Journal of Clinical Pharmacy and Therapeutics, 2015, 40, 339–341
doi: 10.1111/jcpt.12255
Case Report
Initial experience of use of tolvaptan in critically ill patients with fluid overload J. Ruiz-Ramos PharmD, M. Gordon MD, M. A. Cortes MD, M. J. Broch MD and P. Ramirez PhD MD Intensive Care Unit, Hospital Universitario y Politecnico La Fe, Valencia, Spain
Received 21 January 2015, Accepted 4 February 2015
Keywords: clinical pharmacy, drug utilisation, furosemide
without loss of other substances observed with the use of conventional diuretics. The aim of this report was to describe our initial experience in the use of tolvaptan in six septic critically ill patients with fluid overload resistant to diuretic treatment.
ABSTRACT What is known and objective: Positive volume balance is related with high mortality in critically ill patients. We describe our experience in the use of tolvaptan in patients with fluid overload. Case summary: Six patients in the recovery phase from septic shock were included. All patients achieved an increase in diuresis after the first day, with a median fluid balance variation of 2362 (485 to 3447) mL. At the end of treatment, median fluid balance variation was 9080 (26 784 to 4395) mL. What is new and Conclusion: Tolvaptan could be an option in critically ill patients with fluid overload and resistant or not treatable with conventional diuretics.
DETAILS OF THE CASE Six patients in the recovery phase from multiorgan failure due to septic shock and in anasarca state {positive accumulated fluid balance during 7 days before tolvaptan [median = 1947 (range: 906–3208) mL] and low serum albumin concentration [19 (14– 24) g/dL]} were included. Characteristics of patients receiving tolvaptan are shown in Table 1. Five patients had been treated with intravenous furosemide (dose ≥60 mg) without achieving a clinical response. Patient no 5 did not receive furosemide because of a pre-existing renal failure (IgA glomerulonephritis). Three patients (no 1, 3 and 5) received noradrenaline before and during tolvaptan treatment. Analytical control of ions and renal function parameters was performed before starting treatment with tolvaptan and daily until the end of treatment. Daily fluid balance and 24-h diuresis were quantified in each patient during treatment. Patients received a daily dose of 7.5 mg (n = 1) and 15 mg (n = 5) of tolvaptan, being necessary an increase up to 30 mg dose in two patients due to an insufficient diuretic effect. Median treatment duration was 5 days (range: 2–12). All patients presented an increase in their diuresis after the first day of treatment [median increase of 1193 (200–5045) mL], with a median fluid balance variation of 2362 [485 to 3447] mL after 24 h. At the end of treatment, median fluid balance variation was 9090 (26 784 to 4395) mL (Table 2), with consequent reduction/resolution of generalized oedema in all patients. Furosemide dose was reduced in all treated patients, and the drug was withdrawn in three patients. Median serum albumin concentration at the end of treatment was 22 [16– 27] g/dL. Tolvaptan was well tolerated by all patients. One patient developed hypernatremia after 5 days of treatment (with concomitant increase in serum creatinine value). Laboratory parameters returned to normal values 5 days after treatment discontinuation. Mild hypokalemia was observed in three patients. No other analytical alterations were observed. Four patients died during their stay in intensive care unit, all of them because of nosocomial septic complications (death occurred 5 days (range: 1–10) after tolvaptan discontinuation). This initial experience shows that tolvaptan increases urine volume and reduces volume overload in furosemide non-responders
WHAT IS KNOWN AND OBJECTIVE Early fluid therapy plays an essential role in acute resuscitation of critically ill patients,1,2 particularly those with septic shock. International guidelines recommend administration up to 30 mL/kg of crystalloids during the first three hours of septic shock management.3 This therapy, added to administration of other therapeutic fluids, is almost always associated with fluid overload. On the other hand, oncotic pressure reduction and increase of capillary permeability in critically ill patient will promote the development of generalized oedema.4 Several authors have shown that tissue oedema may contribute to a progressive organ dysfunction.5,6 In fact, different studies have found a relationship between negative fluid balance and an improvement in survival rates in critically ill patients.7,8 Conventionally, loop diuretics have been essential tools to control fluid overload in these patients.4 However, such diuretics have several drawbacks, including renal dysfunction, metabolic alkalosis and electrolyte imbalance.9,10 Tolvaptan, a vasopressin type-2 (VR2) receptor antagonist, is approved for the treatment of adult patients with hyponatraemia secondary to inappropriate antidiuretic hormone secretion syndrome (SIADH).11 However, some studies have reported good results in patients with fluid overload secondary to chronic heart failure resistant to diuretic treatment.12,13 In these patients, tolvaptan reduced body weight and relieve congestive symptoms due to excess of volume without presenting relevant adverse effects. Tolvaptan0 s aquaretic nature has opened a new possibility for the treatment of critically ill patient with fluid overload, but Correspondence: J. Ruiz-Ramos, Intensive Care Unit, Hospital Universitario y Politecnico La Fe, Fernando Abril Martorell no 106, Valencia 46026, Spain. Tel.: +34679131309; e-mail: [email protected]
