Nitrate as First Line Monotherapy for Pulmonary Oedema

1. Nitrate as First Line Monotherapy for
Pulmonary Oedema
EVIDENCE BASED GUIDELINES
Dr. Anwer G Almosewi

2. Definition:
• Leakage of fluid from the pulmonary
capillaries and venules into the alveolar
space as a result of increased hydrostatic
pressure
PULMONARY EDEMA

3. Cardiogenic Oedema

In congestive cardiac failure, oedema occurs
as a result of an increase in the pulmonary
venous pressure.

4. Non-Cardiogenic Oedema

In non-cardiogenic oedema, there is usually minimal elevation
of pulmonary capillary pressure, except in volume overload due
to oliguric renal failure.

altered alveolar-capillary membrane permeability, : (ARDS),

lymphatic insufficiency: lung transplant or lymphangitic
carcinomatosis.

diminished plasma oncotic pressure in hypoalbuminemic
states :

Negativity of interstitial pressure following the rapid removal of
pneumothorax.

Unknownmechanisms : narcotic overdose, high-altitude or
neurogenic pulmonary oedema.

5. PATHOPHYSIOLOGY

1. increased preload

2. increased afterload

3. decreased LV function

6. GOALS OF TREATMENT

1. decrease preload

2. decrease afterload

3. improve LV function

7. Note

More than 50% of patients with cardiogenic
pulmonary edema are euvolemic.

Treatment should be based not necessarily on
fluid removal, but on fluid redistribution.

8. PRELOAD REDUCTION

Traditional treatment

Morphine

• Furosemide

Nitrates

9. FUROSEMIDE

Preload reduction

• Diuresis

" increased afterload causes decreased RBF

" delayed effect: 30 – 120 minutes

• Direct vasoactivity

" venodilation — little evidence

10. FUROSEMIDE

In most patients, diuresis does not occur for at
least 20-90 minutes; therefore, the effect is
delayed.

Diminished renal perfusion in CPE may delay
the onset of effects of loop diuretics

11. FUROSEMIDE

Francis, et al (Ann Intern Med, 1985)

Early adverse hemodynamic effects " 20
minutes after administration
─ significant increase in HR, SVR (afterload)
─ significant decrease in SV

Gradual return to baseline with diuresis

12. FUROSEMIDE

! Kraus, et al (Chest, 1990)

• Effects of IV furosemide on PCWP over 1
hour in patients receiving nitrates and/or
captopril

Furosemide alone or furosemide plus nitrates
" increase in PCWP over initial 15 minutes " then
decrease PCWP with diuresis

If premedicated with nitrates plus captopril
" immediate and sustained decrease PCWP

13. American College of Emergency
Physicians (ACEP) recomendations

Level B recommendations. Treat patients with
moderate- to-severe pulmonary edema
resulting from acute heart failure with
furosemide in combination with nitrate therapy.

Level C recommendations. Aggressive diuretic
monotherapy is unlikely to prevent the need for
endotracheal intubation compared with aggressive nitrate
monotherapy.

Diuretics should be administered judiciously, given the
potential association between diuretics, worsening renal
function

14. FUROSEMIDE

Nelson, et al (Eur Heart J, 1983)

• IV furosemide (1 mg/kg) administration in AMI
patients with LV failure

Initial adverse hemodynamic effects
" decreases in CO and SV during initial 90
minutes

• Parameters returned to baseline over next

60 – 90 minutes

15. FUROSEMIDE

Invasive hemodynamic monitoring During the
next 1 to 2 hours, the patients receiving lasix
experienced worsening hemodynamics,
including increased SVR, increased left
ventricular filling pressures, and a decrease in
stroke volume

Other Class II and III studies have similarly
reported improved hemodynamics after nitrate
administration and transiently worsening
hemodynamics for 1 to 2 hours after treatment
with furosemide

16. FUROSEMIDE

Class III study : Butler J et al.
Am Heart J. 2004 : demonstrated
an association between diuretic
use and worsening renal function.

several recent studies have identified an association
between impaired renal function and increased mortality
among acute heart failure syndrome patients

. ADHERE: JAMA. 2005: 60,000 patients:mortality is greater than
20% , Krumholz et al J Card Fail. 2003 : 1,681 patients : mortality 3
times

17. SUMMARY — FUROSEMIDE

Decreases preload through diuresis
Delayed effect

No consistent data regarding immediate direct
preload reducing effect

Initial adverse hemodynamic effects
- Increased SVR
- Decreased SV, CO

18. CONCLUSION - FUROSEMIDE

Furosemide should be considered a third-line
medication in the treatment of cardiogenic
pulmonary edema!

