1. EVIDENCE IN THE ED AMOS SHEMESH, MD, PGY-III MARCH 2014 LMNOP in ADHF: Should Lasix Stay in the Acronym?

2. Diuretics and ADHF Mainstay for the treatment for the past four decades Data on dosing strategies is lacking A few studies have examined the potential toxicities May have a number of adverse effects on patients with HF, including direct activation of RAAS, increased ADH, increased norepi levels, decreased GFR, increased SVR, and electrolyte disturbances. Acute isn’t the same as chronic

3. The Guidelines Evaluation and management of patients with ADHF: Heart Failure Society of America 2010 comprehensive heart failure practice guideline LOE = C It is recommended that patients admitted with ADHF and evidence of fluid overload be treated initially with loop diuretics—usually given intravenously rather than orally. Careful observation for development of side effects, including renal dysfunction, electrolyte abnormalities, symptomatic hypotension, and gout is recommended in patients treated with diuretics, especially when used at high doses and in combination. When congestion fails to improve in response to diuretic therapy, the following options should be considered  Re-evaluating presence/absence of congestion  Sodium and fluid restriction  Increasing doses of loop diuretic  Continuous infusion of a loop diuretic  Addition of a second type of diuretic  Another option, ultrafiltration, may be considered

5. Question Are loop diuretics clinically indicated and beneficial in patients who present with acute cardiogenic pulmonary edema?

6. Articles Hoffman JR, Reynolds S. Comparison of nitroglycerin, morphine and furosemide in treatment of presumed pre-hospital pulmonary edema. Chest 1987; 92: 586-93. Cotter G, Metzkor E, Kaluski E, et al. Randomized trial of high-dose isosorbide dinitrate plus low-dose furosemide versus high-dose furosemide plus low- dose isosorbide dinitrate in severe pulmonary oedema. Lancet 1998; 351:389-93.

7. Articles Hoffman JR, Reynolds S. Comparison of nitroglycerin, morphine and furosemide in treatment of presumed pre-hospital pulmonary edema. Chest 1987; 92: 586-93. Cotter G, Metzkor E, Kaluski E, et al. Randomized trial of high-dose isosorbide dinitrate plus low-dose furosemide versus high-dose furosemide plus low- dose isosorbide dinitrate in severe pulmonary oedema. Lancet 1998; 351:389-93.

8. Hoffman, et al - Methods Prospective non-randomized sequential prehospital trial evaluating various combinations of therapy for presumed pre-hospital cardiogenic pulmonary edema in LA county Study patients got 1 of 4 therapeutic regimens Compared NTG, furosemide, morphine in 57 presumed pulmonary edema patients (Best outcome with NTG)

9. Nitro+Lasix Morphine+Lasix Nitro+ Morphine+ Lasix Nitro+Morphine

10. Nitro+Lasix Morphine+Lasix Nitro+ Morphine+ Lasix Nitro+Morphine Group B pts were 27x more likely to worsen than group A patients by odds ratio testing, and 17.9x more likely to worsen than all groups combined.

11. Nitro+Lasix Morphine+Lasix Nitro+ Morphine+ Lasix Nitro+Morphine Group A pts were 13x more likely to improve than group B patients, and any patient who got nitro (A,B,D) was 6.5 times more likely to improve than those who didn’t.

12. Nitro+Lasix Morphine+Lasix Nitro+ Morphine+ Lasix Nitro+Morphine No significant differences in objective response to therapy between the groups of patients who received Lasix (A, B, and C) compared to the group that didn’t (D)

13. Hoffman, et al –Results Fluid/Electrolyte complications in the first 24h were related primarily to Lasix. Arrhythmias with hypokalemia in 3 pts Fluid repletion needed in 13 pts for hypotension/tachycardia The one group D patient (did not get lasix in the field) who developed hypotension to an SBP of 80 did so after getting 70mg lasix in the ED

14. Hoffman, et al - Conclusions 23% of patients were misdiagnosed, didn’t have pulmonary edema Furosemide may have caused adverse effects with fluid and electrolyte management in some patients Patients in nitro group had no adverse effects Findings are more dramatic for morphine than furosemide. However, >25% who received lasix in the field later required fluid repletion, and several developed important adverse consequences, including severe volume-related hypotension (three). “May be no apparent therapeutic advantage to early use of furosemide” Use caution:  Small study (N=57), multiple treatment arms  Comparing groups with drug combos is not the same as comparing the drugs  Didn’t validate the final diagnoses of hospital physicians  It’s a pre-hospital treatment study… from 1987.

15. Articles Hoffman JR, Reynolds S. Comparison of nitroglycerin, morphine and furosemide in treatment of presumed pre- hospital pulmonary edema. Chest 1987; 92: 586-93. Cotter G, Metzkor E, Kaluski E, et al. Randomized trial of high-dose isosorbide dinitrate plus low-dose furosemide versus high- dose furosemide plus low-dose isosorbide dinitrate in severe pulmonary oedema. Lancet 1998; 351:389-93.

16. Cotter, et al - Methods Pts recruited 1996-1997 from EMS in Israel EMT-P & MD screened for si/sx of cardiogenic pulmonary edema CXR confirmed, Sats <90% All get oxygen, lasix 40mg, morphine 3mg Then Randomized Group A: 3mg nitrate q5 min+40mg lasix Group B: 80mg lasix q15min+nitrate 1mg/h increased by 1 mg/h q10 min Continue until sats >96%, MAP<90 or decreases by 30%. 8x more nitrate 4x more lasix

17. Cotter, et al - Results Mechanical ventilation was required in 7 (13%) patients in the nitrate group and 21 (40%) in the furosemide group (P=0.0041). MI occurred in 9 (17%) and 10 (37%) patients (P=0.047), respectively. Composite end-point (i.e. one or more of the 3 main outcome measures) was recorded in 13 (25%) from group A, and 24 (46%) in group B. Secondary outcome of O2 sats were significantly better in group A than group B.

18. Cotter, et al - Results Intubation and MI occurred in significantly fewer patients in nitrate group than in lasix group Nitrate group more effective than lasix group in controlling severe pulmonary edema Use caution:  Small study  Combination regimens  Lasix dosing in this study was pretty high – mean doses were 56mg (SD 28) and 200mg (65), respectively.  Ideal dosing of lasix remains to be determined

19. National Registry of >100K pts– 89% got IV diuretics Stratified into low 160mg groups according to cumulative dose of IV lasix in first 24h High dose group had a significantly greater decline in renal function, a longer length of stay, and a higher in-hospital mortality rate (OR 0.87; 95% CI 0.78-0.97, P=0.1)

20. HUPism Loop diuretics are a Level C recommendation in ADHF and are appropriate to use, though high doses early in management of acute cardiogenic pulmonary edema may be harmful or lead to further complications. … and maybe consider holding off on diuretics in patients with ADHF and worsening renal function

21. Lasix and Decreased Cardiac Output Braunwald and colleagues demonstrated an average fall in CO of 20% following diuresis inpatients with impaired cardiac function both at rest and during exercise. Nelson and coworkers compared the hemodynamic effects of IV lasix (1mg/kg) with that of IV isosorbide dinitrate (50-200 ug/kg/min) in pts with LV failure following MI. The PAOP fell in both groups, but the CO was maintained in the nitrate group, whereas it fell by about 10% in the furosemide group. Hutton and colleagues compared the effects of IV lasix (0.5 mg/kg) and isosorbide 5-mononitrate (15mg) at the time of cardiac cath in patients with LV dysfunction; furosemide induced acute vasoconstriction with a reduction in CO; in contrast, isosorbide 5-mononitrate maintained CO while reducing the PAOP.