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RESEARCH CORRESPONDENCE B-type natriuretic peptide therapy in total artificial heart implantation: Renal effects with early initiation Sotirios Spiliopoulos, MD, Dilek Guersoy, MD, Reiner Koerfer, MD, and Gero Tenderich, MD From the Heart and Vascular Center Duisburg, Department for the Surgical Therapy of End-stage, Heart Failure and Mechanical Circulatory Support, Duisburg, Germany
B-type natriuretic peptide (BNP) is produced mainly by ventricular myocytes and to a lesser degree by cardiac fibroblasts.1 In the context of end-stage heart failure, chronic myocyte stretch upregulates BNP and intracellular cyclic GMP synthesis, thus inducing vasodilation, diuresis and inhibition of the renin–aldosterone system. In the case of total artificial heart (TAH) implantation, resection of the native ventricles results in a rapid decrease of endogenous BNP production and interruption of these signaling pathways. Consequently, renal function declines.2 Low-dose BNP infusions have been proven to have a positive impact on urine output in the early post-operative setting.3 However, due to the lack of large-study experience, optimal timing of BNP therapy is still unclear. Because prevalence of chronic renal failure in TAH candidates is high,4 we hypothesized that early initiation of low-dose BNP infusion therapy in all patients would help avoid low urine output events3 and diminish the need for renal replacement therapy. Between January and November 2013, 12 patients received a SynCardia TAH. Two patients with dialysisdependent end-stage renal failure due to diabetic nephropathy were excluded from the study (Table 1). One patient Table 1
was on continuous veno-venous hemodiafiltration due to acute renal failure. We started with low-dose BNP infusion therapy (0.005 mg/kg/min), without any loop diuretics, in the operating theater right after the native ventricles were excised. After the first 48 hours, therapy was gradually tapered. NT-pro-BNP levels and glomerular filtration rate were measured during the procedure, namely before initiation of extracorporeal circulation and immediately after excision of the native ventricles and subsequently on a daily basis in the ward (Table 2). Immediately after ventriculectomy and at 24 hours urine output was stable (p ¼ 0.2 and p ¼ 0.16, respectively) and increased in all patients, including the patient on preoperative renal replacement therapy, significantly at 48 hours (p ¼ 0.01) and at 7 days (p ¼ 0.08). Glomerular filtration rate remained stable throughout the BNP infusion therapy and at 7 days (post-ventriculectomy: p ¼ 0.4; 24 hours: p ¼ 0.4; 48 hours: p ¼ 0.15; 7 days: p ¼ 0.33). Compared with pre-procedural levels, NT-pro-BNP levels decreased significantly after excision of the ventricles (p ¼ 0.04), at 24 hours (p ¼ 0.02), at 48 hours (p ¼ 0.01) and at 7 days (p ¼ 0.01). Only 1 patient had to be treated temporarily with continuous veno-venous hemodiafiltration, due to acute renal failure caused by late tamponade and low output of the artificial ventricles at Day 9 post-operatively. In the further course renal function recovered fully. We observed no adverse effect of therapy on fluid management and, consequently, filling volumes and output of the artificial ventricles (Table 3). Although the two massive infarction patients could be easily weaned from BNP infusion therapy at 72 hours, the duration of therapy was longer in the remaining 8 patients
Patients’ Demographics
Patient no.
Age (years)
Gender
Underlying disease
INTERMACS profile
Intention to treat
Pre-operative need for dialysis
1 2 3 4 5 6 7 8 9 10
71 59 67 74 62 67 66 64 41 40
M M M M M M M M M M
DCM DCM ICM Amyloidosis Amyloidosis DCM DCM Massive infarction Massive infarction DCM
2 2 2 2 2 2 2 1 1 2
BTT BTT BTT DT BTT BTT BTT BTT BTT BTT
No No No No No No Yes No No No
BTT, bridge to transplant; DCM, dilated cardiomyopathy; DT, destination therapy; ICM, ischemic cardiomyopathy; M, male.
1053-2498$ - see front matter r 2014 International Society for Heart and Lung Transplantation. All rights reserved. http://dx.doi.org/10.1016/j.healun.2014.03.001
The Journal of Heart and Lung Transplantation, Vol ], No ], Month ]]]]
2 Table 2
Variables Examined
Variable 2
GFR (ml/min/1.73 m )
Preventriculectomy
Postventriculectomya 24 hours
45.5 (13–60)
48.2(23.5–60) p ¼ 0.4 2,150 (600–2,500)a p ¼ 0.2 1,307 (82–7,640) p ¼ 0.04
Urine output (ml/24 h) 2,255 (500– (ml/procedure) 2,380) NT-pro-BNP (pg/ml)
3,393 (1,030– 14,366)
48 hours
7 days
30 days
44.2 (6.9–60) p ¼ 0.4 2,355 (1,000– 3,340) p ¼ 0.16 1,025 (59–6333)
41 (22.9–60) p ¼ 0.15 2,860 (2,070– 3,280) p ¼ 0.01 732 (51–4,178)
43 (33–60) p ¼ 0.33 2550 (1,900– 2,400) p ¼ 0.08 555 (41–1,623)
60 (42.4–60) p ¼ 0.01 2,300 (2,100– 2,800) p ¼ 0.09 550 (46–1,500)
p ¼ 0.02
p ¼ 0.01
p ¼ 0.01
p ¼ 0.01
Data expressed as median (range). Statistical comparison by 2-tailed t-test. GFR, glomerular filtration rate. a Post-ventriculectomy results resemble intra-operative measurements.
