Success with Failure. Evidence-based Management of Acute Cardiogenic Pulmonary Edema. John Bosomworth, MD, CCFP, FCFP Web page:

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1 Success with Failure Evidence-based Management of Acute Cardiogenic Pulmonary Edema John Bosomworth, MD, CCFP, FCFP Web page:

2 Potential Conflicts of Interest Boussignac CPAP masks for demonstration supplied by Vitaid Ltd. without charge. Otherwise: no business affiliations, sponsorships, honoraria, monetary support or other conflict of interest.

3 Objectives and Concepts Pragmatic objectives avoidance of intubation, transport, ICU admission and death. Treatment based on evidence rather than guidelines or standard therapy. Only the ACEP guidelines are current. Treatments must be appropriate to a rural setting. Treatment must avoid harm in patients with an incorrect diagnosis.

4 Patient Subset Sickest of the acute decompensated heart failure patients. Respiratory failure secondary to pulmonary edema. Increased LV filling pressures secondary to increased afterload (hypertensive, vascular) or myocardial dysfunction (infarction, ischemia). Those presenting in cardiogenic shock and hypotension (<10%) have poor prognosis and are best managed using ACLS protocols.

5 Patient Subset Mortality 15-20% in-hospital mortality 30% overall mortality within a year 40% mortality when associated with MI 80% mortality if hypotensive on admission.

6 Patient Subset The majority of patients are dyspneic, well perfused and hypertensive. A smaller number are dyspneic and less well perfused. Some are in cardiogenic shock. Patients presenting with hypertension benefit most from clinical interventions. Patients with hypotension may require inotropes and invasive monitoring (<10%).

7 Pathophysiology Left ventricular contractility can no longer handle pulmonary venous return. Increased preload. Pulmonary hydrostatic pressure exceeds alveolar hydrostatic pressure. Sympathetic activation causes vasoconstriction and increased afterload. Preload, afterload and contractility are often all disordered by the time of ED presentation.

8 Pathophysiology Goals of treatment Decrease preload Decrease afterload Improve LV contractility If first 2 goals are met, contractility usually improves.

9 Core Topics: Treatment Topics Preload and afterload reduction. CPAP discussion and demonstration. Framework for tailored therapy. Harm reduction in case of misdiagnosis. Optional Topics: Evidence for avoiding morphine. Evidence for delay or avoidance of diuretics. Evidence for ACE inhibitors. BNP and Nesiritide. Management of low LV output and cardiogenic shock.

10 Case 1: Simone 65 year old woman, multiple cardiac risk factors Sudden SOB x 2 hr. Diaphoretic, pulse 110, resps 30, BP 180/100 Normal mental status Bilateral rales, increased JVP X-ray suggests pulmonary edema ECG sinus tachycardia On oxygen, non-rebreathing, 2 large IV s, monitored. O 2 sat 85%. What is your initial treatment? 1. Morphine 2. Lasix 3. Morphine + Lasix 4. NTG + 1 of above 5. Nesiritide (recombinant BNP) + 1 of above 6. None of the above

11 Preload & Afterload Reduction Morphine Furosemide Nitroglycerin Sublingual Captopril Noninvasive Positive Pressure Ventilation

12 Morphine Vomiting, rash and urticaria cause release of catecholamines, increasing afterload. Myocardial and respiratory depression Venodilation is peripheral, and a histaminic side effect. Benefit was extrapolated from these studies Pulmonary artery cath studies show no reduction in preload *. * Lappas DG et al. Filling pressures of the heart and pulmonary circulation of the patient with coronary artery disease after large intravenous doses of morphine. Anesthesiology 1975; 42(2): * Timmis AD et al. Haemodynamic effects of intravenous morphine in patients with acute myocardial infarction complicated by severe left ventricular failure. BMJ 1980; 280(6219):

13 Morphine The Swan studies: Lappas 1975 gave 2 mg/kg or 5 mg/min IV. Increase in preload. Reduction in cardiac index. These were very large doses given at time of coronary revascularization. In spite of the numbers, the drug was well tolerated. Timmis 1980 gave 0.2 mg/kg to infarct patients in failure. Mean dose 15 mg IV over 5 min. No reduction in preload. Cardiac index was reduced for 45 min.

14 Morphine The ADHERE Registry shows increased intubation and mortality with morphine *. Independent predictor of mortality with odds ratio 4.84 Increased need for ICU admission and intubation with use of morphine in the ED. These studies are retrospective. * Peacock WF et al. Morphine and outcomes in acute decompensated heart failure: an ADHERE analysis. Emergency Med J 2008; 25: Sacchetti et al. Effect of ED management on ICU use in acute cardiogenic pulmonary edema. Am J Emerg Med 1999; 17(6):

15 Morphine Pre-hospital studies show deterioration in symptoms and hemodynamic parameters in 50% of patients given morphine*. Adverse pre-hospital outcomes are particularly common in patients with a missed respiratory diagnosis eg. Sepsis, pneumonia, COPD exacerbation, asthma. * Hoffman JR, et al. Comparison of nitroglycerin, morphine and furosemide in treatment of presumed pre-hospital pulmonary edema. Chest 1987; 92:

16 Morphine A Nitroglycerin + Furosemide B Morphine + Furosemide C Nitroglycerin + Morphine + Furosemide D Nitroglycerin + Morphine Hoffman JR, et al. Comparison of nitroglycerin, morphine and furosemide in treatment of presumed pre-hospital pulmonary edema. Chest 1987; 92:

17 Morphine Most of the benefit probably results from anxiolysis and reduction of catecholamines, reducing afterload. Some of the benefit may come from respiratory depression reducing dyspnoea. Safer anxiolysis might be achieved with a benzodiazepine.

