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Safety of Plasma Volume Expanders Albert Farrugia J Clin Pharmacol 2011 51: 292 originally published online 25 May 2010 DOI: 10.1177/0091270010372107 The online version of this article can be found at: http://jcp.sagepub.com/content/51/3/292

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Review

Safety of Plasma Volume Expanders Albert Farrugia, PhD

Hypovolemia from a range of etiologies can lead to severe morbidity and mortality unless blood volume and tissue perfusion are restored. The treatment of hypovolemia has included the improvement and restoration of blood volume loss by the intravenous infusion of plasma expanding therapeutic agents. These have included crystalloid and/ or colloid solutions, and a brisk controversy as to which modality is better has engaged therapeutics for the past 30 years. In addition, those favoring either modality have debated which crystalloid, and which colloid, is better. This area was given a dramatic turn a decade ago when a Cochrane meta-analysis concluded that albumin, a

historically important plasma expander, resulted in increased mortality when administered to critically ill patients. Although subsequently modified by other studies, the Cochrane meta-analysis has served to generate an ongoing interest in the safety of plasma expanders. This review will assess the safety of these therapies from the viewpoint of the heterogeneous range of clinical indications for which they are used.

T

description of saline fluid resuscitation in the beginning of the twentieth century.5 The physiology of fluid balance and the pathophysiology of hemorrhagic shock have been reviewed.6 The 1950s saw the introduction of other synthetic colloids including dextrans and hydroxyethyl starches. Presumably, continuing interest in developing these synthetic colloids was partly fueled by concerns about the cost of albumin solutions, which are the same concerns today. Despite the presence of these competitor therapies, albumin continued to be a mainstay in fluid therapy in hemorrhagic shock and became the staple for the then nascent plasma fractionation industry. Albumin’s dominant position was maintained until the growing scrutiny of evidence-based medicine threw doubts on its efficacy as a therapy for shock,7 and it sustained a substantial blow when a meta-analysis from the Cochrane collaboration threw doubts on its safety.8 Although subsequently negated by another metaanalysis,9 pharmacovigilance data for adverse events10,11 and a state of the art randomized clinical trial,12 doubts on the safety of albumin persist through clinical reports comparing it to other modalities. The present review will discuss the adverse event profile of colloidal plasma expanders in light of current and emerging evidence.

rauma is a major cause of mortality and morbidity, being the most common cause of death in Germany in persons under the age of 45 years.1 Hemorrhage from trauma results in loss of blood volume—hypovolemia—resulting in decreased blood and oxygen perfusion of vital organs. Among the earliest descriptions of efficacious hemotherapy, Blundell’s reports of the use of blood transfusion to treat postpartum hemorrhage2 imprinted the medical ethos with the dramatic results of replacing blood loss. The limitations imposed by the storage lesion of labile blood elements led to the search for substitutes for whole banked blood as a volume expander after traumatic injury. Apocryphally, the need for a blood volume expander that could be stored in a “tank in Tobruk”3 led to Edwin Cohn’s development of a method to isolate albumin in a safe and stable form from human plasma. This was the latest colloid to be used for shock, and it was apparently favored over artificial colloids such as gelatin, which was the first artificial plasma substitute to be used for shock in 1915,4 following the

From the Plasma Protein Therapeutics Association, Annapolis, Maryland (Dr Farrugia). Submitted for publication November 4, 2009; revised version accepted February 13, 2010. Address for correspondence: Albert Farrugia, PhD, Plasma Protein Therapeutics Association, 147 Old Solomon’s Island Road, Annapolis, MD 21401 and the School of Surgery, Faculty of Medicine, Dentistry and Health Sciences, The University of Western Australia, 35 Stirling Highway, Crawley WA 6009, Perth, Australia; e-mail: [email protected]. DOI:10.1177/0091270010372107

Keywords: Albumin; colloids; safety; pharmacovigilance Journal of Clinical Pharmacology, 2011;51:292-300 © 2011 The Author(s)

The Natural Colloid—Human Albumin Albumin is the most abundant protein in human plasma (40-50 g/L), with a total body content of 4 to

