Optimizing exchange transfusion for severe unconjugated hyperbilirubinemia: studies in the Gunn rat

Abstract

Background: Severe unconjugated hyperbilirubinemia carries the risk of neurotoxicity. Phototherapy (PT) and exchange transfusion (ET) are cornerstones in the treatment of unconjugated hyperbilirubinemia. Studies to improve ET efficacy have been hampered by the low application of ET in humans and by the lack of an in vivo model. The absence of an appropriate animal model has also prevented to determine the efficacy of adjunct or alternative treatment options such as albumin (Alb) administration.

Aim: To establish an in vivo model for ET and to determine the most effective treatment (combination) of ET, PT and Alb administration.

Methods: Gunn rats received either PT, PT+Alb, ET, ET+PT, ET+PT+Alb or sham operation (each n = 7). ET was performed via the right jugular vein in ≈ 20 min. PT (18 µW/cm(2)/nm) was started after ET or at T0. Albumin i.p. injections (2.5 g/kg) were given after ET or before starting PT. Plasma unconjugated bilirubin (UCB), plasma free bilirubin (Bf), and brain bilirubin concentrations were determined.

Results: We performed ET in 21 Gunn rats with 100% survival. At T1, ET was profoundly more effective in decreasing both UCB -44%, p<0.01) and Bf -81%, p<0.05) than either PT or PT+Alb. After 48 h, the combination of ET+PT+Alb showed the strongest hypobilirubinemic effect (-54% compared to ET).

Conclusions: We optimized ET for severe unconjugated hyperbilirubinemia in the Gunn rat model. Our data indicate that ET is the most effective treatment option, in the acute as well as the follow-up situation.

Figure 1. Course of plasma UCB and Bf concentrations after exchange transfusion.

Course of plasma UCB concentrations (A) and plasma Bf concentrations (B) after sham transfusions (control) or an exchange transfusion (ET) in Gunn rats. Rats were randomized to receive sham transfusions (control) or an exchange transfusion (ET). Values are mean ± SD. *p<0.01 compared to controls. #p<0.001 ET: T₀ compared to T₁.

Figure 2. Plasma UCB and Bf concentrations after 1 h.

Acute effects of sham transfusions (control) or phototherapy (PT), albumin (Alb), an exchange transfusion (ET), or a combination of these on plasma UCB concentrations (A) and plasma Bf concentrations (B) in Gunn rats. Rats were randomized to receive sham transfusions (control) or an exchange transfusion (ET), and were subsequently treated with phototherapy (PT), albumin (Alb) or the combination of PT+Alb. Values are mean ± SD. *p<0.001 compared to controls. #p<0.05 compared to PT. $p<0.05 compared to PT+Alb.

Figure 3. Plasma UCB and Bf concentrations after 48 h.

Long-term effects of an exchange transfusion (ET), with or without the combination of phototherapy (PT), or albumin (Alb), on plasma UCB concentrations (A) and plasma Bf concentrations (B) in Gunn rats. Rats were randomized to receive an exchange transfusion (ET), and were subsequently treated with phototherapy (PT), albumin (Alb) or the combination of PT+Alb. Values are mean ± SD. *p<0.01 compared to ET. #p<0.05 compared to ET+PT.

Figure 4. Brain bilirubin levels.

Effects of sham transfusion (controls), phototherapy (PT), albumin (Alb), an exchange transfusion (ET) or a combination ofn these on brain bilirubin levels in Gunn rats. For experimental setup, kindly refer to the Methods section. Values are mean ± SD. *p<0.05 compared to controls. #p<0.01 compared to PT. $p<0.05 compared to ET and ET+PT.