18 Summary for Morphine No studies have ever shown benefit Reduced symptoms due to sedation and respiratory depression. Not demonstrated to produce venodilation or reduce preload in Swan studies. Increased intubation and death rates in large retrospective studies. Poorer outcomes for pre-hospital patients, especially those with a missed respiratory diagnosis. Benzodiazepines safer for sedation to reduce sympathetic activation. Should probably not be used unless pain or palliation is an issue.

19 Furosemide Pulmonary artery catheter studies show increased preload and afterload prior to diuresis*. Preload reduction does not occur until diuresis. Diuresis safely delayed for minutes and may be preceded by clinical improvement. Prior preload and afterload reduction with NTG and captopril produces immediate diuresis. * Kraus PA, Lipman J, Becker PJ. Acute preload effects of furosemide. Chest 1990; 98:

20 Furosemide Swan studies: 1. Nelson Post MI patients in CHF. Reduced CO and stroke volume in the first 90 min after administration of furosemide due to increased vascular resistance. LV filling pressures gradually dropped. 2. Francis Patients in class 3 and 4 CHF. Increased afterload and reduced stroke volume first 20 min. improving only after onset of diuresis. Postulated to be due to activation of neurohumoral axis. 3. Kraus Furosemide alone increased PCWP until onset of diuresis avg 50 min. If treated as well with agents reducing preload and afterload (high dose nitro or captopril) there was immediate fall in PCWP and immediate diuresis.

21 Furosemide Initial increase in afterload with reduced stroke volume and cardiac output due to increased catecholamines, renin activity and vasopressin *. Renal blood flow reduced to 20% in pulmonary edema due to vasoconstriction. Vasodilators mitigate this process. * Francis GS, et al. Acute vasoconstrictor response to intravenous furosemide in patients with chronic congestive heart failure. Activation of the neurohumoral axis. Ann Int Med. 1985; 103(1): 1-6.

22 Furosemide 40-50% of patients are not volume overloaded*. Vigorous use of diuretics in volume depletion results in hypotension when vasodilators are used as first line agents. Vigorous use of diuresis often results in hypotension the following day. * Figueras J, Weil MH. Blood volume prior to and following treatment of acute cardiogenic pulmonary edema. Circulation 1978; 57(2):

23 Furosemide A Nitroglycerin + Furosemide B Morphine + Furosemide C Nitroglycerin + Morphine + Furosemide D Nitroglycerin + Morphine With prehospital use, 25% of patients required later fluid repletion. Significant hypokalemia in prehospital setting. Misdiagnosed patients with respiratory disease are already volume depleted and at risk for deterioration and death with use of diuretics. Hoffman JR, et al. Comparison of nitroglycerin, morphine and furosemide in presumed pre-hospital pulmonary edema. Chest 1987; 92(4):

24 Summary for Furosemide Renal blood flow in pulmonary edema is 20% of normal. Use vasodilators for at least 30 min. prior to administration of furosemide. Early administration of furosemide increases afterload and reduces cardiac output. Preload reduction does not occur until diuresis. Timely afterload reduction cannot occur without vasodilators % of patients with dyspnoea are volume depleted. Some have a primary respiratory diagnosis. They will get worse with furosemide. Effect accelerated by vasodilator pretreatment. Diuresis may occur with vasodilators alone. Third line after vasodilators. Use the minimum dose.

25 Nitroglycerin First line intervention along with CPAP Preload reduction with low doses Afterload reduction with high doses High-dose therapy superior to: Standard therapy (morphine and furosemide). CPAP alone High-dose furosemide All other treatments administered by pre-hospital personnel.

26 Nitroglycerin Standard dose Up to 60ug/min Preload reduction only Venodilation peaks in 2 hr at low doses Failing myocardium does not benefit as much from reduced preload as reduced afterload

27 High-Dose Nitroglycerin Doses ug/min and higher Required for afterload reduction Progressive arteriolar dilation with increasing dose. This improves cardiac output and stroke volume when L ventricular function is impaired Sublingual NTG 0.4 mg. every 5 minutes approaches this dose level

28 High-Dose Nitroglycerin 0.4 mg. SL nitroglycerine q 5 min. x 3 = 1200 ug. In 15 75% absorption = 900 ug. over 15 min. = 60 ug./min Most patients present with hypertension and tolerate this well. Commonly used in management of acute coronary syndrome.