© 2015 John Wiley & Sons Ltd
339
J. Ruiz-Ramos et al.
Tolvaptan in critically ill patients
Table 1. Demographic and clinical characteristics of patients
No
Age (years)
1 2 3 4 5 6
51 65 67 63 54 60
Sex
Weight (Kg)
Previous ICU LOS
APACHE II
iv Furosemide previous daily dose (mg/24 h)
M M F M M M
60 50 85 77 95 60
60 37 3 24 10 1
15 12 17 22 9 25
110 0 80 160 60 60
Previous Phosphate (mg/dL)
Previous Magnesium (mg/dL)
Previous Corrected Calcium (mg/dL)
Previous Albumin (g/dL)
18 44 42 31 50 24
15 15 22 23 17 22
93 99 91 90 93 92
19 19 17 14 20 24
ICU, intensive care unit. LOS: length of stay from the ICU admission to first day of treatment.
Table 2. Summary of data obtained from patients treated with tolvaptan
No
Tolvaptan maximum dose (mg)
1 2 3 4 5 6
30 15 15 30 15 75
Days of treatment
Diuresis 24 h before tolvaptan (mL/24)
Diuresis 24h after tolvaptan (mL/24)
7 days previous cumulative fluid balance (mL)
EOT fluid balance (mL)
Na i (mEq/L)
Na f (mEq/L)
Cr i 4(mg/dL)
Cr f (mg/dL)
10 13 5 7 3 2
2185 1190 2340 2975 3870 2910
2805 1390 4210 3865 5366 5919
+3125 +1947 +1179 +906 +3284 ND
5125 11520 4395 8296 26784 15447
144 143 144 147 130 135
142 138 159 144 132 137
016 086 087 071 049 040
024 215 073 115 058 038
EOT, end of treatment; iv, intravenous; Na i, initial sodium; Na f, sodium after treatment; Cr i, initial creatinine; Cr f, creatinine after treatment; ND, no data available.
outcome could not be evaluated as patients included presented bad conditions when tolvaptan was started.
critically ill patients. Positive volume balance has been related with higher mortality rates in critically ill patients.7 High furosemide dose cannot reverse this process in a significant number of patients, particularly in those patients at risk or with established acute kidney injury.14 Nowadays, there were not effective alternatives for these patients except for extrarenal purification methods. Vasopressin V2-receptor antagonist has been proposed in the management of hypervolemic hyponatremia in critical care patients.15 In our short experience, tolvaptan rapidly decreases fluid overload in critically ill patients, without important adverse events. The effect of fluid balance improvement in patient’s
WHAT IS NEW AND CONCLUSION According to our short experience, tolvaptan could be a new alternative in critically ill patients with positive fluid balance resistant or not treatable with conventional diuretics. Electrolytes and renal function should be daily monitored. Further studies are required to evaluate the effect of tolvaptan in short-term outcome and mortality in critically ill patients with fluid overload.
REFERENCES 1. Rivers EP, Katranji M, Jaehne KA, Brown S, Abou Dagher G, Cannon C, Coba V. Early interventions in severe sepsis and septic shock: a review of the evidence one decade later. Minerva Anestesiol, 2012;78: 712–724. 2. Lin S-M, Huang C-D, Lin H-C, Liu C-Y, Wang C-H, Kuo H-P. A modified goaldirected protocol improves clinical outcomes in intensive care unit patients with
septic shock: a randomized controlled trial. Shock, 2006;26:551–557. 3. Dellinger RP, Levy MM, Rhodes A et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med, 2013;39:165–228. 4. Bagshaw SM, Brophy PD, Cruz D, Ronco C. Fluid balance as a biomarker: impact of fluid overload on outcome in critically ill
© 2015 John Wiley & Sons Ltd
patients with acute kidney injury. Crit Care, 2008;12:169. 5. Allen SJ. Fluid therapy and outcome: balance is best. J Extra Corpor Technol, 2014;46: 28–32. 6. Mehta RL, Bouchard J. Controversies in acute kidney injury: effects of fluid overload on outcome. Contrib Nephrol, 2011;174:200–211. 7. Upadya A, Tilluckdharry L, Muralidharan V, Amoateng-Adjepong Y, Manthous CA.
