Acute Preload Effects of Furosemide

Acute Preload Effects of Furosemide Peter A. Kraus, M.B., B.Ch.;* jeffrey Lipman, M.B. , B.Ch.;* and Pieter J Becker, Ph.D.t

Acute preload effects (as re8ected by the pulmonary capillary wedge pressure [PCWP]) of an intravenous furosemide bolus were studied in 33 patients. In those patients receiving no vasoactive drug and in those receiving predominantly preload reducing agents, there was an initial rise in PCWP up until 15 minutes followed by a diuresis-induced fall in PCWP below baseline levels at 1 h. Patients who were receiving preload and significant afterload reduction showed an immediate drop in PCWP which was sustained.

This trend is independent of underlying pathology or dose of furosemide used. It is postulated that furosemide causes an early deleterious release of endogenous vasoconstrictors which may be blocked by combined preload and afterload reduction. (Chest 1990; 98:124-28)

furosemide is traditionally administered I ntravenous to patients in order to relieve pulmonary vascular

induced drop in PCWP. Nishimura and Kanbe6 also investigated the effects of intravenous furosemide following acute MI and showed a similar trend. With the above controversy in mind, we decided to study a cross-section of our intensive care unit (ICU) population in order to determine the acute PCWP effects of an intravenous bolus dose of furosemide . Furthermore, since the work by Francis et al5 had suggested that there may in fact be a deleterious neurohumoral vasoconstrictor response to furosemide usage, we studied the above effects with and without the concomitant use of vasodilator drugs.

congestion. Initially, this was thought to be due to rapid diuresis induced by the drug, thereby reducing plasma volume and hence the pulmonary capillary pressure. Biagi and Bapat 1 in 1967 were the first to suggest the possibility of extrarenal mechanisms, as they observed relief of pulmonary edema in a patient before the onset of diuresis. In 1969, Bhatia et al 2 studied seven patients suffering from high altitude pulmonary edema and similarly concluded that there was a significant reduction in pulmonary blood volume before the onset of diuresis. In 1973, Dikshit et al 3 studied renal and extrarenal hemodynamic effects of furosemide in patients in left ventricular failure (LVF) following acute myocardial infarction (MI). They documented that prior to a significant diuresis beginning at 15 minutes post-administration of intravenous furosemide there was a fall in left ventricular enddiastolic pressure as reflected by the pulmonary capillary wedge pressure (PCWP). Their results suggested that there was an earlier increase in venous capacitance either due to a direct pulmonary vascular vasodilatory effect or a peripheral venous pooling effect. Although this work had detractors from early on (Hesse et al 4 ) it remained the standard reference for the effects of intravenous furosemide in relieving pulmonary vascular congestion. However, recently Francis et al5 reported that in chronic congestive cardiac failure bolus doses of intravenous furosemide raised the PCWP initially, followed by a diuresis*Department of Anesthesia and Intensive Care Unit, Baragwanath Hospital and University of the Witwatersrand, Johannesburg, South Africa. tinstitute for Biostatistics, South African Medical Research Council. Manuscript received September 22; revision accepted January 2, 1990.

124

PCWP =pulmonary capillary wedge pressure; PAC= pulmonary artery catheter; TNT= nitroglycerine

MATERIALS AND METHODS

All patients in our ICU during a 12-month period who had had a pulmonary artery catheter (PAC) already in situ and were receiving intravenous furosemide were eligible for the study. The PAC had to be in situ for at least 6 h, there was to be no significant variation in PCWP during this period, and no furosemide was to have been given during this pretrial period . By the nature of our unit (combined medical and surgical ICU), the majority of the patients studied were in acute LVF following a MI, chronic LVF due to cardiomyopathy (CMO), or had the adult respiratory distress syndrome (ARDS). Patients were divided into three groups (with a minimum of ten patients in each group) according to whether vasodilator drugs were being used at the time of the study or not. Patients were eligible for study on more than one occasion. If patients were receiving vasodilator drugs, the dosage of these agents was not adjusted during the trial period. Group 1 consisted of patients receiving no vasodilatory drugs at all. Group 2 consisted of patients on therapy with predominant preload reduction vasodilator. They received either low-dose oral isosorbide dinitrate or low dose intravenous nitroglycerine (TNT) both of which cause predominant venodilatation and hence preload reduction.7-V Group 3 consisted of patients on preload and significant after load reducing vasodilator therapy ("mixed" vasodilator therapy). These patients received high dose TNT" or oral captopril in order to achieve the "mixed" vasodilatation. The PCWP was measured from the transduced pressure trace on a graphic screen at the end of expiration"' just prior to administration of intravenous furosemide . This was recorded as time 0. If the PCWP was 20 mm Hg or less, 20 mg furosemide was given. If the PCWP was 21 to 25 mm Hg, 40 mg of furosemide was Acute Preload Elfecls of Furosemide (Kraus, Upman, Becker)

