- Email: [email protected]
Morphine in the treatment of acute pulmonary oedema — Why?
Morphine in the treatment of acute pulmonary oedema – Why? C. Ellingsrud, S. Agewall PII: DOI: Reference:
S0167-5273(15)30578-7 doi: 10.1016/j.ijcard.2015.10.014 IJCA 21304
To appear in:
International Journal of Cardiology
Received date: Revised date: Accepted date:
19 May 2015 16 September 2015 3 October 2015
Please cite this article as: Ellingsrud C, Agewall S, Morphine in the treatment of acute pulmonary oedema – Why?, International Journal of Cardiology (2015), doi: 10.1016/j.ijcard.2015.10.014
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Morphine in the treatment of acute pulmonary oedema – Why?
SC RI
PT
C Ellingsrud and S Agewall
MA
NU
Department of Cardiology, Oslo University Hospital Ullevål and Institute of Clinical Sciences, University of Oslo, Oslo, Norway
Correspondence to:
AC
CE
PT
ED
S Agewall, Department of Cardiology, Oslo University Hospital Ullevål and Institute of Clinical Sciences, University of Oslo, Oslo, Norway. E-mail; [email protected]
ACCEPTED MANUSCRIPT Abstract Morphine has since a long time, been used in patients with acute pulmonary oedema due to its
PT
anticipated anxiolytic and vasodilatory properties, however a discussion about the benefits and risks has been raised recently. A literature search in Medline and Embase using the
SC RI
keywords «pulmonary oedema» OR «lung oedema» OR «acute heart failure» AND «morphine» was performed. A certain vasodilation has been described after morphine administration, but the evidence for this mechanism is relatively poor and morphine-induced
NU
anxiolysis may possibly be the most important factor of morphine in pulmonary oedema and
MA
therefore some authors have suggested benzodiazepines as an alternative treatment. Respiratory depression seems to be a less relevant clinical problem according to the literature,
ED
whereas vomiting is common, which may cause aspiration. In the largest outcome study, based on the ADHERE registry, morphine given in acute decompensated heart failure was an
PT
independent predictor of increased hospital mortality, with an odds ratio of 4,8 (95 % CI: 4,52-5,18, p < 0,001). Other, smaller studies have shown a significant association between
AC
factors.
CE
morphine administration and mortality, which was lost after adjusting for confounding
Morphine is still used for pulmonary oedema in spite of poor scientific background data. A randomised, controlled study is necessary in order to determine the effect – and especially the risk – when using morphine for pulmonary oedema. Since the positive effects are not sufficiently documented, and since the risk for increased mortality cannot be ruled out, one can advocate that the use should be avoided.
2
ACCEPTED MANUSCRIPT Acute pulmonary oedema is a common condition in the emergency room, associated with considerable mortality [1,2]. The oedema develops when the left ventricle fails, making the
PT
hydrostatic pressure in the pulmonary circulation increase, and therefore fluid builds up in the pulmonary insterstitium and alveoli. The condition is defined by severe respiratory distress
SC RI
that worsens in supine position, crackles over the lung and signs of pulmonary congestion on chest X-ray [3]. Peripheral oxygen saturation is usually below 90 % prior to treatment.
NU
Pharmacological treatment of pulmonary oedema aims at treating the increased hydrostatic pressure in the pulmonary circulation, primarily by lowering filling pressure (preload), and by
MA
lowering the peripheral arterial pressure (afterload) – achieved through venous and arterial dilation [4]. Traditionally there has also been emphasis on removing excess fluid through
PT
ED
increased diuresis [5].
Since the 1960s, three drugs have been most frequently used to achieve these effects,
CE
alongside oxygen treatment. It is furosemide, which inhibits reabsorption of sodium in
AC
Henle´s loop and distal tubuli and thereby increasing excretion of fluids through the kidney. Then there is nitroglycerin, which via cGMP and smooth muscle relaxation induces vasodilatation – at low doses only venous, at high doses also causing arterial relaxation [6,7].