Journal of Clinical Pharmacy and Therapeutics, 2015, 40, 339–341 340
J. Ruiz-Ramos et al.
Tolvaptan in critically ill patients
Fluid balance and weaning outcomes. Intensive Care Med, 2005;31:1643–1647. 8. Alsous F, Khamiees M, DeGirolamo A, Amoateng-Adjepong Y, Manthous CA. Negative fluid balance predicts survival in patients with septic shock: a retrospective pilot study. Chest, 2000;117:1749–1754. 9. Rogers NA, Gupta S, Cuthbert JA. Continuous furosemide infusion in the management of ascites. J Investig Med, 2012;60:671–675. 10. Thomsen G, Bezdjian L, Rodriguez L, Hopkins RO. Clinical outcomes of a furosemide infusion protocol in edematous patients in
the intensive care unit. Crit Care Nurse, 2012;32:25–34. 11. Samsca (Tolvaptan): Product drug information. Available at: http://www.ema.europa.eu (accessed 01 October 2014). 12. Kinugawa K, Sato N, Inomata T, Shimakawa T, Iwatake N, Mizuguchi K. Efficacy and safety of Tolvaptan in heart failure patients with volume overload. Circ J, 2014;78:844– 852. 13. Matsuzaki M, Hori M, Izumi T, Fukunami M. Efficacy and safety of tolvaptan in heart failure patients with volume overload
© 2015 John Wiley & Sons Ltd
despite the standard treatment with conventional diuretics: a phase III, randomized, double-blind, placebo-controlled study (QUEST study). Cardiovasc Drugs Ther, 2011;25:S33–S45. 14. Ho KM, Power BM. Benefits and risks of furosemide in acute kidney injury. Anaesthesia, 2010;65:283–293. 15. Friedman B, Cirulli J. Hyponatremia in critical care patients: frequency, outcome, characteristics, and treatment with the vasopressin V2-receptor antagonist tolvaptan. J Crit Care, 2013;28:219.e1–219.e12.
Journal of Clinical Pharmacy and Therapeutics, 2015, 40, 339–341 341
doi: 10.1111/jcpt.12255
Case Report
Initial experience of use of tolvaptan in critically ill patients with fluid overload J. Ruiz-Ramos PharmD, M. Gordon MD, M. A. Cortes MD, M. J. Broch MD and P. Ramirez PhD MD Intensive Care Unit, Hospital Universitario y Politecnico La Fe, Valencia, Spain
Received 21 January 2015, Accepted 4 February 2015
Keywords: clinical pharmacy, drug utilisation, furosemide
without loss of other substances observed with the use of conventional diuretics. The aim of this report was to describe our initial experience in the use of tolvaptan in six septic critically ill patients with fluid overload resistant to diuretic treatment.
ABSTRACT What is known and objective: Positive volume balance is related with high mortality in critically ill patients. We describe our experience in the use of tolvaptan in patients with fluid overload. Case summary: Six patients in the recovery phase from septic shock were included. All patients achieved an increase in diuresis after the first day, with a median fluid balance variation of 2362 (485 to 3447) mL. At the end of treatment, median fluid balance variation was 9080 (26 784 to 4395) mL. What is new and Conclusion: Tolvaptan could be an option in critically ill patients with fluid overload and resistant or not treatable with conventional diuretics.