29 High-Dose Nitroglycerin The Evidence: Cotter Compared ISDN IV 600ug/min to high dose furosemide RCT blinding not stated. 40 patients Equivalent to IV NTG 75ug/min Excluded systolic BP<110, need for immediate intubation Target O 2 sat 96% or >30% reduction BP or MAP<90 No specific measures needed for hypotension Significant reduction in MI and intubation in ISDN group No mortality reduction Cotter G, Metzkor E, Kaluski E, et al. Randomized trial of high-dose isosorbide dinitrate in severe pulmonary oedema. Lancet 1998; 351:

30 High-Dose Nitroglycerin The Evidence: Sharon Compared ISDN IV 1000ug/min with BiPAP and standard dose nitrates. RCT with 40 patients stopped for ethical reasons Equivalent to NTG 125ug/min. Excluded systolic BP<110, need for immediate intubation Target O 2 sat 96% or >30% reduction BP or systolic <110 1 case hypotension responsive to volume Significant reduction in MI and intubation in ISDN group. These patients improved more rapidly. No significant mortality reduction. Sharon A, et al. High-dose intravenous isosorbide-dinitrate is safer and better than bi-pap ventilation combined with conventional treatment for severe pulmonary edema. J Am Coll Cardiol 2000; 36(3):

31 High-Dose Nitroglycerin The Evidence: Levy Bolus and infusion IV NTG ug/min maximum 29 patients in a convenience sample with retrospective cohort All patients failed conventional therapy with systolic BP>160. Predominantly black. Excluded MI, ischemia and need for immediate intubation Target for stopping therapy systolic BP<90 1 case symptomatic hypotension Significant reduction in intubation, ICU admission, length of stay and CVS events. No mortality reduction. Levy P, et al. Treatment of severe decompensated heart failure with high-dose intravenous nitroglycerin: a feasibility and outcome analysis. Ann Emerg Med 2007; 50(2):

32 Nitroglycerin Pre-Hospital A Nitroglycerin + Furosemide B Morphine + Furosemide C Nitroglycerin + Morphine + Furosemide D Nitroglycerin + Morphine Hoffman JR, et al. Comparison of nitroglycerin, morphine and furosemide in treatment of presumed pre-hospital pulmonary edema. Chest 1987; 92:

33 Nitroglycerin Pre-Hospital Prehospital safety in misdiagnosis: Retrospective study of acute dyspnoea with prehospital treatment of 493 patients 18% rate of misdiagnosis (asthma, COPD, pneumonia) Those given only NTG had 2% mortality Those given morphine and/or furosemide had 22% mortality CHF patients misdiagnosed and given bronchodilators had no increase in mortality Wuerz RC, et al. Effects of prehospital medications on mortality and length of stay in congestive heart failure. Ann Emerg Med 1992;

34 Nitroglycerin Mortality Reduction No prospective trials sufficiently powered to demonstrate mortality reduction. Patients with MI and hypertension with or without pulmonary edema treated with NTG have a relative risk of death of 0.81 at 2 days.* *Perez MI, Musini VM,Wright JM. Effect of early treatment with anti-hypertensive drugs on short and long-term mortality in patients with an acute cardiovascular event. Cochrane Database of Systematic Reviews 2009, Issue 4. Art. No.: CD DOI: / CD pub2.

35 Nitroglycerin IV Protocol Sublingual NTG 0.4 mg. every 5 min. x 4. Equivalent to 60ug/min for 20 min. Check BP before each dose Treat any hypotension with 500 cc. bolus normal saline. This frees up 20 min. for application of CPAP and preparation of the NTG drip. Many patients will improve with only the sublingual dosing and CPAP.

36 Nitroglycerin IV Protocol Prepare 400ug/ml NTG solution This is 100 mg. NTG in 250 ml. G5W in a glass bottle (preferred for solution stability, but not suitable for air transfer). Premixed preparations are available. 1.5 ml./hr infusion administers 10 ug/min

37 Nitroglycerin IV Protocol IV Rate Dosage Given Minutes after First SL Dose ug/min 25 ml/hr 9 ml/hr 60 ug/min ml/hr 12 12ml/hr 13.5 ml/hr 15 ml/hr 16.5 ml/hr 18 ml/hr 70 ug/min ug/min ug/min ug/min ug/min ug/min 60 Infusion Begin IV NTG infusion at 7.5 ml/hr = 50 ug/min (lower than SL rate). Increase infusion by 1.5 ml/hr = 10 ug/min every 5 min (Table). Check BP prior to each increase Treat hypotension with bolus 500 ml. normal saline. This allows for high-dose administration within the first hour.

38 Nitroglycerin IV Protocol Treat to Target Most studies aim for O2 sat of 96% with oxygen or respiratory adjunct (CPAP). Dyspnoea, resp rate, pulse rate, BP and mental status should also improve. A drop in BP of 30% is a reasonable target for the majority of patients presenting with hypertension. A low BP limit should prompt slowing or discontinuation of infusion.

39 Nitroglycerin IV Protocol Tailored Therapy Systolic pressure >140 (50% of patients) Often older, female, hypertensive with good systolic function, but diastolic dysfunction. Not often fluid overloaded. Furosemide should be delayed min. if given. Aggressive high-dose NTG can be used. Tolerate low systolic pressures, but often improve before low pressures occur.

