Renal Toxicity of Polybrene in Open-Heart Surgery

Haller, Julia A.; Ransdell, Herbert T.; Stowens, Daniel; Rubel, W F

doi:10.1016/s0022-5223(19)32941-1

Cited by 26 publications

(6 citation statements)

References 6 publications

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“…In this connection it is interesting to note that the patient had been subjected to no less than 13 dialyses, and although the deafness did not commence during a dialysis it seems possible that the unusual increase in volume of body fluid, with which its onset was associated, might also have produced osmotic injury and so finally precipitated the cochlear degeneration. As discussed elsewhere in this paper, hexadimethrine bromide (Polybrene, Abbott) is a polymeric quaternary ammonium salt found by Haller et al (1962) and others to have a nephrotoxic effect. In addition, evidence will later be presented that its use may cause deafness.…”

Section: (4) Osmotic Disturbances Due To Dialysismentioning

confidence: 97%

Perceptive Deafness in Subjects with Renal Failure Treated with Hæmodialysis and Polybrene (A Clinico-Pathological Study)

Ransome¹,

Ballantyne²,

Shaldon³

et al. 1966

J. Laryngol. Otol.

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Section: (4) Osmotic Disturbances Due To Dialysismentioning

confidence: 97%

Perceptive Deafness in Subjects with Renal Failure Treated with Hæmodialysis and Polybrene (A Clinico-Pathological Study)

Ransome¹,

Ballantyne²,

Shaldon³

et al. 1966

J. Laryngol. Otol.

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“…During the late 1950's and early 1960's, it was utilised as an alternative agent to protamine to neutralise unfractionated heparin in patients undergoing open heart surgery and in those patients with an extracorporeal circulation [Weiss et al, 1958;Keats et al, 1959;Blumberg et al, 1960;Lillehei et al, 1960]. Although found to be as effective as protamine, its clinical application was short lived following reports of renal toxicity [Haller et al, 1962;Ransdell et al, 1965].…”

