nitrate as first line monotherapy for pulmonary oedema
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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
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