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Effect of hemoglobin- and Perflubron-based oxygen carriers on common clinical laboratory tests

Departments of
¹ Pathology, Box 8118, and
² Anesthesiology, Box 8054, Washington University School of Medicine, and
³ Department of Laboratories, Barnes-Jewish Hospital, 660 S. Euclid Ave., St. Louis, MO 63110.
⁴ Biopure Corp., Cambridge, MA.

⁵ Alliance Pharmaceutical Corp., San Diego, CA.
^a Author for correspondence. Fax 314-362-1461; e-mail mscott{at}labmed.wustl.edu

Abstract

Polymerized hemoglobin solutions (Hb-based oxygen carriers; HBOCs) and a second-generation perfluorocarbon (PFC) emulsion (Perflubron) are in clinical trials as temporary oxygen carriers ("blood substitutes"). Plasma and serum samples from patients receiving HBOCs look markedly red, whereas those from patients receiving PFC appear to be lipemic. Because hemolysis and lipemia are well-known interferents in many assays, we examined the effects of these substances on clinical chemistry, immunoassay, therapeutic drug, and coagulation tests. HBOC concentrations up to 50 g/L caused essentially no interference for Na, K, Cl, urea, total CO₂, P, uric acid, Mg, creatinine, and glucose values determined by the Hitachi 747 or Vitros 750 analyzers (or both) or for immunoassays of lidocaine, N-acetylprocainamide, procainamide, digoxin, phenytoin, quinidine, or theophylline performed on the Abbott AxSym or TDx. Gentamycin and vancomycin assays on the AxSym exhibited a significant positive and negative interference, respectively. Immunoassays for TSH on the Abbott IMx and for troponin I on the Dade Stratus were unaffected by HBOC at this concentration. Tests for total protein, albumin, LDH, AST, ALT, GGT, amylase, lipase, and cholesterol were significantly affected to various extents at different HBOC concentrations on the Hitachi 747 and Vitros 750. The CK-MB assay on the Stratus exhibited a negative interference at 5 g/L HBOC. HBOC interference in coagulation tests was method-dependent—fibrometer-based methods on the BBL Fibro System were free from interference, but optical-based methods on the MLA 1000C exhibited interferences at 20 g/L HBOC. A 1:20 dilution of the PFC-based oxygen carrier (600 g/L) caused no interference on any of these chemistry or immunoassay tests except for amylase and ammonia on the Vitros 750 and plasma iron on the Hitachi 747.

The development of a safe and effective erythrocyte substitute for oxygen delivery has been the focus of considerable effort. Bovine hemoglobin (Hb)¹ -based oxygen-carrying (HBOC) solutions and perfluorocarbon (PFC) emulsions are two types of products that have been extensively evaluated and are currently in clinical trials (1)(2)(3)(4). Interest in the use of temporary oxygen carriers as "blood substitutes" is expected to increase as a means to reduce requirements for allogeneic blood. Preliminary results of clinical trials with HBOC- and PFC-based blood substitute have been reported (5)(6)(7)(8) and Phase I and II trials of two oxygen carriers are ongoing at our institution for patients undergoing radical prostatectomy, coronary artery bypass grafts, and acute normovolemic hemodilution. One is a polymerized bovine HBOC from Biopure Corp. (9), the other a PFC-based oxygen carrier, Perflubron emulsion from Alliance Pharmaceutical Corp. (10).

Clinical laboratory assays play an important role in the care of many peri- or postoperative patients and trauma victims and will similarly be required for patients receiving blood substitutes. However, both hemolysis, because of the strong optical absorbances of Hb species between 500 and 600 nm, and lipemia, because of light scattering, are well known to cause interference in many colorimetric and spectrophotometric methods used in clinical laboratories (11)(12)(13). After HBOC administration to patients, there is a dose-related presence in plasma of soluble Hb and a marked red coloration of plasma. Plasma Hb values determined by CO-oximetry can be as great as 50 g/L in these patients, well above the concentrations of Hb described as interfering in many laboratory assays (11)(12)(13). Current Perflubron emulsion dosing concentrations (3.0–4.5 mL/kg) result in a dilution of ~1:20–1:25 of Perflubron in blood, and plasma samples from these patients can have a lipemic appearance. Thus, it is important for clinical laboratories to determine which tests are valid when performed with samples from patients receiving these blood substitutes.