Section: Hexadimethrine Bromide (Polybrene) and Thrombin Generationmentioning

confidence: 99%

Population Pharmacokinetics of Enoxaparin During the Antenatal Period

Patel

Green

Patel

et al. 2012

Blood

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503 The optimal dosing strategy of low molecular weight heparins (LMWH) for the treatment of antenatal venous thromboembolism (VTE) is not known. The physiological changes associated with pregnancy alter the pharmacokinetic (PK) profile of LMWH, and this has led to controversy and subsequent variation in practice, when pregnant women are managed with LMWH for VTE [Voke et al., 2009]. The perceived impact of these PK changes has led to the Royal College of Obstetrics and Gynaecologists (RCOG) recommending a twice daily dose of LMWH, whilst the American College of Chest Physicians recommend that either a once or twice daily dose of LMWH can be used in this setting. We conducted a population PK modelling study of enoxaparin during pregnancy in order to address this issue. Women requiring antenatal enoxaparin, all indications and doses, referred to the specialist haematology clinic at King's College Hospital, a London teaching hospital, were eligible to enrol in the study. Recruited women were reviewed monthly in clinic during their pregnancy, and had up to three anti-Xa activities (trough, 1 hour post dose, and 3 hours post dose) drawn at each clinic attendance. This anti-Xa sampling strategy was based on d-optimal design, to ensure gestation related changes in enoxaparin clearance (CL) and volume of distribution (Vd) were captured in the PK model developed [van Hasselt et al., 2012]. Women under 18 years of age, those with impaired renal function and those non-adherent to enoxaparin were excluded. Compartmental PK modelling was conducted using non linear mixed effects modelling (NONMEM version 7.2.2). One hundred and twenty three patients contributed 795 anti-Xa activities (712 antenatal, 83 postnatal), for PK modelling purposes. A one compartment model with exponential between subject variability on CL and Vd, with a combined proportional and additive error model best fitted the data, with both enoxaparin CL and Vd found to have increased during pregnancy (table). Enoxaparin PK parameter CL (L/hr) Vd (L) Non-pregnancy (literature values) 0.5-0.7 3-7 Pregnancy (this study) 1.6 13.2 Time dependent changes during pregnancy were found to be significant covariates on both CL and Vd. A full covariate analysis identified weight to be a significant covariate for enoxaparin CL and gestation and baseline lean body weight to be significant covariates for Vd during pregnancy. The final pregnancy enoxaparin PK models for CL and Vd can be represented mathematically as: where Wt is the women's actual weight, GEST is their gestational stage, and LBW is their baseline lean body weight. Goodness of fit plots, a bootstrap analysis and a visual predictive check revealed that a robust enoxaparin model for use in pregnancy had been developed. Simulations of women injecting enoxaparin once versus twice daily demonstrate that both dosing regimens will reach RCOG target 3 hour plasma concentrations throughout the duration of the pregnancy (Figure 1). This should provide confidence to clinicians who prescribe a once daily dose of enoxaparin for the antenatal population. Perhaps the more important concentration to assess however is the trough anti-Xa activity, due to the historical thinking that during pregnancy CL increases, therefore so should the dose/dosing frequency. When the trough activity is simulated, the majority of women on a once daily dose, will have measurable anti-Xa activity; with both once and twice daily regimes demonstrating an increase in trough anti-Xa activity with the progression of pregnancy. This occurs due to the increase in Vd and demonstrates that enoxaparin never reaches a steady state during pregnancy. The measurable trough activity confirms the appropriateness of a once daily dose of enoxaparin in this setting. Our work provides compelling evidence that a once daily dose of enoxaparin for the treatment of antenatal VTE is appropriate. As a result, the current guidelines should be revised. Figure 1: Simulation of 3 hour (red) and trough (blue) anti-Xa activity of women receiving once daily and twice daily treatment doses of enoxaparin during their pregnancy. The solid line is the median concentration and the dashed lines represent the 5th and the 95th percentile concentrations. Grey horizontal lines represent RCOG 3 hour target anti-Xa concentration. Figure 1:. Simulation of 3 hour (red) and trough (blue) anti-Xa activity of women receiving once daily and twice daily treatment doses of enoxaparin during their pregnancy. The solid line is the median concentration and the dashed lines represent the 5th and the 95th percentile concentrations. Grey horizontal lines represent RCOG 3 hour target anti-Xa concentration. Disclosures: Off Label Use: Enoxaparin use during the antenatal period.

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“…There is sparse published data to indicate whether hexadimethrine became established in clinical practice following its introduction. However enthusiasm for its use reduced following reports in 1962 and 1965 of acute renal failure (ARF) in patients who received hexadimethrine in doses greater than 5 mg/kg during cardiac surgery 4,10 . Hunsicker et al in 1981 showed that the ARF was reversible and postulated that neutralization of glomerular basement membrane anions altered charge-dependent permeability of the glomerulus, resulting in proteinuria 11 .…”

Section: Discussionmentioning

confidence: 99%

“…Hexadimethrine bromide (Polybrene) is a polycation that was introduced into clinical practice in 1954 and was used extensively for neutralization of heparin after CPB. In 1962, it was reported to cause proteinuric renal failure if given in excessive amounts 4 and its use was largely curtailed. It was recommended for use in protamine-allergic patients by Doolan in 1981 1 .…”

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confidence: 99%

Recent Experiences with Hexadimethrine for Neutralizing Heparin after Cardiopulmonary Bypass

Cooney

1999

Anaesth Intensive Care

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Hexadimethrine bromide was used for the neutralization of heparin during cardiac surgery in the late 1950s. For some years, this institution has used it for patients who may be allergic to protamine. In view of the recent renewal of interest in hexadimethrine, we present four cases outlining its use during cardiac procedures in such patients. Other drugs for reversing the action of heparin such as heparinase or platelet factor IV are not yet widely available.

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Renal Toxicity of Polybrene in Open-Heart Surgery

Cited by 26 publications

References 6 publications

Perceptive Deafness in Subjects with Renal Failure Treated with Hæmodialysis and Polybrene (A Clinico-Pathological Study)

Perceptive Deafness in Subjects with Renal Failure Treated with Hæmodialysis and Polybrene (A Clinico-Pathological Study)

Population Pharmacokinetics of Enoxaparin During the Antenatal Period

Recent Experiences with Hexadimethrine for Neutralizing Heparin after Cardiopulmonary Bypass

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