292 • J Clin Pharmacol 2011;51:292-300 Downloaded from jcp.sagepub.com at CAPES on April 19, 2011

SAFETY OF PLASMA VOLUME EXPANDERS 5 g/kg. It is a hydrophilic, nonglycosylated protein with a molecular weight of 69 kDa. As a natural molecular species, albumin is the only therapeutic colloid that consists of a mono-disperse molecular population. Albumin is distributed one third to two thirds in the intravascular compartment relative to the extravascular compartment, and accounts for 70% to 80% of the plasma colloid oncotic pressure (COP). Congenital analbuminemia is a rare disease that has only been described in less than 40 individuals. It is likely that most sufferers die in utero.13 In survivors, compensatory overproduction of other proteins maintains the COP.14 Albumin’s contribution to COP counters the hydrostatic pressure in the microcirculation, which would otherwise lead to passage of water and loss of blood volume, according to Starling’s hypothesis.15 In addition, albumin’s capacity to bind cations, anions, and toxins, such as bilirubin, gives it an important physiological role in buffering the acid-base balance of the blood, in regulating the ionized fraction of cations including calcium and magnesium, and in scavenging free radicals and transporting proteins and drugs.16,17 Albumin is synthesized in the liver with a mean half-life of 14.8 days and is degraded mostly in muscle, the liver, and the kidney. Hypoalbuminemia from a range of pathologies is a poor prognostic factor,18 contributing to the use of albumin in a number of disease states.19 The issue of albumin’s role as a therapy in these conditions is crucial and controversial,20 but is beyond the immediate focus of this review, which is safety. Fractionated human albumin is available as isooncotic (4%-5%) solutions for intravascular volume expansion and as hyperoncotic solutions (20%-25%) for the maintenance of fluid balance between compartments and the restoration of COP. As mentioned earlier, these products are the result of the fractional precipitation of plasma proteins using ethanol, a technology developed by Edwin Cohn at Harvard during World War II.21 Several modifications of the basic ethanol chemistry have been introduced over the years (Figure 1), and 1 manufacturer uses chromatography for the purification.22 These therapeutics, irrespective of their clinical merit, became venerably embedded in medical practice to an extent that they are considered, by industry and regulatory agencies alike, as commodified generic drugs or biologics,23 with the inherent assumption of identical physiochemical characteristics across all the brands in the market. This has led to an assumption that clinical properties and adverse event profiles will

also be identical, an assumption that may be problematic as will be discussed below. Adverse Events Associated With Albumin Results of Adverse Event Reporting Following the publication of the Cochrane metaanalysis, a number of soundings of the safety of albumin were taken through the assessment of postmarket entry reporting of adverse events.10,11 The level of adverse events reported across these studies was 1 to 5 per million doses, with no deaths attributable to albumin. The range of adverse events explored were those related to potential morbidities ensuing from albumin infusion, which the Cochrane metaanalysis suggested should have been significant, but which a meta-analysis of randomized clinical trials on hospitalized patients24 negated to the extent of finding albumin to be beneficial. This appears to justify the criticisms levied at the Cochrane metaanalysis and what follows is a discussion of some of the significant side effects of albumin reported over the years. Safety from exogenous pathogens. Albumin solutions have been relatively free of the infectious disease risks that plagued the use of other blood derivatives until the current paradigm of blood safety was established.25 From its earliest period of manufacture and use, albumin has been heated to 60oC for 10 hours, a process known as pasteurization, which has been shown subsequently to inactivate a wide range of blood-borne viruses.26 The Cohn manufacturing process itself contributes substantially to eliminating viruses such as hepatitis B,27 and pasteurization alone is insufficient to inactivate viruses in heated unfractionated serum.28 In addition, the precipitation steps clear prions, the infectious agents associated with transmissible spongiform encephalopathies, away from the final product.29 In this context, the role of appropriate analysis of causality in the putative transmission of blood borne pathogens is important.30 This is exemplified by a report describing a patient who developed Creuzfeld Jakob disease following a liver transplant that included administration of a unit of albumin.31 This product was manufactured from a plasma pool, which included a donor who subsequently developed Creuzfeld Jakob disease; no causality to the albumin was ascribed as all other recipients of blood