The third drug, morphine, has been used due to its anticipated anxiolytic and vasodilatory properties. During the last decade, a discussion about the benefits and especially the risks accompanying the use of morphine in cases of pulmonary oedema has been raised [1,4,8-11]. In a retrospective study from 2008 based on the ADHERE registry, morphine given in acute decompensated heart failure was an independent predictor of increased hospital mortality, with an odds ratio of 4,8 (95 % CI: 4,52-5,18, p < 0,001) [2].
3
ACCEPTED MANUSCRIPT
A literature search in Medline using the keywords «pulmonary oedema» OR «lung oedema»
PT
OR «acute heart failure» AND «morphine» was performed. The search was conducted in February 2014 and gave 263 results. A similar search was performed in Embase, where
SC RI
Medline articles were excluded and the search was limited to articles written in English (191 results). We were particularly interested in studies that documented the outcome after using morphine in the treatment of acute pulmonary oedema as well as studies and review articles in
NU
which the physiological effects of the drug were discussed. A total of 24 articles were
MA
discretionary picked out after reviewing abstracts [2,4-26].
Guidelines
ED
The European heart failure guideline from 2012 state that one can consider to give 4-8 mg of
PT
morphine intravenously (repeated as needed) if the patient suffers from severe anxiety or distress caused by pulmonary oedema (figure 1) [27]. American Heart Failure Society does
CE
not include morphine in its recommendations from 2010 and comments that the drug should
AC
be used with caution if administered [28]. The collaboration American College of Cardiology Foundation / American Heart Association does not mention morphine in their guidelines from 2013 [29].
Physiological effects of morphine Morphine induces depression of the central nervous system via opiate receptors in the brain, which causes both sedation and analgesia [12]. In addition to this, morphine has a supposed anxiolytic effect, which together with the sedative effect reduces the activity of the sympathetic nervous system and causes a reduction of both the filling pressure and the arterial pressure [4].
4
ACCEPTED MANUSCRIPT
There are data indicating that morphine has a vasodilating effect in pulmonary oedema
PT
[3,13,28]. The background of this belief, is three trials from 1966 to 1976, where the groups consisted of 12 dogs, 12 patients with myocardial infarction (where nobody received
SC RI
morphine as the sole drug) and 13 patients with mild pulmonary oedema, respectively [14,30,15]. However, in the study by Vismara et al. [15] it was concluded that there must be a different effect than the vasodilation that is responsible for the clinical improvement of
NU
pulmonary oedema seen when using morphine – a theory supported by several studies
MA
towards the 1990s [16,17,31].
In 1994, a trial with vessels from dogs in vitro showed that morphine had a relaxing effect on
ED
the smooth muscles in both veins and arteries [18]. The effect was probably caused by
PT
histamine release [19,32]. In 2008, an in-vivo trial in cats, found a morphine-induced dosedependent vasodilation in the pulmonary vascular bed, expressed by reduced arterial vascular
CE
resistance [33]. Whether the physiological effects of morphine are similar in humans and to
AC
what extent these effects are significant in the altered haemodynamics of pulmonary oedema, is still scarcely elucidated.
A trial from 1979 including 28 patients who underwent coronary artery bypass surgery, showed that large doses of morphine (0,5 mg/kg) produced a transient large reduction in peripheral vascular resistance [34]. However, these doses are considerably larger than those we administer today.
To summarise: Although vasodilation has been described after morphine injection, the morphine-induced anxiolysis through depression of the sympathetic nervous system, might be
5
ACCEPTED MANUSCRIPT the most important factor in pulmonary oedema, without this mechanism being fully
PT
explained and without the effect being objectively measurable [4,20] .