Materials and Methods

Instrumentation.
Biochemical tests were performed with the Hitachi 747 (Boehringer Mannheim Diagnostics), the Vitros 750 (Johnson & Johnson Clinical Diagnostic Systems), the Dade Stratus, and the Abbott IMx and AxSym analyzers, according to the manufacturers' instructions. Coagulation tests were performed with the MLA 1000 C (Medical Laboratory Automation, Pleasantville, NY) and the BBL Fibro System (Becton Dickinson Microbiology Systems). Total plasma Hb was determined with the Radiometer OSM.3.

Patient materials.
Human plasma pools were prepared from excess nonhemolyzed plasma samples received for routine biochemical analysis by the clinical chemistry laboratory at Barnes-Jewish Hospital or were provided by Biopure. This study, as part of ongoing clinical trials of oxygen carriers, was approved by the Washington University Human Studies Committee.

Sample preparation.
A stock bovine HBOC preparation containing HBOC, 130 g/L, and diluent containing no HBOC were provided by Biopure. The highest possible HBOC (as measured plasma Hb) concentration in patients receiving HBOC in clinical trials at our institution was <50 g/L. Samples for the interference studies were prepared by adding to 6.15 mL of a plasma pool 3.85 mL of the 130 g/L stock HBOC (final concentration of HBOC, 50 g/L) or 3.85 mL of the HBOC diluent (final HBOC, 0 g/L). Thus, any constituent in the HBOC diluent was equally included in all samples. Mixtures of these two preparations in 10% increments were prepared and deviations from the value of the plasma pool containing no HBOC were determined.

Interference studies with Perflubron emulsion were performed by adding 250 µL of 600 g/L Perflubron emulsion (AFO144; Alliance Pharmaceutical) or isotonic saline (control) to 4750 µL of a plasma pool and comparing deviations of the Perflubron-containing plasma pool from the control. This 1:20 dilution of Perflubron is ~1.3 times the maximum amount of Perflubron emulsion expected in the plasma of patients in current clinical trials at our institution, who receive a dose of 1.8 g/kg (3 mL/kg); i.e., a 70-kg patient receives ~210 mL of Perflubron emulsion, resulting in ~1:25 dilution of Perflubron in plasma.

Results

Table 1 depicts the values for the plasma pools containing diluent and no soluble HBOC and lists the concentration of HBOC (as plasma Hb) that produced a significant interference in chemistry procedures on the Vitros 750 and Hitachi 747 analyzers. Fig. 1 shows examples of the interference patterns observed for several tests from each of these chemistry analyzers. In general, the HBOC concentration invalidating an assay value at our institution was the concentration resulting in a positive or negative interference for enzymes and proteins >10% and >5% for electrolytes. For instance, on both analyzers we established HBOC concentration cutoffs that produced <10% interference for Ca²⁺ assays, because we consider any interference that alters Ca²⁺ values by >5 mg/L to be clinically significant.

View larger version (21K): [in this window] [in a new window]   Figure 1. Percent change in value from the plasma pool containing 0 g/L HBOC for the indicated tests at various HBOC concentrations (as plasma Hb) on (top) the Vitros 750 and (bottom) the Hitachi 747 analyzers.

Table 2 depicts immunoassays that are unaffected by HBOC concentrations 50 g/L, and Table 3 describes immunoassays that are affected. HBOC interference in coagulation testing was method dependent. Prothrombin time (PT), activated partial thromboplastin time (aPTT), and fibrinogen values from the BBL Fibro-System fibrometer, which utilizes electrical clot detection, were unaffected by HBOC concentrations 50 g/L. In contrast, PT, aPTT, and fibrinogen assays from the MLA 1000C analyzer, which detects clot formation optically, produced a "no clot detected" error flag at 20 g/L HBOC. Finally, manual latex agglutination procedures for D-dimer and fibrin degradation products were unaffected at HBOC 50 g/L.

View this table: [in this window] [in a new window]   Table 2. Immunoassays unaffected by HBOC 50 g/L.