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FARRUGIA

Figure 1. Manufacturing methods for the preparation of albumin therapies. See reference 84 for more details.

products derived from the pool were unaffected.32 Despite the robustness of albumin’s pasteurization processes, the role played by good practices in its manufacture (cGMPs) is equally important, as shown by the transmission of hepatitis B by pasteurized albumin solution, which had been inadequately mixed during the heating of the bulk solution, leading to uneven temperature distribution and, presumably, incomplete viral inactivation.33 Despite this sole incident, albumin’s position as the benchmark biological therapy in terms of pathogen safety remains unchallenged. This is also the case for albumin as an additive stabilizer for other therapeutics such as recombinant proteins and monoclonal antibodies, and the so-called “new generation” formulations of these therapies, which exclude albumin in the context of enhanced safety are addressing perception rather than real risk.

Hypotensive reactions. The association of albumin infusion with hypotensive episodes is mainly a matter of historical interest.34 Prekallikrein activator (PKA) contaminating early preparations has been causally associated with this adverse event.35 As albumin presentations have evolved through successive generations of product purity, this impurity has been progressively minimized, with concurrent decreases in the incidence of hypotensive events.36 This observation has relevance in the context of the unique identity of different albumin preparations, with different product physiochemical and adverse event profiles. The release of free PKA from inhibitor complexes, capable of precipitating hypotension, has been reported in products during storage.37 This may explain how some products may lead to hypotensive events without apparently high PKA levels at release. The role of higher product purification,


SAFETY OF PLASMA VOLUME EXPANDERS further differentiating albumin products on the basis of technology (ethanol precipitation vs chromatography) is also shown in the study of Che et al.36 Renal injury. A recent French study indicates that patients receiving hyperoncotic (20%-25%) are at an increased risk of developing renal adverse events compared with patients receiving hypooncotic (4%5%) albumin and similar hypooncotic fluids.38 The same risk was observed with other hyperoncotic colloids. This large prospective observational study appears to counter earlier randomized clinical trials, which indicated that patients given hyperoncotic albumin for the treatment of shock did not suffer kidney damage.39 Concurrently with the French study, a meta-analysis of randomized clinical trials using hyperoncotic albumin found no deleterious effects, and improved renal function in patients with liver disease receiving hyperoncotic albumin.40 While this systematic review has a higher position in the hierarchy of evidence-based medicine than the French observational study, the number of patients included in the latter and the possible serious effects on patient outcome give credence to the authors’ statement that hyperoncotic albumin should be used with caution in patients with shock and possible renal problems pending further studies. The authors’ comments regarding the possible misuse of hyperoncotic, rather than hypooncotic, albumin, based on the more rapidly observable hemodynamic effects of the concentrated solution, also bear attention; no therapy is immune to the possible effects of its misuse. The Synthetic Colloids Although conventionally viewed as less natural than albumin, the synthetic colloids are also derived from a biological source, although, unlike albumin, they are composed of mixtures of polydisperse molecules. Their use as plasma volume expanders preceded the development of albumin; gelatin was described for the treatment of hypovolemic shock in 1915.41 However, the 3 “artificial” colloids—gelatins, dextrans, and hydroxyethyl starches (HES)—were not introduced into mainstream clinical practice until the 1950s. Gelatins are manufactured from bovine gelatin, a derivative of collagen, which is cross-linked, urealinked, or succinylated to yield the final products. This yields molecules that are retained intravascularly, giving them their hemodynamic effects. The molecular weight ranges from 30 kDa to 35 kDa, and the intravascular survival is short—1 to 3 hours. The recent concerns regarding bovine spongiform