Table 3
Duration and Cumulative Dose of Recombinant BNP, Filling Volumes and Output of Artificial Ventricles
Patient Underlying no. disease 1 2 3 4 5 6 7 8 9 10
DCM DCM ICM Amyloidosis Amyloidosis DCM DCM Massive infarction Massive infarction DCM
Duration of BNP infusion Cumulative BNP dose therapy (mg) (days)
Intravenous furosemide mean Filling volume Filling volume Output of left Output of right ventricle daily doses ventricle of right of left equivalents (mg) (liters/min) ventricle (ml) ventricle (ml) (liters/min)
3 5 7 5 5 5 6 3
4.5 7.5 10.5 7.5 7.5 7.5 9 4.5
51 50.5 55 55 53 54 53 52
3
4.5
55 (52–60)
49 (46–51)
6.8 (6.0–6.9) 6.0 (5.5–6.3)
40 (40–80)
7
10.5
56 (47–58)
44 (42–46)
7.3 (6.6–7.7) 5.4 (5.1–6.0)
80 (80–120)
(50–53) (46–55) (51–61) (47–66) (48–60) (50–59) (49–56) (49–56)
44 46.5 51 50.5 49 44 47.5 47
(43–48) (42–49) (48–56) (48–61) (44–50) (44–52) (45–50) (46–50)
6.9 6.7 7.4 6.9 6.7 6.5 6.8 6.9
(6.6–7.6) (6.2–7.2) (6.9–7.8) (6.5–7.8) (6–7.6) (6.1–6.9) (6.4–7) (6.5–7)
6 6 6.9 6.4 6.3 5.8 6.1 6.3
(5.7–6.5) 80 (60–120) (5.5–6.4) 120 (80–120) (6.8–7.6) 80 (60–120) (6.1–7.3) 80 (60–120) (5.5–6.9) 60 (40–120) (5.5–6.5) 60 (40–120) (5.8–6.5) 120 (60–120) (6–6.5) 40 (40–80)
Data expressed as median (range) during BNP infusion therapy per patient. Intravenous furosemide mean daily doses equivalents for the first 7 days after BNP therapy weaning per patient.
with end-stage heart failure due to ischemic, dilated or infiltrative cardiomyopathy (5 days, range 3 to 7 days) and withdrawal of BNP therapy was more difficult. Table 3 shows intravenous furosemide mean daily dose equivalents for the first 7 days after weaning from BNP infusion therapy. At 30-day follow-up we observed a significant increase in glomerular filtration rate (p ¼ 0.01), resulting presumably from recovery of renal function under TAH therapy. Urine output remained high (p ¼ 0.09) and NT-proBNP levels low (p ¼ 0.01). In this study we examined the impact of early initiation of low-dose BNP infusion therapy on renal function and the need for renal replacement therapy in 10 consecutive TAH patients. We demonstrated that this therapy approach is both effective and safe, as we observed no relevant side effects such as severe hypotension or compromise of the output of the artificial ventricles. Although our findings are statistically significant, only a small number of subjects were studied, a limitation shared by other studies. The establishment of an international registry is urgently needed to overcome this limitation. There is also a need for a comprehensive understanding of the effective
mechanism of BNP infusion therapy on renal function, followed by adoption of a set of general recommendations for TAH patients.
Disclosure statement None of the authors has a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest to disclose.
References 1. Hall C. Essential biochemistry and physiology of (NT-pro) BNP. Eur J Heart Fail 2004;6:257-60. 2. Delgado R, Wadia Y, Kar B, et al. Role of B-type natriuretic peptide and effect of nesiritide after total cardiac replacement with the AbioCor total artificial heart. J Heart Lung Transplant 2005;24:1166-70. 3. Shah KB, Tang DG, Kasirajan V, et al. Impact of low-dose B-type natriuretic peptide infusion on urine output after total artificial heart implantation. J Heart Lung Transplant 2012;31:670-2. 4. Sarraf M, Masoumi A, Schrier RW. Cardiorenal syndrome in acute decompensated heart failure. Clin J Am Soc Nephrol 2009;4:2013-6.