Table 1- Furosemide Only PT Age , Sex, No,

Diagnosis

Dose Furosemide (mg)

1,53,M 2,56,F 3,51,M 4,37,F 5,55,F 6,19,F 7,19,F 8,49,M 9,19,F 10,67,M 11,23,F 12,64,M

ARDS ARDS ARDS MI PE ARDS ARDS ARDS ARDS ARDS ARDS CMO

20 20 20 20 20 20 20 20 20 40 20 20

14 18 20 18 20 15 14 19 16 21 18 20

5'

w

15 16

14 16 20 20 20 16 16 20 16 20 17 24

20

20 20 16 13 19 16 20 17 22

End-Expiratory PCWP in mm Hg (at 5 min intervals) ~

-

~

~

~

•

w

~

55'

60'

15 16 22 21 18 15 15 18 16 20 17 22

12 16 22 18 19 14 16 17 15 20 16 22

12 15 20

12 15 20 20 18 10 15 18 16 19 15

12 15 22 20 17 10 15 17 15 19 15 22

12 16 20 20 15 9 15 16 15

12 14 20 21 15 10 15 16 15

12 15 20 18 16 11 14 16 15

12 12

20

20

20

20

15

15 24

15 22

15 25

12 13 20 15 15 12 15 16 15 20 15 24

55'

60'

20 16 22 10 14 20 25 13 30 30

18 16 22 12 17 20 25 14 27 29

20

18 12 15 18 15 20 15 24

20

20

20

17 15 12 14 17 15

Table 2-Furosemide Plus Preload Reduction PT Age, Sex No,

Diagnosis

1,48,M 2,53,M 3,62,F 4,59,M 5,59,M 6,59,M 7,59,M 8,59,M 9,28,M 10,28,M

MI MI MI MI MI MI MI MI CMO CMO

Dose Furosemide (mg) 40 40 40 20 20 20

Vasoactive Drug TNT TNT I TNT TNT TNT I TNT TNT

80

20 80

80

0'

5'

23

21

24 20

23

24

15 18 17 30 19 30 27

15 20 19 30 18 30 30

End-Expiratory End PCWP mm Hg (at 5 min intervals) 10' 15' 20' 25' 30' 35' 40' 45' 50' 24 20 25 15 20 18 28 19 32 29

24

24

19 25 14 20 17 28 17 30 29

18 25 14 20 17 28 16 29 32

22 18 25 12 19 17 27 16 28 30

20 19 25 10 15 20 26 14 28 29

20

20 27 12 15 20 27 15 28 29

19 15 23 10 15 20 26 12 27 30

20 14 22 10 16 21 26 15 32 30

20

16 22 10 15 22 26 15 30 30

found by doing pairwise comparisons at the Bonferroni adjusted level of significance (0.0513=0.017), again taking into account whether the variances in the groups were equal or not.

given. If the PCWP was >25 mm Hg, 80 mg of furosemide was given. Following the administration of furosemide , the PCWP was measured every 5 minutes for the next hour by the same observer.

Statistical Methods

RESULTS

There were 12 patients in group 1 (furosemide only), ten patients in group 2 (furosemide plus preload reduction) and 11 patients in group 3 (furosemide plus preload and afterload reduction). Group 2 patients received up to a 100 J.Lg/min intravenous TNT or up

At each time and at the 0.05 level of significance, the groups were compared with respect to the mean change from baseline in a one-way analysis of variance. At those times where, according Levene's test , the variances in the groups were not equal, the Welch test was employed to compare the groups with respect to the mean change from baseline. Specific differences between the groups were

Table 3-Furosemide Plus Preload and Afterload Reduction PT Age , Sex No,

Diagnosis

1,61,F 2,53,F 3,58,M 4,46,M 5,78,F 6,18,F 7,18,F 8,66,M 9 ,59,M 10,78,F 11,50,M

MI MI MI CMO MI CMO CMO MI MI MI MI

Dose Furosemide (mg) 40 40 40 20 40 40 40 40 80

40 40

Vasoactive Drug

I, C TNT TNT

c

TNT

c c

TNT TNT TNT TNT

0'