encephalopathy (BSE) have made regulatory agencies and manufacturers assess the manufacturing process for its capacity to destroy the infectious entity,42 an important measure despite the sourcing of the product from BSE-free closed cattle herds. Dextrans are groups of branched polysaccharides of 200 000 glucose units, derived from sucrose by the action of the bacterium Leuconostoc mesenteroides, following which hydrolysis and ethanol fractionation are used to produce the final product. The different dextran preparations are polydisperse mixtures grouped on the basis of their average molecular weight, which is different from the average molecular weight of the particles with colloid oncotic power, which is important for their hemodynamic action. The main types are dextran 40, available as a 10% solution, and dextran 60 and 70, prepared as a 6% solution. The molecular weight is the chief determinant of the pharmacodynamics (Table I). HES are synthesized by partial hydrolysis of amylopectin plant starch and hydroxyethylation at C2, C3, and C6 portions of the glucose molecules. The hydroxylation is important for the pharmacokinetics (Table I). As a higher understanding of the pharmacokinetics and the adverse event profile of HES has evolved, and preparations of different molecular weight and degrees of hydroxylation have entered the market. The earliest generation of HES of high molecular weight is now defunct because of adverse events and medium to low molecular weight products are favored. Safety of the Synthetic Colloids A systematic review of the comparative safety of colloids relative to albumin as a reference43 found the incidence rate ratio for several groups of adverse events to be significantly higher for the synthetic colloids (Table II). In addition to this pooled analysis, significantly higher incidence rates of adverse events were recorded for the synthetic colloids, including coagulopathy, renal failure, and circulatory and hepatic complications. Some of these event types will be reviewed in more detail. Coagulopathy Volume substitution with fluids other than fresh blood may be expected to lead to a progressive dilution of the cellular and protein hemostatic components. This occurs for the anticoagulant as well as the procoagulant proteins, and monitoring with the thromboelastogram (TEG) shows that acute hemodilution with saline induces a hypercoaguable state of 295


FARRUGIA Table I Characteristics of the Synthetic Plasma Expanders Concentration, % Mw (kDa)

Gelatins Urea-linked Cross-linked Succynilated Dextrans 40 60 70 HES 450/0.7 200/0.5 130/0.4

3.5 5.5 4.0

In Vivo Survival (Hours)

35 30 30

1-3 1-3 1-3

10 6 6

40 60 70

3-4 4 5

6 10 6

450 200 130

5-6 3-4 2-3

Mw, molecular weight; HES, hydroxyethyl starches.

Table II Safety of Synthetic Colloids Relative to Albumin43 Product Group

Event

HES Dextran Gelatin HES

Anaphylactoid reactions Anaphylactoid reactions Anaphylactoid reactions Pruritus

Incidence Rate Ratio (95% CI)

4.51 2.32 12.4 1.78

(2.06-1.89) (1.21-4.45) (6.40-24.0) (1.23-2.58)

HES, hydroxyethyl starches.

uncertain origin,44 but probably because of the dilution of antithrombin III (ATIII), the most important physiological anticoagulant, which has a high normal range (plasma levels of 80%-120%).45 Hemodilution, as a result of albumin infusion, leads to in vitro coagulation abnormalities at 30% volume replacement,46 but is not considered to have clinically significant effects.47 In contrast, the synthetic colloids all impair hemostasis to different degrees, through specific effects on the different components of the hemostatic system.48 Although its effects are the least marked of the synthetic colloids, gelatin has induced postoperative hypercoagulation following joint replacement surgery49 and results in decreased TEG-measured clot strength.50 Gelatin also impaired platelet aggregation in normal volunteers51 and during cardiac surgery.47 The effects of dextran and HES on hemostasis are much more profound, and are probably the reason for the continuing decline in the use of dextran. Both