Adverse physiological effects
SC RI
The most common adverse effects of morphine are constipation and nausea. While constipation has no significance in acute medical context, it is described that between one fifth and one third of patients experience nausea when using opioids [35,36]. Vomiting occurs
NU
about half as frequently as nausea. European guidelines recommend the addition of 10 mg of
MA
metoclopramide to counteract nausea if morphine is administered [27]. Nausea in pulmonary oedema is a disadvantageous side effect because of the subjective discomfort and because nausea produces catecholamine release and thereby increased afterload. Nausea and vomiting
ED
is also very unfortunate because of the risk for aspiration, if there is a need for treatment with
PT
continuous positive pressure (CPAP), which European Society of Cardiology recommends if
CE
peripheral oxygen saturation is below 90 % [27].
AC
It has also been found that morphine induces depression of the myocardium that results in decreased heart rate and cardiac output [37]. This effect can be negative for a circulation where the heart is already beginning to fail.
A feared side effect of morphine is respiratory depression. Opioids affect the respiratory centre so that both the respiration rate and the tidal volume decrease [38]. The effect appears to be dose-dependent, but even at low doses, respiration pattern becomes irregular [39]. In addition, morphine has been shown to decrease the sensitivity of the peripheral (in the aorta, carotid arteries and lungs) and the central (in the medulla, separate from the main respiratory centre) chemoreceptors, to both increased pCO2 [38] and to low pO2 [39]. Such an effect on
6
ACCEPTED MANUSCRIPT the sensitivity for pCO2 was recorded with all of the 66 healthy participants in a trial from 2001 [36]. A review article from 2010 described a low incidence of opioid-induced
PT
respiratory depression – only 0,5 % [40]. The article is partly based on a study from Sweden with 14 000 post-operative patients where the incidence was measured to 0.09 % [41].
SC RI
However, these patients were given epidural morphine (4 mg), so the comparison has certain limitations. For post-operative patients in the United Kingdom the incidence was estimated to
NU
1 % [39].
MA
Heterogeneous prognoses
In a review article from 2008 Sosnowski [11] emphasises that there seems to be a correlation between the use of morphine and worsening of the patient's condition, based on five studies
ED
from 1987 to 2003 [10,21-24]. One of these is a small trial of prehospital treatment of
PT
pulmonary oedema. It showed that 38 % of patients treated with morphine and furosemide, experienced subjective deterioration compared with none of the patients who received
CE
nitroglycerin and furosemide [10]. These five studies are small, but the results suggested that
AC
there is a correlation between morphine and worsening of the condition but also that morphine was given to the sickest patients, which of course is a confounder in this analysis.
As mentioned above, Peacock and colleagues published data from the large (more than 147 000 patients) ADHERE registry [2]. Almost 21 000 patients received morphine and after adjusting for factors known to be associated with increased hospital mortality, including advanced age, troponin elevation and hypertension; morphine remained an independent predictor of mortality. In addition, significant correlations between morphine administration and increased intubation rate, more intensive care unit admissions and prolonged hospitalisation were found.
7
ACCEPTED MANUSCRIPT
In a similar but smaller study from 2003 to 2007 in UK, no significant correlation between
PT
morphine administration and mortality was observed [1]. However, there was neither any
patient perceived breathlessness over the first hour.
SC RI
correlation between the use of morphine and improvement in respiratory distress, measured in
In a retrospective study in Israel containing 2336 patients, morphine administration was
NU
associated with an increased mortality [25]. However, after propensity score matching this
MA
association became non-significant. Both in the European and the Israeli study, there was a tendency to aggravation associated with morphine treatment, but the results were not significant. None of the studies tended to demonstrate an improved prognosis when morphine
PT
ED
was given.
When evaluating observational studies one must be aware of the confounding factors despite
CE
sophisticated statistical adjustment analysis. It is likely that morphine is given in a higher rate
AC
to those with a more pronounced acute heart failure situation. Neither is it possible, to evaluate if intubation was an “adverse effect” of receiving morphine or if the patient received morphine as a sedative in conjunction with the intubation in a retrospective registry study.
