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Ann Thorac Surg 1997;63:993-997
© 1997 The Society of Thoracic Surgeons

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Original Article: Cardiovascular

Addition of a Thiazide: An Effective Remedy for Furosemide Resistance After Cardiac Operations

Departments of Cardiothoracic Surgery and Cardiology, Linköping Heart Center, University Hospital, Linköping, Sweden

Accepted for publication October 23, 1996.

	Abstract

Top Footnotes Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
Background. The frequent use of diuretic drugs in cardiac surgical practice contrasts with the lack of documentation regarding diuretic treatment in this setting. The aims of this study were to delineate the need for diuretic drugs in adult cardiac surgical practice and to evaluate the impact of adding a combination of 50 mg hydrochlorothiazide and 5 mg amiloride orally to patients responding poorly to furosemide.

Methods. Two hundred ten consecutive patients, 159 undergoing coronary artery bypass grafting procedures and 51 having valve operations, were studied.

Results. Seventy-seven patients received large doses of furosemide (80 mg/24 h) at some time during the postoperative course, and of these 20 responded poorly to furosemide (weight loss 0.3 ± 0.2 kg) despite considerable fluid retention. The addition of hydrochlorothiazide and amiloride provided a prompt and effective remedy to relative furosemide resistance. Average weight loss was 2.3 ± 0.2 kg (p < 0.01 compared with response to furosemide) and average diuresis was 2,949 ± 156 mL in the following 24 hours.

Conclusions. Relative furosemide resistance is common after cardiac operations. Thiazides, although they are mild diuretic agents, may serve as useful adjuncts in this setting.

	Introduction

Top Footnotes Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
Diuretic drugs, furosemide in particular, are among the most commonly used pharmacologic agents in cardiac surgical practice. The trend in recent years, at least in Scandinavia, has been to use low doses of furosemide in the early postoperative phase. However, it has been our impression that many patients require high doses of furosemide later in the postoperative course, and sometimes respond poorly to this measure. In cardiologic practice, the development of furosemide resistance is well documented [1–4]. Moreover, the addition of thiazides may resolve furosemide-resistant edema in these patients [1–7]. Review of the literature, however, revealed an unexpected lack of documentation regarding the use of diuretic drugs in cardiac surgical practice.

The aims of this study were to delineate the use of diuretic drugs in adult cardiac operations at our institution, to assess the frequency of relative furosemide resistance, and to evaluate the impact of adding a combination of 50 mg of hydrochlorothiazide and 5 of mg amiloride (HT+A) to patients responding poorly to furosemide.

	Patients and Methods

Top Footnotes Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
Two hundred ten consecutive patients, with 159 undergoing coronary artery bypass grafting procedures and 51 having valve operations, valves, were studied. Demographic data are presented in Table 1.

Diuresis and weight were recorded according to routine practice by the staff, who were unaware of the ongoing study or the treatment given. Other clinical indices and laboratory tests were also recorded according to standard routines. Data were retrieved retrospectively from the records.

The study was approved by the Ethical Committee for Medical Research at the University Hospital in Linköping. Because the patients were treated according to standard routines, informed consent was not considered necessary.

Study Groups
The control group included 133 of 210 patients who responded adequately to low or ordinary doses of oral furosemide (highest total dose/24 h <80 mg) during the postoperative course. The F80 group comprised 57 of 77 patients who received a furosemide dose of 80 mg or more orally over 24 hours at some time during the postoperative course and responded adequately. The results presented reflect the impact of the first 80-mg dose given in each patient. The HT+A group consisted of 20 patients who responded poorly to 80 mg of furosemide and therefore received the combination of 50 mg of hydrochlorothiazide and 5 mg of amiloride in addition to 80 mg of furosemide the following day. The data presented reflect the impact of the first HT+A dose given.

Statistical Methods
For comparisons between groups, we used analysis of variance, including post hoc comparisons with the Tukey honestly significant difference test (continuous data) and ² analyses (categoric data). When observations from only two groups were available for comparison, we used Student's t test and ² analyses. Significance was defined as p less than 0.05. Data are presented as mean ± standard error of the mean.

For evaluation of variables predictive of furosemide resistance, univariate logistic regression was used first. Variables were tested for inclusion in a stepwise forward multivariate logistic regression model if the univariate p value was less than 0.25. Statistical analyses were performed using a computerized statistical package (Statistica 5.1; StatSoft, Inc, Tulsa, OK).

	Results

Top Footnotes Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
Detailed results are presented in Tables 1 to 4 and Figures 1 and 2. Additional data and the main findings are presented briefly as follows.

View larger version (34K): [in this window] [in a new window]   Fig 1. . Diuretic requirements in 210 adult patients after cardiac operations illustrated by the highest total dose of furosemide in milligrams (intravenous and oral doses included) given over 24 hours at some time during the postoperative course. (80/HT+A = number of patients who in addition to furosemide 80 mg required 50 mg hydrochlorothiazide and 5 mg amiloride.)