molecules exert an effect on both primary hemostasis and coagulation through a drop in the factor VIII/ von Willebrand factor (FVIII/VWF) complex,52,53 which is higher than predicted through dilution. In vitro, both molecules precipitate FVIII/VWF out of plasma,54 possibly leading to clearance in vivo, but specific binding of FVIII/VWF to the molecules has also been described.55,56 Other effects have been extensively documented in the cited reviews, and are unquestionably linked to clinical bleeding and increased blood usage in surgical procedures.57 While dextrans are apparently in the terminal phase of their therapeutic presence as a result of these adverse effects, HES pharmaceutical development has continued, seeking improvements in product specification aimed at minimizing hemostatic complications. HES preparations of increasingly lower molecular weight and lower hydroxyethyl substitution have been developed, designed to decrease the adverse effects on coagulation by decreasing the in vivo residence time of the molecules in the intravascular space. The available data indicates that these efforts have had mixed results. Early studies indicated no amelioration in the TEGdetectable anomalies when using a 130 kDa product with a degree of substitution of 0.4 (HES 130/0.4) compared with the previous generation (HES 200/0.5).58 This was supported by similar findings in a pig model comparing HES 650/0.42 and HES 130/0.43, showing comparably deleterious effects on hemostasis including FVIII/VWF.59 The in vitro effect of HES 130/0.42 is not reversible by the addition of fibrinogen,60 which appears compatible with an effect on FVIII/VWF. Subsequently, the effect on FVIII/VWF in HES 130/0.42 was shown to be lower than with other HES.61 This is associated with less bleeding and blood product use.62,63 In a pooled analysis of randomized clinical trials of HES 130/0.42 use in major surgery, modestly improved results, equivalent to transfusion of less than 1 whole red cell unit, were obtained relative to HES 200/0.5.64 A polemic around this study65 points out that some trials showing equivalence between the 2 forms of HES were excluded from the pooled analysis66; the authors’ rebuttal that the excluded study compared nonequivalent HES on the basis of plant source is problematic given the finding that this is not the case for HES 130/0.42.67 In patients with severe head injury who received HES 130/0.4 and HES 200/0.5 in high cumulative doses, cerebrovascular bleeding events were similar in both groups.68 In cardiac surgical patients, HES 130/0.4 and HES 200/0.5 at maximum daily doses were associated with similar


SAFETY OF PLASMA VOLUME EXPANDERS incidences of postoperative bleeding.69 In addition, a prospective randomized trial comparing albumin, HES 130/0.42, and HES 200/0.5 in cardiac surgery found significant clot impairment as measured by TEG with both the HES but not with albumin.70 While studies with other groups of patients and examining more hemostatic parameters are needed, it is premature to suggest that HES 130/0.42 is immune from the adverse event profile of its predecessors. It is clear that any relative improvements compared with earlier generation products in the United States, where the middle generation products exemplified by HES 200/0.5 were never licensed, are because of the shorter intravascular residence time.71 Improvements against these low standard products are a modest claim to an adequate therapeutic profile. Renal Dysfunction

130/0.4, which resulted in a similar incidence of delayed graft function as HES 200/0.62 when subjected to a retrospective, matched pair analysis of kidney transplants.83 While the hemodynamic status of the recipient is undoubtedly relevant to this problem, it seems that the high need for ensuring the best outcomes from scarce transplant kidneys justifies the exclusion of synthetic colloids in potential kidney transplant recipients. The recent publication of 2 meta-analyses84,85 indicates a substantial risk of renal impairment in septic patients in intensive care treated with HES, irrespective of the generation and composition—molecular weight/degree of substitution—of the product, leading the authors to recommend more trials with the newer products and a moratorium on the use of HES on septic patients until the publication of such trials. Albumin—Again

The incidence of acute renal failure associated with dextran has been reported as 4.3% in a series of patients who were dehydrated,72 a recognized predisposing factor.73 The observation that this problem could be resolved through plasmapheresis74 contributed to the development of the concept of hyperoncotic acute renal failure, which could be precipitated through administration of colloids in high concentration or of high in vivo molecular weight. Hyperoncotic albumin solutions have also been implicated.38 HES is also associated with this complication75 and was shown to be harmful to the kidney in a recent trial in septic patients76 using HES 200/0.5, a (hyperoncotic) 10% solution. Use of HES 130/0.42 in a 6% (supposedly isooncotic) solution was associated with an incidence of renal adverse events, which was similar to that found with previous generation starches.38 HES 130/0.4 also raised sensitive markers of renal impairment77 and led to a progressive increase of plasma accumulation in relation to pre-existing renal impairment.78 A systematic review of randomized clinical trials using HES in sepsis79 concluded that HES increased the incidence of acute renal failure compared with gelatin and crystalloids and recommended against using HES in sepsis. Given that isooncotic HES and gelatin80 lead to renal injury, oncotic injury cannot be the sole responsible mechanism, but specific effects from the colloid molecules must also play a part. An important facet of the adverse effects of colloids on kidneys is the effect on transplanted organs. Although the series studied are necessarily small, colloidassociated injury in donor kidneys has been associated with poor transplant outcomes,81 an effect particularly accentuated by HES.82 This is also evident with HES