DETAILS OF THE CASE Six patients in the recovery phase from multiorgan failure due to septic shock and in anasarca state {positive accumulated fluid balance during 7 days before tolvaptan [median = 1947 (range: 906–3208) mL] and low serum albumin concentration [19 (14– 24) g/dL]} were included. Characteristics of patients receiving tolvaptan are shown in Table 1. Five patients had been treated with intravenous furosemide (dose ≥60 mg) without achieving a clinical response. Patient no 5 did not receive furosemide because of a pre-existing renal failure (IgA glomerulonephritis). Three patients (no 1, 3 and 5) received noradrenaline before and during tolvaptan treatment. Analytical control of ions and renal function parameters was performed before starting treatment with tolvaptan and daily until the end of treatment. Daily fluid balance and 24-h diuresis were quantified in each patient during treatment. Patients received a daily dose of 7.5 mg (n = 1) and 15 mg (n = 5) of tolvaptan, being necessary an increase up to 30 mg dose in two patients due to an insufficient diuretic effect. Median treatment duration was 5 days (range: 2–12). All patients presented an increase in their diuresis after the first day of treatment [median increase of 1193 (200–5045) mL], with a median fluid balance variation of 2362 [485 to 3447] mL after 24 h. At the end of treatment, median fluid balance variation was 9090 (26 784 to 4395) mL (Table 2), with consequent reduction/resolution of generalized oedema in all patients. Furosemide dose was reduced in all treated patients, and the drug was withdrawn in three patients. Median serum albumin concentration at the end of treatment was 22 [16– 27] g/dL. Tolvaptan was well tolerated by all patients. One patient developed hypernatremia after 5 days of treatment (with concomitant increase in serum creatinine value). Laboratory parameters returned to normal values 5 days after treatment discontinuation. Mild hypokalemia was observed in three patients. No other analytical alterations were observed. Four patients died during their stay in intensive care unit, all of them because of nosocomial septic complications (death occurred 5 days (range: 1–10) after tolvaptan discontinuation). This initial experience shows that tolvaptan increases urine volume and reduces volume overload in furosemide non-responders
WHAT IS KNOWN AND OBJECTIVE Early fluid therapy plays an essential role in acute resuscitation of critically ill patients,1,2 particularly those with septic shock. International guidelines recommend administration up to 30 mL/kg of crystalloids during the first three hours of septic shock management.3 This therapy, added to administration of other therapeutic fluids, is almost always associated with fluid overload. On the other hand, oncotic pressure reduction and increase of capillary permeability in critically ill patient will promote the development of generalized oedema.4 Several authors have shown that tissue oedema may contribute to a progressive organ dysfunction.5,6 In fact, different studies have found a relationship between negative fluid balance and an improvement in survival rates in critically ill patients.7,8 Conventionally, loop diuretics have been essential tools to control fluid overload in these patients.4 However, such diuretics have several drawbacks, including renal dysfunction, metabolic alkalosis and electrolyte imbalance.9,10 Tolvaptan, a vasopressin type-2 (VR2) receptor antagonist, is approved for the treatment of adult patients with hyponatraemia secondary to inappropriate antidiuretic hormone secretion syndrome (SIADH).11 However, some studies have reported good results in patients with fluid overload secondary to chronic heart failure resistant to diuretic treatment.12,13 In these patients, tolvaptan reduced body weight and relieve congestive symptoms due to excess of volume without presenting relevant adverse effects. Tolvaptan0 s aquaretic nature has opened a new possibility for the treatment of critically ill patient with fluid overload, but Correspondence: J. Ruiz-Ramos, Intensive Care Unit, Hospital Universitario y Politecnico La Fe, Fernando Abril Martorell no 106, Valencia 46026, Spain. Tel.: +34679131309; e-mail: [email protected]
© 2015 John Wiley & Sons Ltd
339
J. Ruiz-Ramos et al.
Tolvaptan in critically ill patients
Table 1. Demographic and clinical characteristics of patients
No
Age (years)
1 2 3 4 5 6
51 65 67 63 54 60
Sex
Weight (Kg)
Previous ICU LOS
APACHE II
iv Furosemide previous daily dose (mg/24 h)
M M F M M M
60 50 85 77 95 60
60 37 3 24 10 1
15 12 17 22 9 25
110 0 80 160 60 60
Previous Phosphate (mg/dL)
Previous Magnesium (mg/dL)
Previous Corrected Calcium (mg/dL)
Previous Albumin (g/dL)
18 44 42 31 50 24
15 15 22 23 17 22
93 99 91 90 93 92
19 19 17 14 20 24
ICU, intensive care unit. LOS: length of stay from the ICU admission to first day of treatment.
Table 2. Summary of data obtained from patients treated with tolvaptan
No
Tolvaptan maximum dose (mg)
1 2 3 4 5 6
30 15 15 30 15 75
Days of treatment
Diuresis 24 h before tolvaptan (mL/24)
Diuresis 24h after tolvaptan (mL/24)
7 days previous cumulative fluid balance (mL)
EOT fluid balance (mL)
Na i (mEq/L)
Na f (mEq/L)
Cr i 4(mg/dL)
Cr f (mg/dL)
10 13 5 7 3 2
2185 1190 2340 2975 3870 2910
2805 1390 4210 3865 5366 5919
+3125 +1947 +1179 +906 +3284 ND
5125 11520 4395 8296 26784 15447
144 143 144 147 130 135
142 138 159 144 132 137
016 086 087 071 049 040
024 215 073 115 058 038
EOT, end of treatment; iv, intravenous; Na i, initial sodium; Na f, sodium after treatment; Cr i, initial creatinine; Cr f, creatinine after treatment; ND, no data available.