Based on the results mentioned above, it seems unlikely that serious respiratory depression is a widespread problem due to the use of morphine. Nausea, on the other hand, is a much more common adverse effect, which however may be corrected with antiemetics. Even though nausea is unpleasant, although not a dangerous adverse effect, it can be serious if the patient is receiving CPAP treatment. This illustrates how morphine has various benefits and risks in different subpopulations. The cardiodepressive effect that is described could equivalently be
8
ACCEPTED MANUSCRIPT quite disadvantageous when the cardiac capacity is weakened, whereas it will not be
PT
particularly crucial for hypertensive patients.
Benzodiazepines have been suggested as an alternative for morphine in treatment of
SC RI
pulmonary oedema [4,26]. However, these types of drugs have not been tested in this clinical situation properly. Nevertheless, this is interesting because benzodiazepines have shown to be efficient anxiolytics over a longer period of time, in addition to the fact that they have positive
NU
cardiovascular effects [42]. In a literature study, benzodiazepines were recommended in the
MA
treatment of chest pain due to these properties, and several aspects are presented suggesting
ED
that they could be an alternative in treatment of pulmonary oedema [42].
PT
Conclusion
Morphine is still used for pulmonary oedema in spite of relatively poor scientific background
CE
data. A randomised, controlled study is necessary in order to determine the effect – and
AC
especially the risk – when using morphine for pulmonary oedema. Since the positive effects are not sufficiently documented, and since the risk for increased mortality cannot be ruled out, one can advocate that the use should be avoided.
9
ACCEPTED MANUSCRIPT Legends
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Figure 1 Algorithm for treatment of acute pulmonary oedema, according to the guidelines from the European Society of Cardiology from 2012, which recommend that 4-8 mg of morphine i.v. may be
AC
CE
PT
ED
MA
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considered and possibly repeated if needed by severe anxiety or distress [27]
10
ACCEPTED MANUSCRIPT References
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[1] A. Gray, S. Goodacre, M. Seah, S. Tilley, Diuretic, opiate and nitrate use in severe acidotic acute cardiogenic pulmonary oedema: analysis from the 3CPO trial, QJM 103 (2010) 573-581. [2] W.F. Peacock, J.E. Hollander, D.B. Diercks, M. Lopatin, G. Fonarow, C.L. Emerman, Morphine and outcomes in acute decompensated heart failure: an ADHERE analysis, Emerg. Med. J. 25 (2008) 205209. [3] M.S. Nieminen, M. Bohm, M.R. Cowie, H. Drexler, G.S. Filippatos, G. Jondeau, et al, Executive summary of the guidelines on the diagnosis and treatment of acute heart failure: the Task Force on Acute Heart Failure of the European Society of Cardiology, Eur. Heart J. 26 (2005) 384-416. [4] A. Mattu, J.P. Martinez, B.S. Kelly, Modern management of cardiogenic pulmonary edema, Emerg. Med. Clin. North Am. 23 (2005) 1105-1125. [5] S. Grayson, W.E. Gandy, CHF treatment: is furosemide on the way out? Rethinking the pulmonary edema cocktail, EMS World 41 (2012) 20-24. [6] J.C. Coons, M. McGraw, S. Murali, Pharmacotherapy for acute heart failure syndromes, Am. J. Health Syst. Pharm. 