40 Nitroglycerin IV Protocol Tailored Therapy Systolic pressure (>40% of patients) Likely some impairment of systolic function Some are fluid overloaded. Delay furosemide at least 30 minutes. High-dose NTG can be used, but some increased risk of hypotension. Systolic pressure should not fall below 100.

41 Nitroglycerin IV Protocol Tailored Therapy Systolic pressure <100 <10% of patients) Volume depletion or cardiogenic shock if hypoperfused. Bolus 500 cc. normal saline. If no response go to ACLS protocols including inotropes. These patients do poorly unless they respond to volume. None of our interventions are shown to improve outcomes.

42 Nitroglycerin IV Protocol Contraindications Phosphodiesterase inhibitors Severe volume depletion Hypotension Preload dependent states: Right ventricular infarction Aortic stenosis Mitral regurgitation Pulmonary hypertension

43 Nitroglycerin IV Protocol Adverse Outcomes: Tachyphylaxis after 2-12 hr continuous use. Reflex tachycardia usually not seen, as pulse rates usually drop. Bradycardia rarely, usually with hypotension. Use ACLS protocols. Lower BP reflects clinical improvement. Hypotension usually responds to fluid bolus or discontinuation of drip within 2-3 min. Headache or nausea in up to 11%

44 Bolus Nitroglycerin Possible alternative for IV administration of high dose. No protocols exist, but 3 of the best NTG studies use bolusing. One study excluded patients with SBP<160 and those with MI. Probably very safe in patients with SBP>160 (the majority).

45 Bolus Nitroglycerin Procedure IV NTG supplied as 5 mg/ml. Dilute to 1 mg/ml with saline or D5W. Bolus dosing of mg every 3 5 minutes treated to target. Bolusing up to 2 mg. every 3-5 min. has been used in patients with high presenting BP.

46 Case 2: Lydia 76 year old female extended care resident; no intubation or CPR by advanced directives. History of hypertension and advanced coronary disease Sudden onset SOB without pain. Obese, difficult veins Has been taking more of her NTG recently because she says she gets short of breath, but has no angina. Staff removed her bedside nitro. Pulse 110, BP 188/95, O2 saturation 85%, bilateral rales, increased JVP and orthopnoea. Lucid. Has O2 non-rebreather and has had 80 mg. lasix. Vein has blown.

47 Summary for Nitroglycerin A first-line intervention shown to be superior to CPAP and diuretics. Safe in pre-hospital use and when diagnosis is in doubt. Must be given early and titrated to high dose for optimal outcomes. Treatment to target symptoms and clinical parameters determines optimal therapy Tailored therapy to presenting systolic BP determines minimum BP tolerated and whether use of diuretics may be beneficial.

48 ACE Inhibitors Specific inhibition of maladaptive feedback loop Evidence exists for IV Enalapril and SL Captopril Captopril readily available and easily used as single dose. Gives modest preload and potent afterload reduction; can be used as single agent if NTG not tolerated. Confirmed by many Swan studies.

49 ACE Inhibitors Swan studies: 1. Barnett SL captopril 25 mg, or 12.5 mg if BP<110. Improved dyspnoea, reduced preload and afterload within 10 min. 12 patients who would otherwise have been intubated improved 8 of 12 diuresed without needing furosemide. 2. Langes IV captopril in class III heart failure. Reduced PCWP and SVR onset within 3 min and lasting 180 min after D/C. No reflex tachycardia and no adverse effects. 3. Annane Single 1 mg. IV infusion enalapril in class III and IV heart failure. Reduced PCWP and SVR without reducing CO. No adverse effects. Well done study randomized, blinded, controlled. 4. Varriale IV enalapril in severe mitral regurg and CHF. Reduced afterload and preload and reduced regurgitation. Increased CO and stroke volume. Reasonable alternative in MR where NTG relatively contraindicated.

50 ACE Inhibitors 4. Tohmo Severe CHF. IV enalapril in MI with raised PCWP. Effective lowering with enalapril alone. 5. Haude Compared 0.8 mg. NTG SL (inadequate dose) with 25 mg. captopril. Both decreased preload and afterload. SV index increased more with captopril. NTG effect onset was faster, but captopril produced more pronounced and sustained effect. No side effects. 6. Halon Class IV CHF comparison of oral isosorbide and captopril. The combination produced acute hemodynamic effects (fall in systemic and pulmonary vascular resistance, increased LV contractility) superior to those achieved with either drug alone. 7. Hamilton More rapid and complete improvement adding SL captopril. 62 patients, prospective, randomized, double-blind.

51 Ace Inhibitors Concerns One very large study of over 6000 patients given enalapril immediately after MI showed increased hypotension and mortality. They were not in pulmonary edema*. Recent Cochrane review actually shows reduced mortality at 10 days. European guidelines suggest ACE inhibitors should be used with caution. All existing pertinent studies suggest benefit, although most are small. *Swedberg K, et al. Effects of the early administration of enalapril on mortality in patients with acute myocardial infarction. Results of the Cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS II). N Engl J Med. 1992;327(10): Perez MI, Musini VM,Wright JM. Effect of early treatment with anti-hypertensive drugs on short and long-term mortality in patients with an acute cardiovascular event. Cochrane Database of Systematic Reviews 2009, Issue 4. Art. No.: D006743DOI: / CD pub2.