outcome could not be evaluated as patients included presented bad conditions when tolvaptan was started.
critically ill patients. Positive volume balance has been related with higher mortality rates in critically ill patients.7 High furosemide dose cannot reverse this process in a significant number of patients, particularly in those patients at risk or with established acute kidney injury.14 Nowadays, there were not effective alternatives for these patients except for extrarenal purification methods. Vasopressin V2-receptor antagonist has been proposed in the management of hypervolemic hyponatremia in critical care patients.15 In our short experience, tolvaptan rapidly decreases fluid overload in critically ill patients, without important adverse events. The effect of fluid balance improvement in patient’s
WHAT IS NEW AND CONCLUSION According to our short experience, tolvaptan could be a new alternative in critically ill patients with positive fluid balance resistant or not treatable with conventional diuretics. Electrolytes and renal function should be daily monitored. Further studies are required to evaluate the effect of tolvaptan in short-term outcome and mortality in critically ill patients with fluid overload.
REFERENCES 1. Rivers EP, Katranji M, Jaehne KA, Brown S, Abou Dagher G, Cannon C, Coba V. Early interventions in severe sepsis and septic shock: a review of the evidence one decade later. Minerva Anestesiol, 2012;78: 712–724. 2. Lin S-M, Huang C-D, Lin H-C, Liu C-Y, Wang C-H, Kuo H-P. A modified goaldirected protocol improves clinical outcomes in intensive care unit patients with
septic shock: a randomized controlled trial. Shock, 2006;26:551–557. 3. Dellinger RP, Levy MM, Rhodes A et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med, 2013;39:165–228. 4. Bagshaw SM, Brophy PD, Cruz D, Ronco C. Fluid balance as a biomarker: impact of fluid overload on outcome in critically ill
© 2015 John Wiley & Sons Ltd
patients with acute kidney injury. Crit Care, 2008;12:169. 5. Allen SJ. Fluid therapy and outcome: balance is best. J Extra Corpor Technol, 2014;46: 28–32. 6. Mehta RL, Bouchard J. Controversies in acute kidney injury: effects of fluid overload on outcome. Contrib Nephrol, 2011;174:200–211. 7. Upadya A, Tilluckdharry L, Muralidharan V, Amoateng-Adjepong Y, Manthous CA.
Journal of Clinical Pharmacy and Therapeutics, 2015, 40, 339–341 340
J. Ruiz-Ramos et al.
Tolvaptan in critically ill patients
Fluid balance and weaning outcomes. Intensive Care Med, 2005;31:1643–1647. 8. Alsous F, Khamiees M, DeGirolamo A, Amoateng-Adjepong Y, Manthous CA. Negative fluid balance predicts survival in patients with septic shock: a retrospective pilot study. Chest, 2000;117:1749–1754. 9. Rogers NA, Gupta S, Cuthbert JA. Continuous furosemide infusion in the management of ascites. J Investig Med, 2012;60:671–675. 10. Thomsen G, Bezdjian L, Rodriguez L, Hopkins RO. Clinical outcomes of a furosemide infusion protocol in edematous patients in
the intensive care unit. Crit Care Nurse, 2012;32:25–34. 11. Samsca (Tolvaptan): Product drug information. Available at: http://www.ema.europa.eu (accessed 01 October 2014). 12. Kinugawa K, Sato N, Inomata T, Shimakawa T, Iwatake N, Mizuguchi K. Efficacy and safety of Tolvaptan in heart failure patients with volume overload. Circ J, 2014;78:844– 852. 13. Matsuzaki M, Hori M, Izumi T, Fukunami M. Efficacy and safety of tolvaptan in heart failure patients with volume overload
© 2015 John Wiley & Sons Ltd
despite the standard treatment with conventional diuretics: a phase III, randomized, double-blind, placebo-controlled study (QUEST study). Cardiovasc Drugs Ther, 2011;25:S33–S45. 14. Ho KM, Power BM. Benefits and risks of furosemide in acute kidney injury. Anaesthesia, 2010;65:283–293. 15. Friedman B, Cirulli J. Hyponatremia in critical care patients: frequency, outcome, characteristics, and treatment with the vasopressin V2-receptor antagonist tolvaptan. J Crit Care, 2013;28:219.e1–219.e12.
Journal of Clinical Pharmacy and Therapeutics, 2015, 40, 339–341 341