View larger version (13K): [in this window] [in a new window]   Fig 2. . Average change in weight postoperatively in the hydrochlorothiazide plus amiloride (HT+A) group after furosemide 80 mg orally (F80) and the addition of 50 mg hydrochlorothiazide and 5 mg amiloride to furosemide. Because weight was not recorded in the intensive care unit, the weight curve does not give a representative picture of the change in weight during the early postoperative course. Statistically significant change compared with previous observation: *p < 0.05; **p < 0.01.

Weight
In the HT+A group, there was no significant weight loss (-0.3 ± 0.2 kg) in the following 24-hour period after the administration of furosemide at 80 mg or more orally (see Table 2). Excess weight before the addition of HT+A was 3.3 ± 0.2 kg (see Fig 2). The average weight loss after HT+A was 2.3 ± 0.2 kg in the following 24 hours (p < 0.001 compared with weight loss after previous furosemide dose). Seven patients received a further dose of HT+A and lost another 2.4 ± 0.3 kg on average.

Diuresis
In the F80 group, the average diuresis was 2,254 ± 115 mL (n = 46) in the following 24 hours after F80 administration. In the HT+A group, the average diuresis was 2,950 ± 156 mL (n = 16; p < 0.01 compared with the F80 group) in the following 24 hours after HT+A administration.

Potassium
The patients in the F80 group were given potassium chloride 2.6 ± 0.3 g together with their first F80 dose. Serum potassium level remained unchanged after F80 administration (4.1 ± 0.1 versus 4.1 ± 0.1 mmol/L). The patients in the HT+A group were given 3.8 ± 0.4 g of potassium chloride along with HT+A and furosemide. Serum potassium level increased from 4.0 ± 0.1 to 4.4 ± 0.1 mmol/L (p < 0.001) after HT+A was given. Potassium data were not retrieved from the records for the control group.

Sodium
The level of serum Na⁺ decreased from 142.5 ± 0.9 to 139.2 ± 1.2 mmol/L (n = 15; p < 0.05) after HT+A administration. Sodium data were not retrieved from the records for the other groups.

S-Creatinine
There were no preoperative differences in serum creatinine level between the groups (see Tables 1, 2). A significant increase in serum creatinine level from 105 ± 4 to 123 ± 9 µmol/L (p < 0.05) was observed postoperatively in the F80 group before the administration of F80. The administration of F80 or HT+A was not associated with a change in serum creatinine level.

Preoperative Data
The HT+A group and the F80 group contained significantly more patients with compromised left ventricular function than in the control group (see Table 1). In the HT+A group, the average age was also significantly higher and there were more patients with diabetes mellitus than in the control group.

Perioperative and Postoperative Data
The need for blood transfusions and the incidence of postoperative acute renal failure and perioperative myocardial infarction were significantly greater in the HT+A group and the F80 group than in the control group (see Table 2). The proportion of valve procedures and the duration of cardiopulmonary bypass were significantly greater in the F80 group than in the control group. Hospital stay was significantly longer in the HT+A group compared with both the F80 and the control group.

Predictors of Furosemide Resistance
Univariate and multivariate logistic regression analyses were performed to identify predictors of furosemide resistance (see Tables 3, 4). Because this is not a clear condition and overlap existed between the F80 group and the HT+A group regarding responsiveness to furosemide, 3 patients from the F80 group who required furosemide doses exceeding 250 mg/d were also included in the furosemide-resistant group (n = 23). In the multivariate model, all variables with a univariate p value less than 0.25 were tested for inclusion in the model in a forward stepwise fashion. The final model included the following variables, in order: degree of fluid retention (maximal postoperative weight excess), postoperative renal failure, preoperative compromise of left ventricular function (ejection fraction 0.35), perioperative myocardial infarction, unstable angina, and postoperative atrial fibrillation (see Table 4).

	Comment

Top Footnotes Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
The frequent use of diuretic drugs in the daily management of patients after cardiac operations contrasts with the lack of documentation regarding diuretic treatment in this setting. In Scandinavia, there has been a change toward the use of lower doses of furosemide in the early postoperative course. Today, individual intravenous furosemide doses larger than 2.5 to 5 mg are rarely used during the first postoperative day at our institution. In the present study, however, many patients required higher doses of furosemide later in the postoperative course (see Fig 1). Moreover, because of inadequate responses to furosemide, almost 10% of the patients overall displayed considerable fluid retention as late as the fifth postoperative day on average.

The drugs were administered orally; therefore, impaired intestinal absorption and bioavailability must be considered as a cause of furosemide resistance. Intestinal edema may reduce furosemide uptake, and differences in bioavailability among diuretic drugs have been reported [9]. However, intestinal absorption of hydrochlorothiazide is affected more than that of furosemide in patients with advanced heart failure [10]. Because the patients in the present study responded to HT+A, impaired intestinal absorption as a major cause of furosemide resistance is unlikely.

The single most important predictor of furosemide resistance was the degree of fluid retention. Postoperative renal impairment and factors associated with impaired hemodynamic indices were also predictive of furosemide resistance. These observations agree with experience from cardiologic practice, in which congestive heart failure and renal dysfunction have been identified as major causes of furosemide resistance [4, 9]. There were no preoperative differences in renal function. Thus, it is conceivable that peri- or postoperative impairment of renal function contributed to the reduced sensitivity to furosemide.