52 Captopril Oral tab dipped in water and given SL for more rapid absorption. Systolic BP>110 dosage 25 mg. Systolic BP<110 dosage 12.5 mg. Onset of action within 5 minutes*. Given as single dose. *Ceyhan B, et al. Comparison of sublingual captopril and sublingual nifedipine in hypertensive emergencies. Jpn J Pharmacol 1990; 52:

53 Captopril Can be used with NTG with additive effect. Early use may avoid need for diuretics. Delay diuretic administration 30 minutes after vasodilators. Good hemodynamic stability and few adverse effects*. Improved outcomes with fewer ICU days and fewer intubations with no increased hypotension. *Hamilton RJ, et al. Rapid improvement of acute pulmonary edema with sublingual captopril. Acad. Emerg Med 1996; 3: Southall, JC, et al. ACE inhibitors in acutely decompensated congestive heart failure. Acad. Emerg Med 2004; 11(5): 503

54 Case 3 - Larry 45 year old man on dialysis. Missed his last appointment 2 days ago and presents at 0200 hours in acute pulmonary edema. Signs of acute volume overload, BP 205/105. Poor historian, no medication record, lives in a larger city 1.5 hours away. Some recent alcohol use, but cooperative.

55 Summary for Captopril Can be used in place of NTG Good hemodynamic stability with few side effects. Easily administered in single dose. Additive effects when used with NTG. Reduces ICU use and need for intubation. Good second line intervention

56 BNP and Nesiritide B-type natriuretic peptide (BNP) is synthesized by the ventricle in times of stress. Higher levels in cardiac dyspnoea Measurement helps distinguish cardiac and pulmonary causes of dyspnoea. Useful in combination with other clinical findings in diagnosis of cardiogenic dyspnoea.

57 BNP and Nesiritide BNP levels are much higher in cardiogenic dyspnoea.

58 BNP and Nesiritide Low Cutoff: BNP cutoff < 100 has 91% sensitivity for negative prediction.

59 BNP and Nesiritide High Cutoff: BNP > 400 is 92% specific for presence of cardiac dyspnoea * This figure varies in other papers from 500 to 950 pg/ml. Probably not as clinically useful at present. * Rogers RK, Stoddard GJ, Greene T, et al. Usefulness of adjusting for clinical covariates to improve the ability of B-type natriuretic peptide to distinguish cardiac from noncardiac dyspnea. Am J Cardiol. 2009; 104(5):

60 BNP and Nesiritide Limitations of BNP measurement: Correlates poorly with pulmonary wedge pressure Not useful as marker for clinical improvement. Not useful if Nesiritide has been used. Cannot distinguish acute lung injury/ards from cardiogenic edema. Elevated in Increasing age Increasing creatinine Atrial fibrillation Septic shock Right ventricular failure secondary to pulmonary causes Reduced in obesity

61 BNP and Nesiritide Possible use in Cardiogenic Pulmonary Edema: Unlikely to rule in cardiac dyspnoea. Levels < 100 pg/ml. help to rule out pulmonary causes of dyspnoea. Isolated pulmonary disease needs to be excluded as carefully as possible if diuretics are to be used, as these patients are already volume depleted and will be made worse. BNP possibly useful here. Dyspnoeic patients with uncertain diagnosis who are not volume overloaded need no diuretics. They will be made no worse by nitroglycerin and will benefit from CPAP and beta agonists. BNP less likely to change treatment.

62 BNP and Nesiritide Nesiritide is a recombinant form of BNP. Primarily preload and some afterload reduction. Increasing use in USA a result of VMAC* study and numerous other manufacturer supported trials. Licensed in Canada in 2007 as Natrecor. 40 times the cost of NTG Trend to increased renal insufficiency and mortality in meta-analyses. *Young A, et al. Intravenous nesisitide vs nitroglycerin for treatment of decompensated heart failure. JAMA 2002; 287(12): Sackner-Bernstein JD, et al. Short-term risk of death after treatment with nesiritide for decompensated heart failure. JAMA 2005; 293:

63 Summary for BNP and Nesiritide BNP may be useful if <100 where diuretics are being considered in an uncertain diagnosis. Nesiritide requires more safety data and is costly as compared to nitroglycerin. There are more important priorities for the rural ER in evaluation and treatment of acute dyspnoea.

64 Noninvasive Positive Pressure Ventilation Includes CPAP and BiPAP CPAP much simpler to administer and equally effective CPAP of 10 cm. water used in most studies. Effective in both preload and afterload reduction. Early implementation gives the best results. Multiple prehospital studies show benefit.