RESEARCH CORRESPONDENCE B-type natriuretic peptide therapy in total artificial heart implantation: Renal effects with early initiation Sotirios Spiliopoulos, MD, Dilek Guersoy, MD, Reiner Koerfer, MD, and Gero Tenderich, MD From the Heart and Vascular Center Duisburg, Department for the Surgical Therapy of End-stage, Heart Failure and Mechanical Circulatory Support, Duisburg, Germany
B-type natriuretic peptide (BNP) is produced mainly by ventricular myocytes and to a lesser degree by cardiac fibroblasts.1 In the context of end-stage heart failure, chronic myocyte stretch upregulates BNP and intracellular cyclic GMP synthesis, thus inducing vasodilation, diuresis and inhibition of the renin–aldosterone system. In the case of total artificial heart (TAH) implantation, resection of the native ventricles results in a rapid decrease of endogenous BNP production and interruption of these signaling pathways. Consequently, renal function declines.2 Low-dose BNP infusions have been proven to have a positive impact on urine output in the early post-operative setting.3 However, due to the lack of large-study experience, optimal timing of BNP therapy is still unclear. Because prevalence of chronic renal failure in TAH candidates is high,4 we hypothesized that early initiation of low-dose BNP infusion therapy in all patients would help avoid low urine output events3 and diminish the need for renal replacement therapy. Between January and November 2013, 12 patients received a SynCardia TAH. Two patients with dialysisdependent end-stage renal failure due to diabetic nephropathy were excluded from the study (Table 1). One patient Table 1
was on continuous veno-venous hemodiafiltration due to acute renal failure. We started with low-dose BNP infusion therapy (0.005 mg/kg/min), without any loop diuretics, in the operating theater right after the native ventricles were excised. After the first 48 hours, therapy was gradually tapered. NT-pro-BNP levels and glomerular filtration rate were measured during the procedure, namely before initiation of extracorporeal circulation and immediately after excision of the native ventricles and subsequently on a daily basis in the ward (Table 2). Immediately after ventriculectomy and at 24 hours urine output was stable (p ¼ 0.2 and p ¼ 0.16, respectively) and increased in all patients, including the patient on preoperative renal replacement therapy, significantly at 48 hours (p ¼ 0.01) and at 7 days (p ¼ 0.08). Glomerular filtration rate remained stable throughout the BNP infusion therapy and at 7 days (post-ventriculectomy: p ¼ 0.4; 24 hours: p ¼ 0.4; 48 hours: p ¼ 0.15; 7 days: p ¼ 0.33). Compared with pre-procedural levels, NT-pro-BNP levels decreased significantly after excision of the ventricles (p ¼ 0.04), at 24 hours (p ¼ 0.02), at 48 hours (p ¼ 0.01) and at 7 days (p ¼ 0.01). Only 1 patient had to be treated temporarily with continuous veno-venous hemodiafiltration, due to acute renal failure caused by late tamponade and low output of the artificial ventricles at Day 9 post-operatively. In the further course renal function recovered fully. We observed no adverse effect of therapy on fluid management and, consequently, filling volumes and output of the artificial ventricles (Table 3). Although the two massive infarction patients could be easily weaned from BNP infusion therapy at 72 hours, the duration of therapy was longer in the remaining 8 patients
Patients’ Demographics
Patient no.
Age (years)
Gender
Underlying disease
INTERMACS profile
Intention to treat
Pre-operative need for dialysis
1 2 3 4 5 6 7 8 9 10
71 59 67 74 62 67 66 64 41 40
M M M M M M M M M M
DCM DCM ICM Amyloidosis Amyloidosis DCM DCM Massive infarction Massive infarction DCM
2 2 2 2 2 2 2 1 1 2
BTT BTT BTT DT BTT BTT BTT BTT BTT BTT
No No No No No No Yes No No No
BTT, bridge to transplant; DCM, dilated cardiomyopathy; DT, destination therapy; ICM, ischemic cardiomyopathy; M, male.
1053-2498$ - see front matter r 2014 International Society for Heart and Lung Transplantation. All rights reserved. http://dx.doi.org/10.1016/j.healun.2014.03.001
The Journal of Heart and Lung Transplantation, Vol ], No ], Month ]]]]
2 Table 2
Variables Examined
Variable 2
GFR (ml/min/1.73 m )
Preventriculectomy
Postventriculectomya 24 hours
45.5 (13–60)
48.2(23.5–60) p ¼ 0.4 2,150 (600–2,500)a p ¼ 0.2 1,307 (82–7,640) p ¼ 0.04
Urine output (ml/24 h) 2,255 (500– (ml/procedure) 2,380) NT-pro-BNP (pg/ml)
3,393 (1,030– 14,366)
48 hours
7 days
30 days
44.2 (6.9–60) p ¼ 0.4 2,355 (1,000– 3,340) p ¼ 0.16 1,025 (59–6333)
41 (22.9–60) p ¼ 0.15 2,860 (2,070– 3,280) p ¼ 0.01 732 (51–4,178)
43 (33–60) p ¼ 0.33 2550 (1,900– 2,400) p ¼ 0.08 555 (41–1,623)
60 (42.4–60) p ¼ 0.01 2,300 (2,100– 2,800) p ¼ 0.09 550 (46–1,500)
p ¼ 0.02
p ¼ 0.01
p ¼ 0.01
p ¼ 0.01
Data expressed as median (range). Statistical comparison by 2-tailed t-test. GFR, glomerular filtration rate. a Post-ventriculectomy results resemble intra-operative measurements.