68 (2011) 21-35. [7] G. Cotter, E. Metzkor, E. Kaluski, Z. Faigenberg, R. Miller, A. Simovitz, et al, Randomised trial of high-dose isosorbide dinitrate plus low-dose furosemide versus high-dose furosemide plus low-dose isosorbide dinitrate in severe pulmonary oedema, Lancet 351 (1998) 389-393. [8] M. Hall, R. Griffiths, B. Appadu, Is morphine indicated in acute pulmonary oedema, Emerg. Med. J. 22 (2005) 391. [9] G.N. Cattermole, C.A. Graham, Opiates should be avoided in acute decompensated heart failure, Emerg. Med. J. 26 (2009) 230-231. [10] J.R. Hoffman, S. Reynolds, Comparison of nitroglycerin, morphine and furosemide in treatment of presumed pre-hospital pulmonary edema, Chest 92 (1987) 586-593. [11] M.A. Sosnowski, Review article: lack of effect of opiates in the treatment of acute cardiogenic pulmonary oedema, Emerg. Med. Australas. 20 (2008) 384-390. [12] M.R. Johnson, Acute Pulmonary Edema, Curr. Treat. Options Cardiovasc. Med. 1 (1999) 269-276. [13] R.C. Allison, Initial treatment of pulmonary edema: a physiological approach, Am. J. Med. Sci. 302 (1991) 385-391. [14] J.S. Vasko, R.P. Henney, H.N. Oldham, R.K. Brawley, A.G. Morrow, Mechanisms of action of morphine in the treatment of experimental pulmonary edema, Am. J. Cardiol. 18 (1966) 876-883. [15] L.A. Vismara, D.M. Leaman, R. Zelis, The effects of morphine on venous tone in patients with acute pulmonary edema, Circulation 54 (1976) 335-337. [16] A.D. Timmis, M.T. Rothman, M.A. Henderson, P.W. Geal, D.A. Chamberlain, Haemodynamic effects of intravenous morphine in patients with acute myocardial infarction complicated by severe left ventricular failure, Br. Med. J. 280 (1980) 980-982. [17] A.D. Redmond, The haemodynamic effects of morphine, Arch. Emerg. Med. 4 (1987) 131-132. [18] S. Greenberg, C. McGowan, J. Xie, W.R. Summer, Selective pulmonary and venous smooth muscle relaxation by furosemide: a comparison with morphine, J. Pharmacol. Exp. Ther. 270 (1994) 1077-1085. [19] M. Grossmann, A. Abiose, O. Tangphao, T.F. Blaschke, B.B. Hoffman, Morphine-induced venodilation in humans, Clin. Pharmacol. Ther. 60 (1996) 554-560. [20] J. Kosowsky, W.T. Abraham, A. Storrow, Evaluation and management of acutely decompensated chronic heart failure in the emergency department, Congest. Heart Fail. 7 (2001) 124-136. [21] J.A. Chambers, C.J. Baggoley, Pulmonary oedema--prehospital treatment. Caution with morphine dosage, Med. J. Aust. 157 (1992) 326-328. [22] J.F. Beltrame, C.J. Zeitz, S.A. Unger, R.J. Brennan, A. Hunt, J.L. Moran, et al, Nitrate therapy is an alternative to furosemide/morphine therapy in the management of acute cardiogenic pulmonary edema, J. Card. Fail. 4 (1998) 271-279.
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[23] A. Sacchetti, E. Ramoska, M.E. Moakes, P. McDermott, V. Moyer, Effect of ED management on ICU use in acute pulmonary edema, Am. J. Emerg. Med. 17 (1999) 571-574. [24] M. Fiutowski, T. Waszyrowski, M. Krzeminska-Pakula, J.D. Kasprzak, Clinical presentation and pharmacological therapy in patients with cardiogenic pulmonary oedema, Kardiol. Pol. 61 (2004) 561-569; discussion 70. [25] Z. Iakobishvili, E. Cohen, M. Garty, S. Behar, A. Shotan, A. Sandach, et al, Use of intravenous morphine for acute decompensated heart failure in patients with and without acute coronary syndromes, Acute Card. Care. 13 (2011) 76-80. [26] J. Bosomworth, Rural treatment of acute cardiogenic pulmonary edema: applying the