65 Noninvasive Positive Pressure Ventilation 3 meta-analyses show reduced mortality and intubation rates. Taking into account the evidence presented here, it does not seem advisable, from an ethical point of view, to pursue further research comparing non-invasive ventilation methods with SMT in ACPE patients. Winck JC, et al. Efficacy and safety of non-invasive ventilation in the treatment of acute cardiogenic pulmonary edema a systematic review and meta-analysis. Critical Care 2006, 10:R69 we did not have a group with oxygen alone. This point was discussed during the planning phase of the study, but it was not deemed ethical to include a group with oxygen alone because CPAP and bilevel PAP had already been shown to improve respiratory distress and to reduce the intubation rate in patients with acute cardiogenic pulmonary edema. Moritz F, et al. Continuous positive airway pressure versus bilevel noninvasive ventilation in acute cardiogenic pulmonary edema: a randomized multicenter trial. Ann Emerg Med 2007; 50:

66 Non-Invasive Positive Pressure Ventilation Meta-analyses: Peter JV, Moran JL, Phillips-Hughes J, et al. Effect of noninvasive positive pressure ventilation (NIPPV) on mortality in patients with acute cardiogenic pulmonary oedema: A metaanalysis. Lancet 2006 Apr 8; 367: Masip J, Roque M, Sanchez B, et al. Noninvasive ventilation in acute cardiogenic pulmonary edema: systematic review and meta-analysis. JAMA 2005; 294(24): Winck JC, Azevedo LF, Costa-Pereira A, Antonelli M, Wyatt JC. Efficacy and safety of non-invasive ventilation in the treatment of acute cardiogenic pulmonary edema a systematic review and meta-analysis. Critical Care 2006, 10:R69

67 Noninvasive Positive Pressure Ventilation A dissenting opinion: N Engl J Med 2008;359:

68 Noninvasive Positive Pressure Ventilation A dissenting opinion: N Engl J Med 2008;359: Results A total of 1069 patients (mean [±SD] age, 77.7±9.7 years; female sex, 56.9%) were assigned to standard oxygen therapy (367 patients), CPAP (346 patients), or NIPPV (356patients). There was no significant difference in 7-day mortality between patients receiving standard oxygen therapy (9.8%) and those undergoing noninvasive ventilation (9.5%, P = 0.87). There was no significant difference in the combined end point of death or intubation within 7 days between the two groups of patients undergoing noninvasive ventilation (11.7% for CPAP and 11.1% for NIPPV, P = 0.81). As compared with standard oxygen therapy, noninvasive ventilation was associated with greater mean improvements at 1 hour after the beginning of treatment in patient-reported dyspnea (treatment difference, 0.7 on a visual-analogue scale ranging from 1 to 10; 95% confidence interval [CI], 0.2 to 1.3; P = 0.008), heart rate (treatment difference, 4 beats per minute; 95% CI, 1 to 6; P = 0.004), acidosis (treatment difference, ph 0.03; 95% CI, 0.02 to 0.04; P<0.001), and hypercapnia (treatment difference, 0.7 kpa[5.2 mm Hg]; 95% CI, 0.4 to 0.9; P<0.001). There were no treatment-related adverse events. Conclusions In patients with acute cardiogenic pulmonary edema, noninvasive ventilation induces a more rapid improvement in respiratory distress and metabolic disturbance than does standard oxygen therapy but has no effect on short-term mortality.

69 Noninvasive Positive Pressure Ventilation A dissenting opinion: N Engl J Med 2008;359: Possible reasons for differing findings: 1. Excluded sick patients who might require life saving or emergency intervention. 2. Only 29 patients intubated in this study (3%). Death rate (15.3%) greatly exceeded intubation rate. 3. Treatment crossover was 20% with most failures going to CPAP or BiPAP. Analysis by intention to treat. 4. Only 20% of patients had MI or ischemia. These patients have poorer prognosis and constitute a larger segment in prior studies. 5. Time to treatment institution is critical. This was not stated.

70 Noninvasive Positive Pressure A new meta-analysis: Ventilation Compared with standard therapy, continuous positive airway pressure reduced mortality (relative risk [RR], 0.64[95% CI, 0.44 to 0.92]) and need for intubation (RR, 0.44 [CI, 0.32 to 0.60]) but not incidence of new MI (RR, 1.07 [CI, 0.84 to 1.37]). The effect was more prominent in trials in which myocardial ischemia or infarction caused ACPE in higher proportions of patients (RR, 0.92 [CI, 0.76 to 1.10] when 10% of patients had ischemia or MI vs [CI, 0.17 to 1.07] when 50% had ischemia or MI).

71 Noninvasive Positive Pressure Ventilation Conclusions: 1. CPAP equally effective to BiPAP and easier to use. 2. Must be applied early. Few contraindications. Very safe. 3. Strong evidence for early improvement in symptoms and physiologic parameters. 4. Patients treated initially with NIV do better than those with standard therapy even if intubation eventually needed.* 5. Very likely to reduce intubation and death. 6. Any further large prospective studies need to avoid crossover of treatments. Doubtful if this will clear ethics. *Tallman TA, Peacock FW, Emerman CL, Lopatin M, Blicker JZ, et al. Noninvasive Ventilation Outcomes in 2,430 Acute Decompensated Heart Failure Patients: An ADHERE Registry Analysis. Acad Emerg Med 2008; 15(4):

72 Application of CPAP Criteria for respiratory failure usually present: Respiratory distress, use of accessory muscles Tachypnoea (RR 24-30) ph <7.35 pco2 >45 po2 <90 on maximal FIO2 Chest X-ray may be useful in diagnosis, but is not sensitive enough for decision making. Changes due to acute pulmonary edema may take many hours to appear. No evidence for harm if applied in absence of resp failure. Outstanding evidence for use in COPD exacerbation if diagnosis uncertain.