5'

10'

21 25 23 20 21 25 25 22 27 25 22

20 25 22 20 24 20 25 18 27 27 20

22 25 18 18 21 18 22 15 27 25 17

End-Expiratory PCWP mm Hg (at 5 min intervals) 15' 20' 25' 30' 35' 40' 45' 50' 20 24

18 18 17 16 21 20 27 26 17

20 22 19 18 14 17 18 20 27 25 15

20 20 18 18 14 17 19 20 26 22 12

20 25 17 18 15 15 20 18 27 20 12

20 24 18 17 14 15 20 18 27 19 10

21 22 18 17 20 15 20 18 27 22 10

27 22 19 17 17 15 18 20 26 19 10

20 22 19 19 16 16 22 20 27 15 12

55'

60'

20 20 17 16 17

20 19 20 17 15 16

23

20

20

16 27 18 12

18 25

19 10

ARDS =adult respiratory distress syndrome; MI =myocardial infarction; PE =pulmonary embolism; CMO =cardiomyopathy; I= isosorbide dinitrate; TNT= nitroglycerine; C =captopril CHEST I 98 I 1 I JULY. 1990

125

Table 4-Mean Change in PCWP in mm Hg (5 Min Intervals)

Croup 1 Croup 2 Croup3

0'

5'

10'

15'

20'

25'

30'

35'

40'

45'

50'

55 '

60'

0 0 0

0 +0.7 -0.72

+0.5 +0.7 -2.45

+0.16 0 -2.9

-0.5 0 -3.72

-0.75 -0.9 -4 .54

-1.25 -1.0 - 4.45

-1.16 -1.7 -4 .9

-1.66 -2.6 -4.18

-1.33 -1.6 - 4. 18

-1.58 -1.5 -4 .27

-1.75 -2.3 -4 .36

-1.75 -2.2 -4.81

to 20 mg isosorbide dinitrate every 8 h. Group 3 patients received doses which were more than the above. With reference to Tables 1, 2 and 3, it should be noted that patients in group 1 were younger than those in groups 2 and 3 (average age 43 years vs 51 and 53 years). The diagnosis was usually ARDS in group 1 (MI and CMO in groups 2 and 3). The initial PCWP was lower than those in groups 2 and 3 (average 18 mm Hg vs 22 and 23 mm Hg); hence, the average dose of furosemide was less (20 mg vs 40 mg). Patients in groups 2 and 3 were similar in age, diagnosis, initial PCWP and dose of furosemide . Sex distribution in all groups was similar, except for group 3 who had a preponderance of men. Table 4 shows the mean change in PCWP from baseline in the various groups. The most notable feature on comparing these three groups is that the patients in group 3 (furosemide plus preload and afterload reduction) generally showed an immediate fall in PCWP following furosemide administration. In comparison, groups 1 and 2 patients initially showed an increase in PCWP up until 15

I

DISCUSSION

Nitrates are often used to decrease preload. Unfortunately, for a clinical study, TNT and isosorbide dinitrate are not pure preload reducing agents and especially in higher doses reduce afterload too. 7· 9 We divided the patients receiving nitrates into those with predominant preload effects (low dose, group 2) from those with both preload and afterload effects (high

•·----.• o-·-·-·0

3

......

minutes, thereafter showing a drop but not to the same degree as group 3 patients. From the appropriate one-way analysis of variance, the three groups were found to be significantly different (p<0.05) with respect to the change from baseline for the times 5 to 35 minutes. In particular, from the pairwise comparisons done at the Bonferroni adjusted level of significance groups 1 and 2 were not significantly different, but both changed significantly less than group 3. This trend is depicted in Figure 1 where the mean change in PCWP from the initial PCWP is plotted according to time post administration offurosemide.

2

Cl

Group 1 (Furosemide only) Group 2 (Furosemide + Preload) Group 3 (Furosemide+ Preload + Afte

E E

Q)

c

0

Q) Cl)

ctl .0

E 0 ....