The 1:20 dilution of Perflubron emulsion in plasma had a slightly lipemic appearance and produced a "lipemic index" of 35 on the Hitachi 747—lower than the index value of 50 we use as the minimum value to flag a sample as "lipemic" at our institution. Thus it is not surprising that none of the assays performed on the Vitros or Hitachi analyzers shown in Table 4 exhibited any interference as a result of this concentration of Perflubron emulsion. The 1:20 dilution of Perflubron did produce a negative interference of 30–50 U/L in the amylase assay and a positive interference of 20–30 mmol/L in the ammonia assay on the Vitros 750 analyzer, and a negative interference of 20–30 mg/L was observed on the Hitachi 747 iron method. An increase of 71 g/L phosphorus was observed on both analyzers; however, the Perflubron diluent contains a phosphate buffer. The Perflubron emulsion-containing sample exhibited no interference in thyroxine or thyroid-stimulating hormone assays on the AxSym, nor in the creatine kinase (CK) MB isoenzyme, troponin I, or human chorionic gonadotropin assays on the Stratus analyzer (Table 4 ). Thus, at current dosing values (1.8–2.7 g/kg), Perflubron emulsion does not appear to present any significant problems to the clinical chemistry laboratory.

Discussion

The most important observation from these studies is that neither bovine Hb-based HBOC at plasma Hb concentrations as high as 50 g/L nor Perflubron emulsion at current maximum dosing rates interferes in assays of most "critical care" analytes that might be urgently required peri- or postoperatively. This is not surprising because most electrolyte determinations are performed by ion-selective electrodes and should not be affected by colored substances or by those that scatter light. We also currently report electrode-based results from the ABL 505 blood gas analyzer for samples from patients receiving these blood substitutes. No interference was observed in the Vitros 750 enzymatic creatinine method at HBOC concentrations up to 50 g/L. However, a marked negative interference from HBOC was observed in the Hitachi 747 colorimetric Jaffe method, which measures the picric acid creatinine reaction at 505 and 570 nm. Other "critical care" blood analytes such as glucose and urea were unaffected on one or both of the analyzers we examined. Nevertheless, because many laboratories may not have more than one chemistry system, it is important for manufacturers to examine the effect of HBOCs or PFCs on tests that might be needed during critical care periods.

Another test that may occasionally be needed in the operative or postoperative period is a cardiac marker. The troponin I assay in the Stratus is clearly free from interference at HBOC Hb concentration as high as 50 g/L in both positive (troponin 15.6 µg/L) and negative (troponin <0.4 µg/L) patient pools. In contrast, the CK-MB assay exhibited an unusual interference pattern in the positive patient pool (CK-MB 15.5 mg/L), where HBOC concentrations of 5–20 g/L produced a 20% negative interference and those >40 g/L produced a slight (5%) positive interference. Although a previous study found no interference in this assay at an Hb concentration of 3 g/L (14), repeat analysis with a separate patient pool confirmed our observation. No positive interference was observed for the negative patient pool. Given these observations, we use troponin I instead of CK-MB as a cardiac marker for patients receiving HBOC at our institution.

Taken together, these results make clear that tests of water and electrolyte homeostasis, acid–base status, renal function, and cardiac damage can be performed for patients receiving these oxygen carriers by using the instrumentation at our institution. However, it is important to note that although HBOC does not affect K+ values the way that true erythrocyte hemolysis does, it is not possible to determine whether hemolysis in an HBOC-containing sample contains a component of erythrocyte hemolysis. Therefore, clinicians must realize that a K+ value reported from a sample containing HBOC might be falsely increased if true hemolysis is present and, furthermore, that the laboratory currently has no means to determine this.

Electrolytes not measured by ion-selective electrodes exhibited various degrees of interference from HBOC. Both magnesium and phosphorus show >10% positive interference on the Vitros analyzers at HBOC concentrations >20 and 25 g/L, respectively. In contrast, on the Hitachi analyzer these assays are not affected. Calcium values were influenced by HBOC on both analyzers, which is consistent with previous studies (15)(16)(17) in which increased Hb concentration influenced calcium measurement on many methods and instruments but is not mentioned in package inserts. The marked interference (~70 g/L) we observed in both the Vitros 750 and Hitachi 747 assays for phosphorus with the Perflubron-containing samples was caused by the phosphate-buffered saline content of the Perflubron emulsion.