evidence to achieve success with failure, Can. J. Rural Med. 13 (2008) 121-128. [27] J.J. McMurray, S. Adamopoulos, S.D. Anker, A. Auricchio, M. Bohm, K. Dickstein, et al, ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur. J. Heart Fail. 14 (2012) 803-869. [28] Heart Failure Society of America, Evaluation and Management of Patients with Acute Decompensated Heart Failure, St. Paul, Minnesota: HFSA, 2010. www.sciencedirect.com/science/article/pii/S1071916410002277 (12/09/15) [29] C.W. Yancy, M. Jessup, B. Bozkurt, J. Butler, D.E. Casey Jr., M.H. Drazner, et al, 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines, Circulation 128 (2013) e240-327. [30] G. Lee, A.N. DeMaria, E.A. Amsterdam, F. Realyvasquez, J. Angel, S. Morrison, et al, Comparative effects of morphine, meperidine and pentazocine on cardiocirculatory dynamics in patients with acute myocardial infarction, Am. J. Med. 60 (1976) 949-955. [31] R. Zelis, E.J. Mansour, R.J. Capone, D.T. Mason, The cardiovascular effects of morphine. The peripheral capacitance and resistance vessels in human subjects, J. Clin. Invest. 54 (1974) 1247-1258. [32] C.E. Rosow, J. Moss, D.M. Philbin, J.J. Savarese, Histamine release during morphine and fentanyl anesthesia, Anesthesiology 56 (1982) 93-96. [33] A.D. Kaye, J.M. Hoover, A.J. Kaye, I.N. Ibrahim, C. Fox, A. Bajwa, et al, Morphine, opioids, and the feline pulmonary vascular bed, Acta Anaesthesiol. Scand. 52 (2008) 931-937. [34] H.O. Hsu, R.F. Hickey, A.R. Forbes, Morphine decreases peripheral vascular resistance and increases capacitance in man, Anesthesiology 50 (1979) 98-102. [35] H.S. Smith, A. Laufer, Opioid induced nausea and vomiting, Eur. J. Pharmacol. 722 (2014) 67-78. [36] M.S. Cepeda, J.T. Farrar, J.H. Roa, R. Boston, Q.C. Meng, F. Ruiz, et al, Ethnicity influences morphine pharmacokinetics and pharmacodynamics, Clin. Pharmacol. Ther. 70 (2001) 351-361. [37] T.R. Riggs, Y. Yano, T. Vargish, Morphine depression of myocardial function, Circ. Shock 19 (1986) 31-38. [38] J.B. Radke, K.P. Owen, M.E. Sutter, et al, The Effects of opioids on the lung, Clin. Rev. Allergy Immunol. 46 (2014) 54-64. [39] K.T. Pattinson, Opioids and the control of respiration, Br. J. Anaesth. 100 (2008) 747-758. [40] A. Dahan, L. Aarts, T.W. Smith, Incidence, Reversal, and Prevention of Opioid-induced Respiratory Depression, Anesthesiology 112 (2010) 226-238. [41] N. Rawal, S. Arner, L.L. Gustafsson, R. Allvin, Present state of extradural and intrathecal opioid analgesia in Sweden. A nationwide follow-up survey, Br. J. Anaesth. 59 (1987) 791-799. [42] J.C. Huffman, T.A. Stern, The use of benzodiazepines in the treatment of chest pain: a review of the literature, J. Emerg. Med. 25 (2003) 427-437.
12
ACCEPTED MANUSCRIPT
Highlights
PT
Morphine may cause harm in patients with acute pulmonary oedema.
AC
CE
PT
ED
MA
NU
SC RI
The evidence for a vasodilatory effect is poor
13
S0167-5273(15)30578-7 doi: 10.1016/j.ijcard.2015.10.014 IJCA 21304
To appear in:
International Journal of Cardiology
Received date: Revised date: Accepted date:
19 May 2015 16 September 2015 3 October 2015
Please cite this article as: Ellingsrud C, Agewall S, Morphine in the treatment of acute pulmonary oedema – Why?, International Journal of Cardiology (2015), doi: 10.1016/j.ijcard.2015.10.014
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Morphine in the treatment of acute pulmonary oedema – Why?
