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European Journal of Heart Failure 2005 7(5):888-891; doi:10.1016/j.ejheart.2004.12.012
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© 2005 European Society of Cardiology

Hypotension is associated with diuretic resistance in severe chronic heart failure, independent of renal function

C.G. De Pasqualea,*, J.S. Dunnea, R.B. Minsona and L.F. Arnoldab

a Cardiac Services, Flinders Medical Centre Flinders Drive, Bedford Park, 5042, South Australia, Australia
b Cardiology Department, Royal Perth Hospital Wellington St, Perth, 6000, Western Australia, Australia

* Corresponding author. Tel.: +61 8 8204 5511; fax: +61 8 8204 5450. E-mial address: carmine.depasquale{at}fmc.sa.gov.au


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: Diuretic resistance and systemic hypotension are common in chronic heart failure (CHF), however, the two have not been associated.

Aims: Since blood pressure (BP) might be an important determinant of sodium excretion, we searched for an association between BP and diuretic dosage in severe CHF.

Methods: Our heart failure database was retrospectively reviewed for patients with severe left ventricular systolic dysfunction. The 54-patient cohort was divided on the basis of frusemide dosage (high-dose ≥250 mg daily, n=26).

Results: Patients taking high-dose frusemide had higher serum creatinine, and lower systolic and diastolic BP. On logistic regression analysis, increased serum creatinine and reduced diastolic BP were independent predictors of the use of high-dose frusemide. Grouping these variables into tertiles, the odds ratio for the use of high-dose frusemide was 4.0 as diastolic BP decreased (p<0.01), and 6.8 as serum creatinine increased (p<0.001).

Conclusions: We have found an association between hypotension and the use of high-dose frusemide in severe CHF, which is independent of renal function, and which may be an important physiologic mechanism of diuretic resistance in severe CHF.

Key Words: Heart failure • Diuretic resistance • Blood pressure • Frusemide

Received July 11, 2003; Revised May 31, 2004; Accepted December 8, 2004


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Loop diuretics are important for the pharmacological management of advanced chronic heart failure (CHF), by opposing maladaptive, compensatory, renal sodium and water retention, they ameliorate symptoms of vascular congestion and edema [1–3].

However, the use of diuretics in CHF is frequently complicated by diuretic resistance [2]. In CHF this phenomenon results from the interplay of several different mechanisms including; altered pharmacokinetics through reduced drug absorption [4], and reduced drug delivery to its site of action secondary to reduced renal blood flow and reduced drug tubular absorption, due to competition with accumulated organic anions [4]. Finally, there are physiologic mechanisms of diuretic resistance in CHF. The "braking phenomenon" refers to avid tubular re-absorption of sodium in the post-diuretic phase [5], and occurs even in normal subjects [2]. A more powerful physiological compensatory mechanism in CHF is distal tubular compensation [3,6]. A potential physiologic mechanism of diuretic resistance, which has been largely overlooked, is "renal-body fluid" feedback.

The renal-body fluid feedback response was initially described by Guyton and co-workers [7] and refers to the ability of the kidneys to respond to changes in arterial pressure by altering renal excretion of salt and water (Fig. 1) [8,9]. In the setting of systemic arterial hypotension, the kidney responds by increasing salt and water retention, thereby increasing extracellular fluid volume and returning blood pressure to normal [10]. Systemic arterial hypotension is common in CHF due to the disease or its treatment including frusemide.


Figure 1
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  		Fig. 1 The renal-body fluid feedback response.

 
To explore the hypothesis that hypotension in CHF contributes to diuretic resistance through the renal-body fluid feedback response, we searched for an association between blood pressure and the use of high-dose loop diuretic in a cohort of patients with severe CHF.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Data collection
The Flinders Medical Centre Heart Failure Clinic Database maintains data on all patients seen in the clinic. The data set represents all patients seen through the heart failure clinic over a 5-year period. After each clinic visit, data is drawn from the clinical record and the database updated.

The Flinders Medical Centre is a 400 bed tertiary level teaching hospital in Adelaide, South Australia. It serves the Southern region of Adelaide which covers a population of approximately 350000. The heart failure clinic and database was set up in 1997, initially by one cardiologist (two since 1999). The heart failure clinic is largely a quaternary referral clinic where difficult heart failure cases are sent, patients are seen more frequently in the heart failure clinic than might be the case in a general cardiology clinic and have the benefit of access to a heart failure nurse. At the time of this study, there were 160 patients on the database (living or deceased). Our retrospective database review identified 54 patients who fitted the specified inclusion criteria of severe LV dysfunction on echocardiography. It is likely that eligible patients were excluded because of lack of documentation of echocardiographic left ventricular function, however, large numbers of patients were excluded due to less severe LV systolic dysfunction or preserved LV systolic function CHF.