19. MORPHINE

Advantages

Histamine effect causes decrease in preload

Anxiolysis may decrease catecholamines
" decrease afterload

20. MORPHINE

Disadvantages

• Side-effects may increase catecholamines
" rash/urticaria from histamine release
" nausea/vomiting

Respiratory depression with high doses

Concerns if patient has low blood pressure
" myocardial depressant

Limited evidence (none?) to support direct
hemodynamic benefits

21. MORPHINE

Timmis, et al, (Br Med J, 1980)


15 and 45 minutes after injection, BP, HR, and
CI decreased

No decrease in preload

22. MORPHINE

Hoffman, et al (Chest, 1987

46% objective deterioration

No patients receiving NTG without morphine
had deterioration

23. MORPHINE

Peacock WF, et al (Emerg Med J, 2008)

Morphine vs. no morphine for acute
decompensated heart failure

independent predictor of mortality (OR 4.84)

" increased need for mechanical ventilation,
ICU admission, prolonged hospitalization

24. MORPHINE

Anxiolysis

Decrease in catecholamines, afterload

Why not use a benzodiazepine???

" no concerns with rash/urticaria

" no concerns with nausea/vomiting

" no concerns with respiratory depression

" no concerns with hypotension

25. SUMMARY — MORPHINE

Preload reduction

Nitrates are superior

Anxiolysis

Side-effect profile favors benzodiazepines

26. CONCLUSION — MORPHINE
Morphine has no role in the treatment
of cardiogenic pulmonary edema!

27. NITROGLYCERIN

Nitroglycerin vs. furosemide for preload
reduction

Cotter, et al (Lancet, 1998)

Beltrame, et al (J Card Fail, 1998)

Kraus, et al (Chest, 1990)

Hoffman, et al (Chest, 1987)

Nelson, et al (Lancet, 1983)

28. NITROGLYCERIN

Advantages

Rapid, reliable preload reduction

Moderate/high doses reduce SVR (afterload)

" maintains or improves SV and CO

Multiple forms of administration — topical, SL,
IV (be aggressive!)

Short half-life; especially important if
prehospital misdiagnosis

29. NITROGLYCERIN

Caution in the presence of…

Hypotension

Acute mitral regurgitation

Aortic stenosis

Pulmonary hypertension

Patients taking sildenafil

30. NITROGLYCERIN

Cotter et al,Lancet. 1998 : 104 patients with
severe, acute heart failure high-dose nitrates
with low-dose furosemide was a more effective
than low-dose nitrate and high-dose
furosemide

. The combined endpoint of hospital death,
myocardial infarction within 24 hours, and
intubation within 12 hours was significantly
lower in the high-dose nitrate group (25%
versus 46%
- Intubation: (13% versus 40%)

31. American College of Emergency
Physicians (ACEP) recomendations

Level B recommendations. Administer
intravenous nitra therapy to patients with acute
heart failure syndromes and associated
dyspnea.

32. SUMMARY - NITROGLYCERIN

Better than morphine or furosemide for
preload reduction

Safer than morphine or furosemide in
prehospital setting
SL nitroglycerin provides rapid and effective
initiation of treatment

Followed by topical NTG if moderate CPE

Followed by IV NTG if severe CPE

33. CONCLUSION -NITROGLYCERIN

Nitroglycerin should be first-line
prehospital and emergency
department treatment for moderate
CHF and pulmonary edema.

34. Nesiritide
Human BNP that decreases PCWP, pulmonary
artery pressure, RA pressure, and systemic
vascular resistance while increasing the cardiac
index and stroke volume index.

35. Nesiritide
Therapy with nesiritide has decreased plasma
renin, aldosterone, norepinephrine, and
endothelin-1 levels and has reduced ventricular
ectopy and ventricular tachycardia

36. Nesiritide

. Investigators compared IV nesiritide with IV
NTG. IV nesiritide was associated with some
hypotension but was otherwise well tolerated

Analysis, which included 5 randomized trials,
showed that patients who received nesiritide
were more likely than others to have significant
renal failure..

37. Nesiritide

increased mortality in the IV nesiritide group
compared with the patients receiving IV NTG,
although the difference was not statically
significant
A Meta-analysis of 3 randomized trials of 485 patients
receiving nesiritide and 377 patients not receiving
nesiritide showed a 7.2% 30-day mortality with nesiritide
versus 4% without nesiritide.