SC RI
PT
C Ellingsrud and S Agewall
MA
NU
Department of Cardiology, Oslo University Hospital Ullevål and Institute of Clinical Sciences, University of Oslo, Oslo, Norway
Correspondence to:
AC
CE
PT
ED
S Agewall, Department of Cardiology, Oslo University Hospital Ullevål and Institute of Clinical Sciences, University of Oslo, Oslo, Norway. E-mail; [email protected]
ACCEPTED MANUSCRIPT Abstract Morphine has since a long time, been used in patients with acute pulmonary oedema due to its
PT
anticipated anxiolytic and vasodilatory properties, however a discussion about the benefits and risks has been raised recently. A literature search in Medline and Embase using the
SC RI
keywords «pulmonary oedema» OR «lung oedema» OR «acute heart failure» AND «morphine» was performed. A certain vasodilation has been described after morphine administration, but the evidence for this mechanism is relatively poor and morphine-induced
NU
anxiolysis may possibly be the most important factor of morphine in pulmonary oedema and
MA
therefore some authors have suggested benzodiazepines as an alternative treatment. Respiratory depression seems to be a less relevant clinical problem according to the literature,
ED
whereas vomiting is common, which may cause aspiration. In the largest outcome study, based on the ADHERE registry, morphine given in acute decompensated heart failure was an
PT
independent predictor of increased hospital mortality, with an odds ratio of 4,8 (95 % CI: 4,52-5,18, p < 0,001). Other, smaller studies have shown a significant association between
AC
factors.
CE
morphine administration and mortality, which was lost after adjusting for confounding
Morphine is still used for pulmonary oedema in spite of poor scientific background data. A randomised, controlled study is necessary in order to determine the effect – and especially the risk – when using morphine for pulmonary oedema. Since the positive effects are not sufficiently documented, and since the risk for increased mortality cannot be ruled out, one can advocate that the use should be avoided.
2
ACCEPTED MANUSCRIPT Acute pulmonary oedema is a common condition in the emergency room, associated with considerable mortality [1,2]. The oedema develops when the left ventricle fails, making the
PT
hydrostatic pressure in the pulmonary circulation increase, and therefore fluid builds up in the pulmonary insterstitium and alveoli. The condition is defined by severe respiratory distress
SC RI
that worsens in supine position, crackles over the lung and signs of pulmonary congestion on chest X-ray [3]. Peripheral oxygen saturation is usually below 90 % prior to treatment.
NU
Pharmacological treatment of pulmonary oedema aims at treating the increased hydrostatic pressure in the pulmonary circulation, primarily by lowering filling pressure (preload), and by
MA
lowering the peripheral arterial pressure (afterload) – achieved through venous and arterial dilation [4]. Traditionally there has also been emphasis on removing excess fluid through
PT
ED
increased diuresis [5].
Since the 1960s, three drugs have been most frequently used to achieve these effects,
CE
alongside oxygen treatment. It is furosemide, which inhibits reabsorption of sodium in
AC
Henle´s loop and distal tubuli and thereby increasing excretion of fluids through the kidney. Then there is nitroglycerin, which via cGMP and smooth muscle relaxation induces vasodilatation – at low doses only venous, at high doses also causing arterial relaxation [6,7].
The third drug, morphine, has been used due to its anticipated anxiolytic and vasodilatory properties. During the last decade, a discussion about the benefits and especially the risks accompanying the use of morphine in cases of pulmonary oedema has been raised [1,4,8-11]. In a retrospective study from 2008 based on the ADHERE registry, morphine given in acute decompensated heart failure was an independent predictor of increased hospital mortality, with an odds ratio of 4,8 (95 % CI: 4,52-5,18, p < 0,001) [2].
3
ACCEPTED MANUSCRIPT
A literature search in Medline using the keywords «pulmonary oedema» OR «lung oedema»
PT
OR «acute heart failure» AND «morphine» was performed. The search was conducted in February 2014 and gave 263 results. A similar search was performed in Embase, where
SC RI
Medline articles were excluded and the search was limited to articles written in English (191 results). We were particularly interested in studies that documented the outcome after using morphine in the treatment of acute pulmonary oedema as well as studies and review articles in
NU
which the physiological effects of the drug were discussed. A total of 24 articles were
MA
discretionary picked out after reviewing abstracts [2,4-26].
