Ricerc@Sapienza

HES history
HES was introduced in clinical practice in the 1960s, since then concerns on its safety and efficacy have been consistently and extensively raised (0, 1, 14b). As early as in 1968, it was reported abnormal massive bleeding in patients that received HES and Authors commented: “(…)there is need for further investigation (…)in patients being transfused with this substance” (1g). In 1975, Alexander B and coll reported: “(…)the hemostatic defect associated with the use of (HES-like) plasma substitutes is a form of induced von Willebrand-disease or disseminated intravascular clotting, ensuing from precipitation and removal of v. W. factor(s), Factors VIII and I, microcirculatory abnormality, and platelet malfunction” (1b). These evidence were further confirmed in 1981 when was reported: “Following massive infusions,(...) a wide variety of laboratory abnormalities were observed, and hemorrhage was documented(…)”(1f). In 2002 the Blood Products Advisory Committee, recommended the Food and Drug Administration (FDA) to change the labeling of a 6% HES product because of the increased risk of bleeding during cardiopulmonary bypass in patients whose coagulation status is already impaired; this request was approved by the FDA in 2003 that added a warning statement (1e).
Additional concerns, related to renal damage, were reported since 1991 when was found: “(…)acute deterioration of an already existing nephropathy“ with development of transient renal failure in patients underwent to hemorheological therapy through hemodilution (2b). These evidence were further confirmed in 1993 when renal histological lesions on transplanted kidneys associated with HES use were described (1c, 1d). In 2008, was reported that: “fluid resuscitation with(...) HES(...) is harmful in patients with severe sepsis. At recommended doses, it causes renal impairment, and at high doses, it impairs long-term survival. (…)until long-term studies -will be accomplished- (…)HES solutions should be avoided” (5). In 2012, two large clinical trials reported more alarming evidence on HES safety: the 6S trial demonstrated an enhanced risk of death and of renal-replacement therapy in ICU patients treated with HES than in patients treated with Ringer’s Acetate solution; the CHEST study showed that: “(...)the use of HES resulted in an increased rate of renal-replacement therapy”; “(...)there are no evidences that resuscitation with 6% HES (130/0.4), as compared with saline, in the ICU provides any clinical benefit (6, 7).
Of interest, since 2010, Joachim Boldt -a German anesthesiologist and worldwide known scientist, an “eminence” in fluid therapy and a strong supporter of HES- was accused of forgery and falsification of study data and subsequently condemned in penal court and stripped of his professorship (2). After that, >90 studies related to HES have been withdrawn by international anesthesia and critical care journals (3). His case has been included among the biggest medical research scandal and his fraudulent studies caused significant harm to critically ill patients (4). In 2013, a meta-analysis on HES use in ICU patients -that excluded data from Boldt’s studies- showed an increase risk of acute kidney injury and higher mortality (8). In 2013, because of the growing evidence on potential risks associated with HES use, the German Federal Institute for Drugs and Medical Devices required to EMA-PRAC to withdrawn HES from the market (9b). At an initial evaluation, in June 2013, the EMA-PRAC suggested to suspend HES market authorization (9) In November 2013 -also because of the producers pressures (10, 11)- the PRAC made a step back and delivered restrictive criteria for HES clinical use: “HES solutions may continue to be used in patients to treat hypovolaemia(...) caused by acute (...)blood loss, where treatment with alternative infusions solutions known as ‘cryst