73 Application of CPAP Indications with decreasing level of evidence COPD with exacerbation Acute cardiogenic pulmonary edema Pneumonia with immunocompromised patient. Do Not Intubate status Extubation failure Asthma Other causes of respiratory failure (ARDS, Trauma) * No evidence for harm with CPAP provided contraindications are observed.

74 Application of CPAP Complications Pain or ulcer over bridge of nose Mucosal dryness Fear that device is limiting ability to breathe Eye irritation if mask seal is suboptimal Aspiration or gastric insufflation (rare) Pneumothorax (very rare)

75 Application of CPAP Contraindications: Medical instability with need for intubation Pneumothorax must always be excluded Reduced LOC with airway at risk Vomiting Agitation or inability to attain mask seal Hypotension with SBP <90 Hypovolemia, RV infarction, phosphodiesterase inhibitors or other preload dependent conditions. CPAP will impair RV filling High intracranial pressure

76 Application of CPAP The Boussignac CPAP System: An easily applied method for non-invasive ventilation.

77 Application of CPAP Boussignac system components: 1. Sized mask, valve and tubing for connection to oxygen source 2. Oxygen port capable of 25 L/min. with flow regulator. 3. Optional pressure manometer 4. Optional nebulizer. 5. Port for optional (but recommended) ETCO 2 monitor.

78 Application of CPAP 1. Select mask size. child - #3 adult female - #4-5 adult male # Inflate the air cuff around the mask using cc. air. Have a 20 cc syringe available to subsequently facilitate an air-tight seal to the patient s face. 3. Connect green tubing to oxygen source 4. Connect white end of the valve to the face mask 5. Connect the end tidal CO2 sensor, if used, to the clear port. A cannula can also be slipped under the mask.

79 Application of CPAP 1. With the patient in the sitting position, hold the mask to the patient s face, begin oxygen at 15 L/min (CPAP of 5 cm. H 2 O), and take time to explain the procedure. 2. Secure the harness around the head with straps above and below the ears. Check for leaks around the mask and adjust the air seal as necessary. 3. Gradually increase oxygen flow to 25 L/min (CPAP of 10 cm. H 2 O) as tolerated. 4. Suction through the large end port of the mask as necessary. 5. If the manometer is used, place it in line between the valve and the mask. 6. If a nebulizer is used, place it in line between the valve and the mask. Set the valve oxygen source at 15 L/min. and the nebulizer source at 6 L/min.

80 Application of CPAP Subsequent actions: Do not remove CPAP without a backup plan for deterioration either resumption of CPAP or intubation Look for indication that intervention is working: 1. Reduced respiratory rate 2. Reduced heart rate 3. Reduced dyspnoea 4. Normalization of BP 5. Increasing oxygen saturation 6. Decreasing end tidal CO2 7. Improving mental status

81 Application of CPAP If not improving: Troubleshoot the equipment Check for pneumothorax Consider correctable conditions which might reduce preload (hypovolemia, dehydration) Consider pulmonary embolism. 1 in 4 COPD exacerbation patients requiring admission may have PE. Consider proceeding to intubation

82 Goals of Treatment Decrease preload Decrease afterload Improve LV contractility

83 Improving Contractility Indicated only in situations of hypotension with poor perfusion All agents improve numbers, but are associated with increased mortality Effects of some agents blunted by chronic beta blockade Alpha acting agents increase myocardial oxygen demand, arrhythmias and ischemia These patients probably require pulmonary artery catheterization if response is not prompt.

84 Improving Contractility Remember: The patient may be hypovolemic especially if diuretics have been given. Always consider a cautious fluid challenge. Further management follows ACLS protocols.

85 Improving Contractility Agents Digoxin no role Dobutamine primarily beta 1 activity Milrinone unaffected by beta blockade inodilator Norepinephrine primarily alpha activity Dopamine alpha and beta 1 activity Levosimendan sensitizes myocardium to calcium

86 Improving Contractility Variable Dobutamine Milrinone Mechanism of Action Beta Receptor Agonist Type III Phosphodiesterase Inhibitor Dosing mcg./kg./min mcg./kg./min Monitoring Symptom relief, vital signs, ECG, urine output Limitations Tachycardia Proarrhythmia Mortality Concerns Tachycardia Proarrhythmia Mortality Concerns Hypotension Vasodilator No Yes Use in Patients taking Beta Blockers Accumulation in Decreased Renal Function No? No Yes Yes

87 Treat to Target Goals may indicate success or failure: Most studies aim for O2 sat of 96% with oxygen or respiratory adjunct (CPAP). Dyspnoea, resp rate, pulse rate, BP and mental status should also improve. A drop in BP of 30% is a target for the majority of patients presenting with hypertension. A low BP limit should prompt slowing or discontinuation of infusion. Diuresis may eventually happen if there is volume overload. Not always a criterion for success.