In the present study, the addition of HT+A provided an effective remedy for relative furosemide resistance in all patients (see Fig 2). It may be argued that time, as opposed to a change in regimen, was responsible for the improvement. If so, the third arm of the study, involving the addition of amiloride alone as an adjunct for patients fulfilling the criteria for HT+A, could have been studied. In contrast, the importance of providing a reliable diuretic treatment for these patients was emphasized as 2 of them demonstrated signs of pulmonary edema that required urgent treatment with intravenous furosemide and oral HT+A. Furthermore, the first HT+A dose was added on the fifth postoperative day on average, and as late as the tenth postoperative day in 1 patient. Thus, several patients received repeated doses of furosemide without responding before the addition of HT+A.

The additive diuretic effect of thiazides, particularly metolazone, in furosemide-resistant edema has been documented in cardiologic practice [1–7]. The synergistic effect of thiazides with furosemide is explained by the different sites of action, thereby providing sequential nephron blockade [9]. Although metolazone has received the greatest attention with respect to this phenomenon, other thiazides have been reported to be equally effective [1].

The induction of a pronounced diuresis may raise concern regarding adverse effects such as hypovolemia, arrhythmias, and electrolyte disturbances. These apprehensions were not justified. None of the patients showed clinical signs of hypovolemia after HT+A treatment. On the contrary, treatment of hypervolemia may have contributed to a beneficial effect on atrial rhythm. Although atrial fibrillation developed at some time during the postoperative course in 65% of the patients in the HT+A group, only 1 patient of 20 experienced atrial fibrillation during the remaining hospital stay after HT+A treatment. Preventive measures such as the choice of a thiazide-amiloride combination and the routine administration of potassium chloride (median dose, 4 g) prevented hypokalemia. In fact, there was an increase of serum potassium, suggesting that a lower dosage of potassium would have sufficed.

True furosemide resistance is rare even in cardiologic practice [3, 4]. Relative furosemide resistance or an inadequate response to furosemide usually can be overcome by increasing the dose. However, the required dose of furosemide may be difficult to predict, and intravenous administration may be necessary. Therefore, and because of its simplicity and reliability, we believe that one should take advantage of the synergistic effect of adding a thiazide. More important, because fluid retention aggravates many physiologic dysfunctions after cardiac operations, a prompt diuretic response facilitates the postoperative course. Considering the number of patients who could benefit from this simple measure, it may contribute to cost containment.

In conclusion, various degrees of furosemide resistance are common after adult cardiac operations. In the present study, the addition of HT+A provided a simple and effective remedy for furosemide resistance. Thus, thiazides, although they are considered mild diuretic agents, may serve as useful adjuncts for diuretic therapy after cardiac operations.

	Acknowledgments

Top Footnotes Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
We gratefully acknowledge Tomas Larsson, Institution for Mathematics, Linköping University, for statistical assistance.

	Footnotes

Top Footnotes Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
Address reprint requests to Dr Svedjeholm, Department of Cardiothoracic Surgery, University Hospital, S-581 85 Linköping, Sweden.

	References

Top Footnotes Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 

1. Channer KS, McLean KA, Lawson-Matthew P, Richardson M. Combination diuretic treatment in severe heart failure: a randomised controlled trial. Br Heart J 1994;71:146–50.[Abstract/Free Full Text]
2. Kiyingi A, Field MJ, Pawsey CC, Yiannikas J, Lawrence JR, Arter WJ. Metolazone in treatment of severe refractory congestive cardiac failure. Lancet 1990;335:29–31.[Medline]
3. Epstein M, Lepp BA, Hoffman DS, Levinson R. Potentiation of furosemide by metolazone in refractory edema. Curr Ther Res 1977;21:656–67.
4. Asscher AW. Treatment of frusemide resistant oedema with metolazone. Clin Trials J 1974;4:134–9.
5. Ghose RR, Gupta SK. Synergistic action of metolazone with "loop" diuretics. BMJ 1981;282:281–2.
6. Channer KS, Richardson M, Crook R, Jones JV. Thiazides with loop diuretics for severe congestive heart failure. Lancet 1990;335:922–3.
7. Gunstone RF, Wing AJ, Shani HGP, Njemo D, Sabuka EMW. Clinical experience with metolazone in fifty-two African patients: synergy with frusemide. Postgrad Med J 1971;47:789–93.[Abstract/Free Full Text]
8. Andersson LG, Ekroth R, Bratteby LE, Hallhagen S, Wesslén Ö. Acute renal failure after coronary surgery-a study of incidence and risk factors in 2009 consecutive patients. Thorac Cardiovasc Surg 1993;41:237–41.[Medline]
9. Puschett JB. Clinical pharmacologic implications in diuretic selection. Am J Cardiol 1986;57:6A–13A.[Medline]
10. Beermann B. Thiazides and loop diuretics therapeutic aspects. Acta Med Scand Suppl 1986;707:75–8.[Medline]

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