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Department of Anesthesia and Perioperative Medicine, Medical University of South Carolina, Charleston, SC
To the Editor:
Neff et al. (1) describe a randomized trial of 31 craniocerebral trauma patients receiving repetitive infusions over a maximum of 28 d of either hydroxyethyl starch (HES) 130/0.4 up to 70 mL · kg–1 · d–1 or HES 200/0.5 up to 33 mL · kg–1 · d–1. Albumin was administered for additional intravascular volume needed in the HES 200/0.5 group. Patients with a history of coagulation disorders, chronic renal insufficiency, severe liver insufficiency, or cardiac insufficiency were excluded.
The investigational plan of Neff et al. was to enroll 40 patients. Of 128 patients screened, 95 failed to meet the enrollment criteria, and two could not be enrolled for logistic reasons. After 31 patients had been enrolled, the institutional ethics committee raised questions regarding the occurrence of intracranial bleeding complications in both groups and requested an interim analysis. Intracranial bleeding complications occurred in 31% of the HES 130/0.4 group and 33% of HES 200/0.5 recipients. The investigators stated, without providing evidence, that the intracranial bleeding complications "were related to the underlying cerebral trauma and were not accompanied by coagulation disorders." They further indicated that the trial was not resumed after the interim analysis because of more frequent episodes of elevated intracerebral pressure in the control group, which they speculated may have been attributable to the cumulative 7 L of albumin administered in this group rather than the 22 L of HES 200/0.5. They did not, however, acknowledge two randomized trials (2,3) and a prospective clinical outcome study (4) providing evidence that albumin improves outcomes of brain injury. Nor did they mention coagulation abnormalities due to HES 200/0.5 demonstrated in one randomized (5) and two nonrandomized (6,7) controlled trials of patients with cerebrovascular diseases. They also did not cite a pharmacovigilance study documenting 9 cases of acquired type I von Willebrand’s disease associated with HES 200/0.5 administered to patients with subarachnoid hemorrhage (8). Four of the cases were complicated by cerebral hemorrhage and one by extradural hematoma. Three of the four cerebral hemorrhage cases were fatal.
No significant between-group differences were detected by Neff et al. in blood loss, use of blood products, or neurological outcomes at up to 6 mo. Factor VIII and von Willebrand factor antigen and ristocetin cofactor were transiently and modestly higher in the HES 130/0.4 group; however, these observations may have been due to the higher mean daily volume of fresh frozen plasma administered to the HES 130/0.4 (274 ± 518 mL) compared with the HES 200/0.5 group (251 ± 385 mL).
The trial of Neff et al. is the third randomized trial in brain injury to be prematurely discontinued because of serious complications in HES recipients. One of these was a multicenter trial of 88 acute ischemic stroke patients (9), in which there was significantly increased mortality related to cerebral edema in recipients of HES 200/0.5. In the other involving 70 patients with acute ischemic stroke (10), clinical deterioration occurred in 8 HES 200/0.5 recipients versus none of the control group patients (P < 0.01).
In the abstract of their paper Neff et al. conclude that "HES 130/0.4 can safely be used in critically ill head trauma patients over several days at doses of up to 70 mL · kg–1 · d–1." This sanguine assessment appears difficult to justify in light of the high incidence of intracranial bleeding complications in both study groups as well as the other similar effects of HES 130/0.4 compared with HES 200/0.5, a HES preparation consistently associated with increased risk of hemorrhagic and other serious complications in brain injury patients. Indeed, the preponderance of currently available evidence suggests that HES is not safe in brain injury indications.
References
Department of Pathology, The University of Michigan Medical School, Ann Arbor, MI Zurich, Switzerland Lausanne, Switzerland
In Response:
We appreciate the interest of Dr. Haynes in our article on large-dose administration of medium molecular weight (130 kd) hydroxyethyl starch with a molar substitution of 0.4 (HES 130/0.4) in patients following severe head injury (1).
Dr. Haynes has not correctly understood the paper when claiming that our trial was "prematurely discontinued because of serious complications in HES recipients." In contrast, we clearly reported that the increased incidence of ICP peaks in the control group was the reason for the study discontinuation. This decision was taken voluntarily by the investigators and was not demanded by the IRB. In fact, the IRB had given us clearance for study continuation after the interim analysis.
Under the conditions of our study (up to 70 mL · kg–1 · d–1 HES 130/0.4 or HES 200/0.5 up to 33 mL · kg–1 · d–1 for up to 28 days) no acquired type I von Willebrand disease was induced in either group, including the subjects with bleeding events. Again, contrary to that purported by Dr. Haynes, we did in fact provide strong evidence that intracranial bleeding complications in both groups were not related to any coagulation disorders. In the original article (1) we have already presented extensive coagulation data for the whole group (Table 4 in our article). Shown in Table 1 (4a) below are the same parameters for the 5 patients in each group that had bleeding events. Not one single minimum value after baseline was below the lower limit of the normal range. In addition, TEG measurements were done (data not shown), which also did not reveal any infusion-induced coagulation disorder in any of the cases. On the basis of such extensive coagulation data, all bleeding events were therefore regarded as nonrelated to the study medications.
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It is scientifically incorrect to infer a difference between groups that had similar low volumes of fresh frozen plasma administered (274 ± 518 mL vs 251 ± 385 mL). It is also questionable to state that our study had a "high incidence of intracranial bleeding complications" without referring to a specific point of reference. Delayed traumatic intracerebral hematomas (DTICH) are common, and comparable incidences are reported in the pertinent literature (7,8). In addition, all of the 31 patients enrolled in our study were diagnosed with very severe head injury as determined by stringent inclusion criteria. The severity of the head injury in this cohort bore per se a high risk for posttraumatic bleeding complications.
As evidenced by our coagulation data, the significantly increased incidence of ICP peaks in the control group was not due to induced bleeding disorders. Other explanations might be hypothesized. It has recently been shown that HES does not penetrate into the cerebrospinal fluid, even when the blood-brain barrier is disrupted (9), and it is per se unlikely that the larger HES 200/0.5 molecules should have penetrated more easily than HES 130/0.4. In contrast, albumin (approximately 66 kd) is suspected to leak from the disrupted blood-brain barrier (10,11), which might result in an increased incidence of ICP peaks.
Dr. Haynes cites older studies claiming beneficial effects of albumin on the outcome in brain injury. However, a number of recent publications, especially since the Cochrane Group’s meta-analyses on the value and potential detrimental effect of albumin in the critically ill have been published in 1998, report opposing views (12–15).
Furthermore, Dr. Haynes did not acknowledge a recent randomized trial in stroke patients. Rudolf and the HES in Acute Stroke Study Group 2002 (16) completed a double-blind trial with HES 130/0.4 (10%, 70 patients) versus normal saline (36 patients), concluding that the safety profiles were similar for the two treatment groups. There was also a nonsignificant trend towards a better functional outcome with HES therapy. HES 130/0.4 (6%) proved safe compared with crystalloids, especially regarding coagulation, in another recent trial (17).
On the basis of the results of our study, we therefore remain convinced that 70 mL · kg–1 · d–1 HES 130/0.4 can safely be used over several days for maintenance of cerebral perfusion pressure and reduction of detrimental ICP peaks in critically ill patients with head trauma. This regimen has become the new standard in the institution where the study was performed.
References
This article has been cited by other articles:
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