-1

-2

Q)

Cl

c ..c

ctl

-3

()

-4 -5 0

5

10

15

20

25

30

35

40

45

50

55

60

Time (mins) FIGURE I. Mean change from baseline in pulmonary capillary wedge pressure over first hour. Croup 1: furosemide only; group 2: furosemide plus preload reduction; group 3: furosemide plus preload plus afterload reduction. Differences between groups 1 and 2 vs group 3 are statistically significant (p < O.OS) between 5 and 35 minutes (see text for more details).

126

Acute Preload Effects of Furosemide (Kraus, Lipman, Becker)

dose, group 3). This is a technically artifactual differentiation, but does have some clinical relevance. The doses of furosemide given were compatible with those used in most of the controversial literature3 ·s·6 studying its effects on hemodynamics. The design of the study was to keep as close to the normal clinical situation as possible . Larger doses have been used, but like Kiely et al 11 we prefer to use lower repeated doses to achieve a desired effect rather than running the risk of a precipitous fall in cardiac output and systemic pressure. Although group 1 patients in general had a different underlying pathology than groups 2 and 3, the change in PCWP was virtually the same as group 2 patients (Fig 1). Following administration of furosemide they showed an actual increase in PCWP up until 10 minutes, only falling below baseline levels after 15 minutes. Group 3 patients had an immediate drop in PCWP which was sustained and of greater magnitude than groups 1 and 2 (Fig 1). The causes of pulmonary congestion in groups 2 and 3 patients were similar, yet the response to furosemide of the PCWP differed significantly. Hence, we feel that our results were not influenced by the nature of the underlying pathology but by the concomitant vasodilator therapy used. 3·M Patients who received furosemide only showed an initial increase in the PCWP up until approximately 15 minutes. This is at variance with the study by Dikshit et al,3 yet is in agreement with the more recent findings of Nishimura and Kanbe6 and Francis et al.s Dikshit et al3 had shown an increase in venous capacitance to account for an early drop in PCWP, but these results were questioned by Hesse et al. • Dikshit et al3 studied 20 acute MI patients with LVF and showed that following intravenous furosemide the PCWP dropped significantly within the first 15 minutes accompanied by a significant increase in calf venous capacitance. Diuresis reached a peak at 30 minutes causing a further drop in PCWP. Hesse et al4 studied nine patients not in cardiac failure and showed that, although there was a gradual drop in PCWP, there was no change in forearm venous tone and attributed this fall purely to diuresis. In addition, he documented increased renin activity prior to this diuresis. Francis et al5 documented a similar increase in renin activity prior to diuresis in 15 patients in chronic heart failure, as well as increased noradrenaline and vasopressin levels. The resultant early vasoconstriction was their explanation for the PCWP actually going up in the first 20 minutes post-administration of furosemide . They felt that renin was released earlier due to direct mechanisms rather than later as a result of diuresis-induced plasma volume depletion. This had also been suggested by the earlier work of Hesse et al 4 and Rosenthal et al. 12 Francis et als also queried the possibility of using angiotensin-

converting enzyme (ACE) inhibitors to block this initial rise in PCWP. By giving "mixed" vasodilator therapy (high dose nitrates, ACE inhibitors) we have blocked this rise in PCWP. Nishimura and Kanbe6 studied 30 patients with acute MI and showed that following administration of furosemide the PCWP originally increased only falling below baseline after 15 minutes. Our study showed very similar results (Fig 1, groups 1 and 2). We have thus shown that by using "mixed" vasodilators (pre- and afterload reducing agents) the initial, possibly deleterious, effects of furosemide may be eliminated. Conversely, furosemide-induced release of endogenous vasoconstrictors would explain why group 1 and 2 patients had an initial rise in PCWP. The subsequent fall in PCWP in all groups can then be attributed to the diuretic effect on plasma volume. In addition, the greater overall drop in PCWP in those who have afterload reduction has been documented previously by Nelson et al.11 The fall in PCWP in all groups from approximately 15 minutes onward is universally accepted as being due to the furosemide-induced diuresis. We therefore did not see the need to document urine output over 5 min intervals during the trial period. In addition, most of the patients were not catheterized, and hence, an accurate time course for urine output could not be determined. Nevertheless, the urine output at the end of the hour showed a marked increase from the previous hourly urine outputs (not shown here) and was dose-dependent, as previously shown.6 The effects of furosemide on hemodynamics and the relief of pulmonary congestion remains contentious according to the world literature. The dose of furosemide plus the duration of the pulmonary congestion (according to underlying pathology) are often cited as the reasons for these discrepant results. We feel that our study cuts across these differences and shows that intravenous furosemide without concomitant "mixed" vasodilation increases the PCWP initially probably due to increased endogenous vasoconstricting hormones. Thereafter, there is a drop in PCWP due to a diuresis-induced drop in plasma volume. This trend is independent of underlying pathology or dose of furosemide used . In summary, our study shows that furosem ide, when given as a bolus dose , does not immediately decrease pulmonary pressures. In fact, unless "mixed" vasodilating agents are given concomitantly, there is a rise in PCWP. This would be in keeping with results of Francis et al5 and Nishimura and Kanbe. 6 Only when pre- and afterload reduction is used is there an immediate fall in PCWP. One of the reasons we undertook this study was that occasionally a patient in pulmonary edema, given furosemide, in our opinion would deteriorate clinically prior to improving. AICHEST I 98 I 1 I JULY, 1990