38. AFTERLOAD REDUCTION

Results in increased CO, restores renal blood
flow

Nitroglycerin

excellent single agent for simultaneous
preload and afterload reduction

Nitroprusside " acute mitral regurgitation,
severe hypertension

Hydralazine

ACE-inhibitors…for acute CPE

39. ACE-INHIBITORS

Barnett, et al (Curr Ther Res, 1991)

25 mg SL captopril if BP > 110

12.5 mg SL captopril if BP < 110

Decreased PCWP (preload) noted by 10
minutes

No change in HR, MAP

abrupt increase in diuresis without the use of a diuretic! (due to
improved renal blood flow)

40. ACE-INHIBITORS

! Varriale, et al (Clin Cardiol, 1993)

• Hemodynamic response to 1.25 mg IV
enalaprilat in patients with severe CHF and
severe MR
• Increased CO and SV
• Decreased MAP and SVR (afterload)
• Decreased PCWP (preload)
• Decreased the magnitude of MR

41. ACE-INHIBITORS

Langes, et al (Curr Ther Res, 1993)

IV captopril infusion in moderate CHF or
pulmonary edema patients

• Onset of action by 6 minutes

Decreased PCWP (preload)

Increased CO

No adverse effects

42. ACE-INHIBITORS

SL captopril

• Hamilton, et al (Acad Emerg Med, 1996)

• Haude, et al (Int J Cardiol, 1990)

IV enalaprilat

• Tohmo H, et al (Eur Heart J, 1994)

• Annane, et al (Circulation, 1996)

Dialysis patients with pulmonary edema

• Sacchetti A, et al (Am J Emerg Med, 1993)

SL and IV forms: hemodynamic and subjective

improvement can be seen in 6 – 12 minutes!!

43. ACE-INHIBITORS

Southall JC, et al (Acad Emerg Med, 2004)

Safety of ED use of SL captopril in NYHA
Class IV patients

" no increased incidence of hypotension or
need forvasopressors

" decreased ICU length of stay (29 hrs vs. 78
hrs.)

44. 
Level C recommendations.
. Angiotensin-converting enzyme (ACE) inhibitors
may be used in the initial management of acute
heart failuresyndromes, although patients must
be monitored for first dose hypotension.

45. SUMMARY - ACE-INHIBITORS

Rapid reduction in afterload and preload

Rapid reduction in level of distress

Decreased need for intubation, ICU use

Combination with NTG exceeds benefit of
either drug alone

Acceptable alternative to IV NTG

46. CONCLUSION - ACE-INHIBITORS
ACE-inhibitors should be considered
second-line agents for moderate CHF
or pulmonary edema; first-line in
patients unable to tolerate nitrates.

47. INOTROPIC SUPPORT

Choices

Catecholamines
" dopamine
" dobutamine

Phosphodiesterase inhibitors (milrinone)

IABP (bridging device before PTCA/CABG)

48. CATECHOLAMINES

Drawbacks

Tachycardia/arrhythmias

Increased MO2 consumption, ischemia

• Myocardial beta-receptors up-regulated in
severe CHF, tolerance develops
─ standard doses are less effective
─ higher doses needed, more adverse effects

Chronic beta-blocker use decreases efficacy

49. PHOSPHODIESTERASE INHIBITORS
MILRINONE

Work independent of adrenoreceptor activity
and plasma CA levels

Work well even in patients on beta-blockers

Induce inotropic support as well as decreased

preload and afterload

No development of tolerance

But…no mortality benefit vs. dobutamine

50. NONINVASIVE POSITIVE
PRESSURE VENTILATION

Maintains positive airway pressure during
entire respiratory cycle

Maintains patency of stiff fluid-filled alveoli,
prevents collapse during exhalation

Increases intrathoracic pressure " decreases
preload and afterload (and increases CO)

51. SUMMARY — NPPV

Noninvasive positive pressure ventilation is
associated with:

Decreased work of breathing
• Improved O2 and CO2 exchange
• Improved preload, afterload, and CO
• Reduced need for intubation, ICU
• Reduced mortality

52. CONCLUSION — NPPV
NPPV is an effective method of providing airway
support and averting intubation in some
patients (but it must be used early!!)

53. Level of evidences of Management
The Royal Melbourne Hospital 2005
Level of evidence General Management
IV Sit Patient Up
IV Maximal Oxygen
II Nitrates
III Diuresis
IV Morphine
II Inotropic

54. Guidelines of The Royal Melbourne
Hospital 2005

Initial management of APO should include sub-
lingual or topical glyceryl trinitrate provided that
the systolic blood-pressure is greater than or
equal to 90mmHg.

In high-dependency environments intravenous
nitrates can be commenced at 10-20mcg /min
and titrated to patients clinical response.

55. SUMMARY

Nitroglycerin — first-line agent
- IV nitroglycerin is excellent single-agent

ACE-inhibitors — second-line agent
- In addition to or instead of nitroglycerin

Furosemide — third-line agent
- After preload and afterload reduction

56. SUMMARY

Morphine — “no role”
• Preload reduction — NTG more effective
• Anxiolysis — BZDs have fewer side effects

Nesiritide
• May prove useful for patients not responding to
“optimal treatment” pending more studies

57. SUMMARY

Inotropic support
- No data favors any specific agent…
- Use what you are comfortable with!
- NPPV — consider early use

Decreased intubations, ICU length of stay, and
hospital costs