared to one in the Hetastarch LEI group. In addition, patients in the Hetastarch NaCl group exhibited an overall significant slowing of onset of clot formation during surgery, compared with Hetastarch LEI (P < 0.05). No specific data were given in the reference publication for this outcome; several graphs were provided that indicated the difference between the clot formation times. This would be considered a weakness of this trial. There were no overall differences in the laboratory-measured hematological, biochemical, and coagulation variables (e.g., hematocrit, PT, aPTT, and platelets). However, there were trends toward less bleeding in the Hetastarch LEI group, judged by blood loss and requirement for blood products.
Hetastarch LEI contains calcium levels similar to those normally found in blood and Hetastarch NaCl contains none. Ionized calcium is essential to the pathways underlying effective clot formations. The transient reduction in ionized calcium may lead to less effective clotting at the cut tissue edge.
In conclusion, this trial found Hetastarch LEI as effective as Hetastarch NaCl for the treatment of hypovolemia, and it may be a safer alternative. Hetastarch LEI also has a more favorable side effect profile in terms of coagulation, blood loss, and intraoperative calcium needed when compared to Hetastarch NaCl. There were no serious adverse events related to the administration of Hetastarch LEI in volumes of up to 5 L.
Huntsville Hospital’s cost: Hetastarch LEI: 500 mL = $17.00; Hetastarch NaCl: 500 mL = $16.12; Albumin 5%: 500 mL = $70.00; Albumin 25%: 100 mL = $70.00.
Cost-savings analysis
In term of cost savings, Hetastarch NaCl and Hetastarch LEI are attractive choices compared with albumin because they are considerably less expensive (to see Table 8, click here). For example, at the University of Virginia Medical Center in Charlottesville, the hospital cost of 500 mL of Hetastarch NaCl is $43, whereas 500mL of albumin is $66. Examining the use at the University of Virginia Medical Center from 1994 to 1995 and then extrapolating these data to all hospitals in the United States suggests that exclusive use of hetastarch could save approximately $50 million per year.12 If the albumin use could be cut in half (decreased 50%) by using Hetastarch LEI, then the hospital could save a large amount of money.
Summary and recommendations
Hetastarch LEI has been proven safe and effective in plasma volume expansion. It has been suggested that Hetastarch LEI has a more favorable side effect profile in regard to coagulation profiles and presentation of metabolic acidosis when compared to Hetastarch NaCl (to see Table 9, click here). However, the Hetastarch LEI trials have all had one weakness in common: a small sample size.
Hetastarch LEI should not be used is in patients who experience lactic acidosis.
It is recommended that Hetastarch LEI be approved as the hetastarch formulary agent replacing Hetastarch NaCl. The plan for Huntsville Hospital is to use Hetastarch LEI instead of Hetastarch NaCl because it is just as effective and may be safer. Thus, Hetastarch LEI can be used in the place of albumin without the same concern of the coagulation side effects seen with Hetastarch NaCl.
If Huntsville Hospital could increase the use of Hetastarch LEI for albumin (decrease albumin use by 50%), that change would in turn reduce the hospital’s cost by about $130,000 a year. Currently, some of the surgery units (anesthesia) are switching to Hetastarch LEI as their primary hetastarch plasma volume expander. Hetastarch NaCl, however, may be needed in specific cases such as those involving lactic acidosis.
References
1. Hetastarch LEI product monograph. Abbott Park, IL: Abbott Laboratories; 2001.
2. Mythen M, Bennett-Guerrero E. Special report: Volume replacement issues. Anesthesiology News 2001; Sept:1-7.
3. Micromedex. [cited 2001]. Available at: www.micromedex.com. Accessed on Jan. 8, 2002.
4. Trissel L, et al. Compatibility screening of Hetastarch LEI during simulated Y-site administration with other drugs. Int J Pharmaceutical Compounding 2001;5:69-73.
5. Petroni K, et al. Hetastarch LEI is a safe alternative to 5% human albumin for patients undergoing elective cardiac surgery (abstract). Anesthesiology 2001 ;95:A198.
6. Waters J, et al. Normal saline versus lactated ringer’s solution for intraoperative fluid management in patients undergoing abdominal aortic aneurysm repair: an outcome study. Anesth Analg 2001; 93:817-822.
7. Williams E, et al. The effect of intravenous lactated ringer’s solution versus 0.9% sodium chloride solution on serum osmolality in human volunteers. Anesth Analg 1999; 88:999-1003.
8. Martin G, et al. Hetastarch LEI has a better coagulation profile than Hetastarch NaCl and lactated ringers. Anesthesiology 1999; abstract.
9. Bick R. Evaluation of a new hydroxyethyl starch preparation (Hetastarch LEI) on selected coagulation parameters. Appl Thrombosis/Hemostasis 1995; 1:215-229.
10. Wilkes N, et al. The effects of balanced versus saline-based hetastarch and crystalloid solutions on acid-base and electrolyte status and gastric mucosal perfusion in elderly surgical patients. Anesth Analg 2001; 93:811-816.
11. Gan T, et al. Hetastarch LEI, a physiologically balanced plasma expander for large volume use in major surgery:A randomized phase III clinical trial. Anesth Analg 1999 ;88:992-998.
12. Warren B, Durieux M. Hydroxyethyl starch: Safe or not? Anesth Analg 1997;84:206-212.
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