127

though not specifically addressed in the protocol, this could be explained by an early increase in PCWP after administration of furosemide . The increased PCWP could lead to increased interstitial water, 13 and hence, clinical deterioration. However, whether the increase we documented is clinically significant in relation to pulmonary edema, we cannot answer at this stage . If the clinician wants to prevent this rise in PCWP and cause a fall in venous pressures, before the onset of furosemide-induced diuresis, we suggest concomitant use of a "mixed" vasodilator, eg, high dose nitrates or ACE inhibitors. ACKNOWLEDGMENT; The authors wish to acknowledge Sr. J. Scribante for the pilot study of this work and Hoechst Pharmaceuticals for their financial support.

REFERENCES Biagi RW, Bapat BN. Frusemide in acute pulmonary oedema. Lancet I967; I:849 2 Bhatia ML, Singh I, Manchanda SC, Khanna PK, Roy SB. Effect of frusemide on pulmonary blood volume. Br Med J I969; 2:55I-52 3 Dikshit K, Vyden JK, Forrester JS, Chatterjee K, Prakash R, Swan HJC. Renal and extrarenal hemodynamic effects of furosemide in congestive heart failure after acute myocardial infarction. NEngl J Med I973; 288:1087-90 4 Hesse B, Nielsen I, Lund-Jacobsen H. The early effects of intravenous frusemide on central haemodynamics, venous tone

128

and plasma renin activity. Clin Sci Mol Med 1975; 49:551-55 5 Francis GS, Siegel RM, Goldsmith SR, Olivari MT, Levine TB, Cohn JN. Vasoconstrictor response to intravenous furosemide in patients with chronic congestive heart failure-Activation of the neurohumoral axis. Ann Intern Med 1985; 103:I-6 6 Nishimura N, Kanbe N. The renal and hemodynamic effects of furosemide in acute myocardial infarction. Crit Care Med 1981; 9:829-32 7 Rabinowitz B, Tamari I, Elazar E , Neufeld HN. Intravenous isosorbide dinitrate in patients with refractory pump failure and acute myocardial infarction. Circulation 1982; 65:771-78 8 Nelson GIC, Silke B, Forsyth DR, Venna SP, Hussain M, lllylor SH. Hemodynamic comparison of primary venous or arteriolar dilatation and the subsequent effect of furosemide in left ventricular failure after acute myocardial infarction. Am J Cardiol1983; 52:1036-40 9 Flaherty JT, Come PC, Baird MG, Rouleau J, Taylor DR, Weisfeldt ML, et al. Effects of intravenous nitroglycerin on left ventricular function and ST segment changes in acute myocardial infarction. Br Heart J I976; 38:612-21 IO Berryhill RE, Benumof JL, Rauscher LA. Pulmonary vascular pressure reading at the end of exhalation. Anesthesiology 1978; 49:365-68 II Kiely J, Kelly DT, lllylor DR, Pitt B. The role of furosemide in the treatment of left ventricular dysfunction associated with acute myocardial infarction. Circulation I973; 48:581-87 12 Rosenthal J, Boucher R, Nowaczynski W, Genest J. Acute changes in plasma volume, renin activity, and free aldosterone levels in healthy subjects following fursemide administration. Can J Physiol Phannacol1968; 46:85-91 I3 Staub NC. The pathogenesis of pulmonary edema. Prog Cardiovasc Dis I980; 23:53-80

Acute Pnlload Effects of Furosemide (Kraus, Upman, Becker)