88 Tailored Therapy Systolic pressure >140 (50% of patients) All should receive CPAP Often older, female, hypertensive with good systolic function, but diastolic dysfunction. Not often fluid overloaded. Furosemide should be delayed min. if given. Aggressive high-dose NTG can be used. Tolerate low systolic pressures, but often improve before low pressures occur.

89 Tailored Therapy Systolic pressure (>40% of patients) All should receive CPAP Likely some impairment of systolic function Some are fluid overloaded. Delay furosemide at least 30 minutes. High-dose NTG can be used, but some increased risk of hypotension. Systolic pressure should not fall below 100.

90 Tailored Therapy Systolic pressure <100 <10% of patients) Volume depletion or cardiogenic shock if hypoperfused. CPAP only with great caution. May be preload dependent. Consider bolus 500 cc. normal saline. If no response go to ACLS protocols including inotropes. These patients do poorly. None of our interventions are shown to improve outcomes.

91 Tailored Therapy Algorithm Systolic BP can be a reliable guide for choice of therapy Chatti R, et al. Algorithm for therapeutic management of acute heart failure syndromes. Heart Fail Rev 2007; 12:

92 Harm Reduction Early CPAP helpful or not harmful in misdiagnosis of COPD, pneumonia, asthma, pulmonary fibrosis. Early NTG causes no harm in misdiagnosis Use morphine only for pain or palliation. Use furosemide only in volume overload and in lowest possible doses. Delay at least 30 minutes and avoid if diagnosis is in doubt. Wuerz RC, et al. Effects of prehospital medications on mortality and length of stay in congestive heart failure. Ann Emerg Med 1992;

93 Harm Reduction Beta agonists do not worsen pulmonary edema if diagnosis is in doubt. The majority of patients have some degree of reversible airways obstruction *. Continuing usual dose of chronic beta blocker therapy is non-inferior to discontinuation. A larger number of patients continue chronic beta blockade on discharge if this strategy is used. Jondeau G, et al. B-CONVINCED: Beta-blocker CONtinuation Vs. INterruption in patients with Congestive heart failure hospitalized for a decompensation episode. Eur Heart J. 2009;30(18): * Maak CA, et al. Should Acute Treatment with Inhaled Beta Agonists be Withheld from Patients with Dyspnea Who May Have Heart Failure? J Emerg Med Jun 20. [Epub ahead of print].

94 Case 1: Simone 65 year old woman, multiple cardiac risk factors Sudden SOB x 2 hr. Diaphoretic, pulse 110, resps 30, BP 180/100 Normal mental status Bilateral rales, increased JVP X-ray suggests pulmonary edema ECG sinus tachycardia On oxygen, non-rebreathing, 2 large IV s, monitored What is your initial treatment? 1. Morphine 2. Lasix 3. Morphine + Lasix 4. NTG + 1 of above 5. Nesiritide (recombinant BNP) + 1 of above 6. None of the above

95 Case 4: Heide 69 year-old tourist from Holland. Had enoxaparin prophylaxis. Increasing SOB over 2 weeks with no chest pain. Acute severe SOB. O 2 sat 50% > 78% on non-rebreather. Smoker, interstitial lung disease, clubbing, edema, chronic cough No JVP, lucid, rales, CXR suggests acute pulmonary edema. Meds include bronchodilators, imuran and prednisone. BP 106/70, pulse 100 reg., resps 30. Normal ECG, troponin 0.47 (N< 0.66), BNP 255, D-dimer mg. NTG > BP 97/68 CPAP 10 cm H 2 O Furosemide 80 mg. IV Enoxaparin, ASA, Plavix

96 Case 2: Heide Clinical response: O2 sat > 92% on CPAP, dyspnoea improved, BP 120/70 in 30 minutes 02 sat > 96% on non-rebreather 5 hr later. Modest diuresis in 1.5 hours Ambulance transfer at 3 hours with CPAP in place Receiving hospital: Stable on 3L/min O2 for 24 hours Non-diagnostic CT pulmonary angiogram. Gradual deterioration of sats improving again with CPAP Considering need for intubation for transfer back home. Differential Diagnosis?

97 Conclusions for Rural Management Use of treatment algorithm based on BP and exam. Early administration of 10 mm Hg. CPAP. First line Early high dose sublingual and IV nitroglycerin. First line Early consideration of SL captopril in specific settings. Second line. Delayed administration of furosemide in volume overload. Third line.

98 Conclusions for Rural Management Continue chronic beta blocker therapy if previously used. Avoidance of morphine Consider trial of volume replacement for hypotension Consider early referral if inotropes or vasoconstrictors are needed When diagnosis is in doubt, use of CPAP, nitroglycerin and salbutamol do not seem to impart increased risk

99 Causes of Cardiogenic Pulmonary Edema Remember to correct the cause MADHATTER mnemonic: Myocardial infarction Anemia Drugs, Diet (salt) Hypertension Arrhythmia Thyroid disease Toxic (infection) Embolism (pulmonary), Endocarditis, valvular disorders Renal failure

100 Cardiogenic Pulmonary Edema END