Ten years after the publication of the Cochrane metaanalysis, the flurry of debate it provoked appears to have settled to a sometimes grudging consensus that albumin is a safe therapy. The following are issues that have arisen from the debate: 1. Despite the justified criticisms levied at it, the Cochrane meta-analysis was responsible for stimulating interest, and more importantly, clinical investigation, into a therapy, which, although widely used in several areas of medicine, was underpinned by modest evidence in terms of its safety and efficacy. Given its wide usage and its importance to the economics of the plasma protein industry, the scrutiny of albumin’s safety was timely and ultimately beneficial. 2. In this regard, one of the chief criticisms levied at the Cochrane meta-analysis—that it included studies involving a wide range of albumin preparations, including products preceding the current generation of high purity albumin solutions—may be seen as one of the meta-analysis’s “covert” benefits. By showing that a heterogeneous safety profile could be generated by different generations of albumin products, and thus contributing possibly to the reported effect on mortality, the Cochrane meta-analysis contributed to the emerging evidence that albumin preparations may be heterogeneous in their safety and efficacy profiles. 3. This concept is supported by pharmacovigilance data showing increasing purity,86 and increasingly favorable safety profiles between different generations of albumin.36 The heterogeneity of albumin solutions from different manufacturers has been shown in relation to their potential to induce inflammatory reactions in endothelial cells87 and their capacity to bind

297


FARRUGIA dyes.88 In addition, different batches of a single product from a single manufacturer may differ in their capacity to precipitate adverse events.89 Therefore, heterogeneity between and within products may explain the residual adverse events ascribed to albumin solutions, including the endothelial activation markers observed en vivo by Nohé et al85 and in abdominal surgery patients by Boldt et al.90

On the basis that albumin preparations are heterogeneous and may be expected to have different safety and efficacy profiles, particularly in the extremely wide range of clinical conditions in which they are used, it is worth reflecting on the implications of the safe study,12 which underpins the reassurance regarding the safety of albumin post the Cochrane metaanalysis. The preparation used for this study was a very high purity albumin solution prepared by chromatography and lacking many of the potential contaminants permitted by the current pharmacopeial specification of 95% purity. The extent to which data from this study can be extrapolated to the whole range of currently available albumin products is, in the view of this author, dubious. Greater reliance may be placed on the various pharmacovigilance studies cited in this review, which demonstrate the extraordinarily high safety levels of albumin. What is the way forward for albumin? It is time that the plasma industry and its regulatory overseers accepted that albumin is not a commodified, generic product, as what seems to be the view of the US Food and Drug Administration,23 but a complex protein with myriad functions and potential therapeutic benefits. As a biological product subject to alterations in structure and composition imposed by the different manufacturing processes (Figure 1), some of which are described in this review, albumin solution needs to be treated as a different drug whenever it originates from a different source, and should be backed by appropriate safety and efficacy data. In the meantime, this natural colloid is clearly associated with an enhanced safety profile compared with its artificial competitors. Commercially, it is disadvantaged by its high cost and by its basic immutability compared with HES whose advocates appear to address each new safety concern by developing a new generation of products (while the previous generations are allowed to stay on the market). So far, a convincingly therapeutically superior product has not appeared to challenge evolution’s major plasma protein. Nature is still the best option. Financial disclosure: The author provides contractual services to the Plasma Protein Therapeutics Association, which represents

the commercial plasma protein industry. No financial disclosure declared. Any views expressed are solely those of the author.

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