Previous studies indicated that Hb dramatically interfered with bilirubin measurement in both total and conjugated bilirubin assays (13)(18)(19)(20). Our results confirmed this effect, regardless of whether the Jendrassik–Grof diazotization method or the Vitros method was used. Hb interferes with a large number of colorimetrically detected assays, so our results are not surprising. Most of our results are consistent with manufacturers' package inserts, stating the limitations of performing analyses on hemolyzed samples, and with our own internal data obtained by assaying samples containing soluble human Hb. Examples include all of the tests not exhibiting interference and the amount of HBOC (as Hb) causing negative interference in the Hitachi alkaline phosphatase and -glutamyltransferase methods; the Hitachi methods for uric acid, albumin, and bicarbonate; and the Vitros method for conjugated bilirubin. Exceptions to manufacturers' package insert claims on Hb interference include the Hitachi methods for alanine aminotransferase (ALT), aspartate aminotransferase (AST), cholesterol, and calcium and the Vitros methods for calcium, phosphorus, ALT, amylase, AST, and magnesium. One likely cause for this is that the package inserts usually state no interference up to a particular Hb concentration such as 6 or 10 g/L—considerably less than that tested in these studies. Interferences probably were not examined at Hb concentrations as high as 50 g/L. In other cases, bovine HBOC may behave differently from soluble human Hb from erythrocytes. Finally, for some tests (e.g., ALT, AST, and calcium on the Hitachi and calcium on the Vitros), the manufacturer may not have deemed the extent of interference to be clinically significant; indeed, in some cases, the interferences we found only slightly exceeded our criteria for determining whether or not to report a result.

While many assays are affected by HBOC concentrations that can be present in patients, it is important to note that HBOC and Perflubron emulsion have short half-lives (2–12 h) (1)(2)(3)(4). Together with the lack of interference by these substances in most critical care analyte methods, patient care is unlikely to be affected if some enzyme and electrolyte tests need to be delayed for a day. Indeed, in clinical trials at our institution spanning 3 years and including >125 patients, we have had only one insistent request for a test result affected by HBOC. In settings where such a result is absolutely required, dilution of the sample might decrease the HBOC concentration to an amount that does not interfere.

In our current studies, as well as in others (e.g., (21)), interferences by oxygen carriers have generally been examined at only a single concentration of the analyte in question. Thus, reporting the extent of interference as a percentage might be misleading. For instance, a 30% interference for a sample with an amylase of 95 U/L might actually be trivial if the maximum interference is a constant 30 U/L at all amylase concentrations. Assessment of these interferences at multiple analyte concentrations will allow laboratories to determine when an interference actually invalidates clinical information. For example, an amylase value of 500 U/L in the presence of 50 g/L HBOC would indeed still be useful if the interference was only 30 U/L. Similarly, a "one-way" result might also be clinically useful; in other words, if HBOC produces a positive interference, a low result might be informative, if the laboratory and clinician discuss the situation.

As blood substitute products approach clinical use, it is the responsibility of the laboratory to assess their impact on clinical laboratory values and, along with clinicians, determine what amounts of interference are acceptable for patient care. We have established guidelines for our institution based on Tables 1 and 3 . All samples from patients receiving these oxygen carriers are identified by colored stickers that alert the laboratory. If HBOC concentrations (as plasma Hb) are greater than depicted, the resulting assay values are not reported.

This study and that by Callas et al. (21) are the first step toward assessing the impact of these substances on laboratory values. Future studies should examine their impact by using multiple analyte concentrations, determine the effect of changing sample matrices when these samples are diluted to minimize an interference, particularly in immunoassays and dry-chemistry methods, and assess methods to remove these substances before biochemical testing (22). It will also be necessary to examine the effect of these substances in nonfluorometric homogeneous immunoassays, which we did not examine at our institution. Thus, while this and other studies will be useful guidelines, individual laboratories should assess these interferences in light of the myriad testing methods in use, differences in the various hemoglobin-based blood substitute products, and institutional-specific opinions as to what constitutes significant interference.

Footnotes

¹ Nonstandard abbreviations: Hb, hemoglobin; PFC, perfluorocarbon; HBOC, hemoglobin based-oxygen carrier; CK, creatine kinase; AST, aspartate aminotransferase; ALT, alanine aminotransferase; PT, prothrombin time; and aPTT, activated partial thromboplastin time.

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (39) Citing Articles via Google Scholar Google Scholar Articles by Ma, Z. Articles by Scott, M. G. Search for Related Content PubMed PubMed Citation Articles by Ma, Z. Articles by Scott, M. G. Related Collections General Clinical Chemistry Oak Ridge Conference Drug Monitoring and Toxicology Hematology