Nitrate as First Line Monotherapy for Pulmonary Oedema

EVIDENCE BASED GUIDELINES

Dr. Anwer G Almosewi

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

PULMONARY EDEMA

Cardiogenic Oedema

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

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.

PATHOPHYSIOLOGY

1. increased preload 2. increased afterload 3. decreased LV function

GOALS OF TREATMENT

1. decrease preload 2. decrease afterload 3. improve LV function

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.

PRELOAD REDUCTION

Traditional treatment   Morphine • Furosemide Nitrates

FUROSEMIDE

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

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

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

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

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

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

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

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

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

CONCLUSION - FUROSEMIDE

Furosemide should be considered a third-line medication in the treatment of cardiogenic pulmonary edema!

MORPHINE

  Advantages Histamine effect causes decrease in preload Anxiolysis may decrease catecholamines

"  decrease afterload

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

MORPHINE

Timmis, et al, (Br Med J, 1980) 15 and 45 minutes after injection, BP, HR, and

CI decreased   No decrease in preload

MORPHINE

Hoffman, et al (Chest, 1987   46% objective deterioration   No patients receiving NTG without morphine

had deterioration

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

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

SUMMARY — MORPHINE

Preload reduction   Nitrates are superior   Anxiolysis   Side-effect profile favors benzodiazepines

CONCLUSION — MORPHINE

Morphine has no role in the treatment of cardiogenic pulmonary edema!

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)

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

NITROGLYCERIN

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

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%)

American College of Emergency Physicians (ACEP) recomendations Level B recommendations. Administer

intravenous nitra therapy to patients with acute heart failure syndromes and associated dyspnea.

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

CONCLUSION -NITROGLYCERIN

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

Nesiritide

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

Nesiritide

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

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..

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.

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

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)

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

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

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!!

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.)

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.

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

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.

INOTROPIC SUPPORT

Choices   Catecholamines

"  dopamine

"  dobutamine Phosphodiesterase inhibitors (milrinone) IABP (bridging device before PTCA/CABG)

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

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

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)

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

CONCLUSION — NPPV

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

Level of evidences of Management The Royal Melbourne Hospital 2005

Level of evidenceGeneral Management IVSit Patient UpIVMaximal OxygenIINitrates IIIDiuresisIVMorphineIIInotropic

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.

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

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

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