Table 3
Duration and Cumulative Dose of Recombinant BNP, Filling Volumes and Output of Artificial Ventricles
Patient Underlying no. disease 1 2 3 4 5 6 7 8 9 10
DCM DCM ICM Amyloidosis Amyloidosis DCM DCM Massive infarction Massive infarction DCM
Duration of BNP infusion Cumulative BNP dose therapy (mg) (days)
Intravenous furosemide mean Filling volume Filling volume Output of left Output of right ventricle daily doses ventricle of right of left equivalents (mg) (liters/min) ventricle (ml) ventricle (ml) (liters/min)
3 5 7 5 5 5 6 3
4.5 7.5 10.5 7.5 7.5 7.5 9 4.5
51 50.5 55 55 53 54 53 52
3
4.5
55 (52–60)
49 (46–51)
6.8 (6.0–6.9) 6.0 (5.5–6.3)
40 (40–80)
7
10.5
56 (47–58)
44 (42–46)
7.3 (6.6–7.7) 5.4 (5.1–6.0)
80 (80–120)
(50–53) (46–55) (51–61) (47–66) (48–60) (50–59) (49–56) (49–56)
44 46.5 51 50.5 49 44 47.5 47
(43–48) (42–49) (48–56) (48–61) (44–50) (44–52) (45–50) (46–50)
6.9 6.7 7.4 6.9 6.7 6.5 6.8 6.9
(6.6–7.6) (6.2–7.2) (6.9–7.8) (6.5–7.8) (6–7.6) (6.1–6.9) (6.4–7) (6.5–7)
6 6 6.9 6.4 6.3 5.8 6.1 6.3
(5.7–6.5) 80 (60–120) (5.5–6.4) 120 (80–120) (6.8–7.6) 80 (60–120) (6.1–7.3) 80 (60–120) (5.5–6.9) 60 (40–120) (5.5–6.5) 60 (40–120) (5.8–6.5) 120 (60–120) (6–6.5) 40 (40–80)
Data expressed as median (range) during BNP infusion therapy per patient. Intravenous furosemide mean daily doses equivalents for the first 7 days after BNP therapy weaning per patient.
with end-stage heart failure due to ischemic, dilated or infiltrative cardiomyopathy (5 days, range 3 to 7 days) and withdrawal of BNP therapy was more difficult. Table 3 shows intravenous furosemide mean daily dose equivalents for the first 7 days after weaning from BNP infusion therapy. At 30-day follow-up we observed a significant increase in glomerular filtration rate (p ¼ 0.01), resulting presumably from recovery of renal function under TAH therapy. Urine output remained high (p ¼ 0.09) and NT-proBNP levels low (p ¼ 0.01). In this study we examined the impact of early initiation of low-dose BNP infusion therapy on renal function and the need for renal replacement therapy in 10 consecutive TAH patients. We demonstrated that this therapy approach is both effective and safe, as we observed no relevant side effects such as severe hypotension or compromise of the output of the artificial ventricles. Although our findings are statistically significant, only a small number of subjects were studied, a limitation shared by other studies. The establishment of an international registry is urgently needed to overcome this limitation. There is also a need for a comprehensive understanding of the effective
mechanism of BNP infusion therapy on renal function, followed by adoption of a set of general recommendations for TAH patients.
Disclosure statement None of the authors has a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest to disclose.
References 1. Hall C. Essential biochemistry and physiology of (NT-pro) BNP. Eur J Heart Fail 2004;6:257-60. 2. Delgado R, Wadia Y, Kar B, et al. Role of B-type natriuretic peptide and effect of nesiritide after total cardiac replacement with the AbioCor total artificial heart. J Heart Lung Transplant 2005;24:1166-70. 3. Shah KB, Tang DG, Kasirajan V, et al. Impact of low-dose B-type natriuretic peptide infusion on urine output after total artificial heart implantation. J Heart Lung Transplant 2012;31:670-2. 4. Sarraf M, Masoumi A, Schrier RW. Cardiorenal syndrome in acute decompensated heart failure. Clin J Am Soc Nephrol 2009;4:2013-6.