2.2. Analysis
The database was retrospectively reviewed and all patients with severe left ventricular (LV) dysfunction on echocardiography were included. The cohort was then divided into two groups on the basis of loop diuretic (frusemide) dosage (high-dose was defined as ≥250 mg/day). The following data was recorded: age, weight, blood pressure in the supine position, ejection fraction (EF), New York Heart Association (NYHA) functional classification and serum creatinine, where dynamic parameters were recorded over several clinic visits, the results were averaged (e.g. blood pressure). We recorded the dichotomous variables of mortality, presence of diabetes or peripheral vascular disease and the use of cardiac medications. Creatinine clearance was calculated using the Cockroft and Gault formula [11].

2.3. Statistical analysis
Statistical analysis was performed using SPSS 10.0 for Windows. Continuous variables were tested for normality using Kolmogrov–Sminov test. Systolic blood pressure and serum creatinine were not normally distributed, while age, diastolic blood pressure and EF were normally distributed. Differences between the groups were tested using the Mann–Whitney U-test for ordinal and non-normally distributed continuous variables, the Student's t-test for normally distributed continuous variables, and Fisher's Exact test for dichotomous variables. Correlations were performed using Spearman's test and logistic regression analysis was used to determine which parameters independently predicted the use of high-dose frusemide. Statistical significance was defined as p<0.05, and results are presented as mean±S.E.M.

The investigation conforms with the principles outlined in the Declaration of Helsinki.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
Of the 54 CHF patients in the cohort, 26 were taking high-dose frusemide (≥250 mg/day), these patients were older and had a higher 5-year mortality rate, despite having similar functional limitations to the control group (Table 1).


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  		Table 1 Cohort characteristics

 
Serum creatinine was elevated in the high-dose frusemide group, and creatinine clearance was reduced (Fig. 2). Both systolic and diastolic blood pressures were lower in the high-dose frusemide group compared to controls (Fig. 3). There was no difference in cardiac medication use between the two groups (Table 2).


Figure 2
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  		Fig. 2 Differences in renal function between groups. Data are mean±S.E.M. n=26 severe chronic heart failure patients taking high-dose oral frusemide (≥250 mg/day) and n=28 severe chronic heart failure patients who were not on high-dose frusemide (controls). (a) Serum creatinine was elevated in the high-dose frusemide group compared to controls, 0.186±0.02 versus 0.104±0.01 mmol/L, *p<0.001. (b) Creatinine clearance was reduced in the high-dose frusemide group compared to controls, 40±6 versus 82±9 ml/min, *p<0.001.

 


Figure 3
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  		Fig. 3 Differences in blood pressure between groups. Data are as for Fig. 2. (a) Systolic blood pressure was reduced in the high-dose frusemide group compared to controls, 113±3 versus 124±4 mm Hg, *p<0.05. (b) Diastolic blood pressure was reduced in the high-dose frusemide group compared to controls, 77±1 versus 68±2 mm Hg, {dagger}p<0.001.

 


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  		Table 2 Cohort pharmacotherapy

 
There was no relationship between blood pressure and markers of renal function (serum creatinine or creatinine clearance) in the high-dose frusemide group. However, on logistic regression analysis increased serum creatinine (B=1.917, SE=0.55) and reduced diastolic BP (B=–1.395, SE=0.51) were independent predictors of the need for high-dose frusemide, p<0.001, p<0.01 respectively. After grouping, these two variables into tertiles, the odds ratio for the use of high-dose frusemide was 4.0 (95% CI 1.5–10.9) as diastolic BP decreased (p<0.01) and 6.8 (2.3–19.8) as creatinine increased (p<0.001).


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
In the setting of advanced CHF, the need for high-dose frusemide often combined with thiazide diuretics (diuretic resistance) is associated with systemic hypotension. We speculate that this relationship may reflect the renal-body fluid feedback response, which encourages renal sodium and water retention in the setting of systemic arterial hypotension and may therefore be an important contributor to diuretic resistance in advanced CHF.

Our cohort of CHF patients was characterised by similar objective evidence of severe left ventricular dysfunction. The subjects were then divided on the basis of their need for chronic high-dose frusemide. Given that the major aim of diuretic use in CHF is symptom relief [1], the similar NYHA functional classification of both groups confirms the presence of diuretic resistance in the high-dose group, where more loop diuretic was required to achieve the same level of symptom control. Furthermore, although lack of documented central hemodynamics makes certainty of central filling pressures impossible, overuse of diuretic leading to hypovolaemia and consequent hypotension and renal impairment is unlikely given the similar symptomatic state of patients in both groups and their management in a specialized heart failure clinic setting.

The most striking difference between the two groups of CHF patients was in their renal function. This result was predictable as renal impairment will reduce the effectiveness of loop diuretics through pharmacokinetic alterations in peak drug concentrations at the site of action on the luminal side of the loop of Henle [4]. The cause of renal impairment in the high-dose frusemide group was not a focus of this study, however, the higher prevalence of diabetes mellitus and older age is likely to have been contributory.

The other variable that was found to differ significantly between the two groups was blood pressure (systolic and diastolic). An effect of hypotension on renal sodium excretion and diuretic resistance has not been clearly documented in CHF, however the renal-body fluid feedback response provides a theoretical reason for a relationship between the two.

The renal-body fluid feedback response describes the innate action of the kidney in maintaining optimal arterial blood pressure through alterations in salt and water handling [7]. In the setting of hypotension (which in evolutionary terms is catastrophic as it would usually result from hypovolaemia; dehydration or hemorrhage), the kidney will avidly reabsorb sodium and water to increase intravascular volume and therefore blood pressure. The specific mechanisms responsible for the renal-body fluid feedback response remain unresolved [10,12], although associations with changes in renal interstitial fluid pressure, peritubular physical forces, changes in medullary blood flow [11] and extrarenal mechanisms have been suggested [12,13]. These extra renal systems include the sympathetic nervous system and natriuretic peptide system, but most importantly the renin–angiotensin–aldosterone system [10]. It follows that the situation in CHF is particularly complex as several of these modulating mechanisms are already activated by the hemodynamics of CHF and variably suppressed by CHF medications, making isolation of the role of the renal-body fluid feedback response difficult. Indeed, studies in experimental heart failure in dogs reveal a blunted renal-body fluid feedback response to hypotension, which is due to increased atrial natriuretic peptide in this setting [14].

This observational study supports the concept that resistant sodium and water retention in severe CHF may be due in part to hypotension and the renal-body fluid response. Consequently, temporary reduction of vasodilating medication may be worth considering as a means of potentiating sodium and water loss in the setting of resistant fluid retention.

This study has significant limitations; it is a retrospective database study. Although the numbers are small, the results are consistent with the primary hypothesis and support a prospective study of the effect of blood pressure on diuretic resistance in severe CHF. Such a study should ideally include hemodynamic data allowing documentation of the size of intra and extravascular fluid spaces, vascular resistance and cardiac filling pressures.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

  1. S.A. Hunt, et al. ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult (2002).
  2. Bristow M.R., Port J.D., Kelly R.A. Treatment of heart failure: pharmacological methods. In: Heart disease. A textbook in cardiovascular medicine—Braunwald E., ed. (2001) 6th edition. Philadelphia: WB Saunders Co. 562–592. Chap. 18.
  3. Cody R.J., Kubo S.H., Pickworth K.K. Diuretic treatment for the sodium retention of congestive heart failure. Arch. Int. Med. (1994) 154:1905–1914.[Abstract/Free Full Text]
  4. Kramer B.K., Schweda F., Riegger G.A. Diuretic treatment and diuretic resistance in heart failure. Am. J. Med. (1999) 106:90–96.[CrossRef][Web of Science][Medline]
  5. Brater D.C. Clinical pharmacology of loop diuretics. Drugs (1991) 41(Suppl. 3):14–22.[CrossRef][Medline]
  6. Loon N.R., Wilcox C.S., Unwin R.J. Mechanism of impaired natriuretic response to furosemide during prolonged therapy. Kidney Int. (1989) 36:682–689.[Web of Science][Medline]
  7. Guyton A.C., Coleman T.G., Cowley A.V. Jr., Scheel K.W., Manning R.D. Jr, Norman R.A. Jr. Arterial pressure regulation. Overriding dominance of the kidneys in long-term regulation and in hypertension. Am. J. Med. (1972) 52:584–594.[CrossRef][Web of Science][Medline]
  8. Cowley A.W. Jr., Roman R.J. The role of the kidney in hypertension. JAMA (1996) 275:1581–1589.[Abstract/Free Full Text]
  9. Omvik P., Tarazi R.C., Bravo E.L. Regulation of sodium balance in hypertension. Hypertension (1980) 2:515–523.[Free Full Text]
  10. Hall J.E., Guyton A.C., Coleman T.G., Mizelle H.L., Woods L.L. Regulation of arterial pressure: role of pressure natriuresis and diuresis. Fed. Proc. (1986) 45:2897–2903.[Web of Science][Medline]
  11. Cockroft D.W., Gault M.H. Prediction of creatinine clearance from serum creatinine. Nephron (1976) 16:31–41.[Web of Science][Medline]
  12. Navar L.G. The kidney in blood pressure regulation and development of hypertension. Med. Clin. North Am. (1997) 81:1165–1198.[CrossRef][Web of Science][Medline]
  13. Guyton A.C. Arterial pressure and hypertension. (1980) Philadelphia: Saunders.
  14. Lohmeier T.E., Mizelle H.L., Reinhart G.A. Role of atrial natriuretic peptide in long-term volume homeostasis. Clin. Exp. Pharmacol. Physiol. (1995) 22:55–61.[Web of Science][Medline]

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