Guidelines
ED
The European heart failure guideline from 2012 state that one can consider to give 4-8 mg of
PT
morphine intravenously (repeated as needed) if the patient suffers from severe anxiety or distress caused by pulmonary oedema (figure 1) [27]. American Heart Failure Society does
CE
not include morphine in its recommendations from 2010 and comments that the drug should
AC
be used with caution if administered [28]. The collaboration American College of Cardiology Foundation / American Heart Association does not mention morphine in their guidelines from 2013 [29].
Physiological effects of morphine Morphine induces depression of the central nervous system via opiate receptors in the brain, which causes both sedation and analgesia [12]. In addition to this, morphine has a supposed anxiolytic effect, which together with the sedative effect reduces the activity of the sympathetic nervous system and causes a reduction of both the filling pressure and the arterial pressure [4].
4
ACCEPTED MANUSCRIPT
There are data indicating that morphine has a vasodilating effect in pulmonary oedema
PT
[3,13,28]. The background of this belief, is three trials from 1966 to 1976, where the groups consisted of 12 dogs, 12 patients with myocardial infarction (where nobody received
SC RI
morphine as the sole drug) and 13 patients with mild pulmonary oedema, respectively [14,30,15]. However, in the study by Vismara et al. [15] it was concluded that there must be a different effect than the vasodilation that is responsible for the clinical improvement of
NU
pulmonary oedema seen when using morphine – a theory supported by several studies
MA
towards the 1990s [16,17,31].
In 1994, a trial with vessels from dogs in vitro showed that morphine had a relaxing effect on
ED
the smooth muscles in both veins and arteries [18]. The effect was probably caused by
PT
histamine release [19,32]. In 2008, an in-vivo trial in cats, found a morphine-induced dosedependent vasodilation in the pulmonary vascular bed, expressed by reduced arterial vascular
CE
resistance [33]. Whether the physiological effects of morphine are similar in humans and to
AC
what extent these effects are significant in the altered haemodynamics of pulmonary oedema, is still scarcely elucidated.
A trial from 1979 including 28 patients who underwent coronary artery bypass surgery, showed that large doses of morphine (0,5 mg/kg) produced a transient large reduction in peripheral vascular resistance [34]. However, these doses are considerably larger than those we administer today.
To summarise: Although vasodilation has been described after morphine injection, the morphine-induced anxiolysis through depression of the sympathetic nervous system, might be
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explained and without the effect being objectively measurable [4,20] .
Adverse physiological effects
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The most common adverse effects of morphine are constipation and nausea. While constipation has no significance in acute medical context, it is described that between one fifth and one third of patients experience nausea when using opioids [35,36]. Vomiting occurs
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about half as frequently as nausea. European guidelines recommend the addition of 10 mg of
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metoclopramide to counteract nausea if morphine is administered [27]. Nausea in pulmonary oedema is a disadvantageous side effect because of the subjective discomfort and because nausea produces catecholamine release and thereby increased afterload. Nausea and vomiting
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is also very unfortunate because of the risk for aspiration, if there is a need for treatment with
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continuous positive pressure (CPAP), which European Society of Cardiology recommends if
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peripheral oxygen saturation is below 90 % [27].
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It has also been found that morphine induces depression of the myocardium that results in decreased heart rate and cardiac output [37]. This effect can be negative for a circulation where the heart is already beginning to fail.
A feared side effect of morphine is respiratory depression. Opioids affect the respiratory centre so that both the respiration rate and the tidal volume decrease [38]. The effect appears to be dose-dependent, but even at low doses, respiration pattern becomes irregular [39]. In addition, morphine has been shown to decrease the sensitivity of the peripheral (in the aorta, carotid arteries and lungs) and the central (in the medulla, separate from the main respiratory centre) chemoreceptors, to both increased pCO2 [38] and to low pO2 [39]. Such an effect on
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respiratory depression – only 0,5 % [40]. The article is partly based on a study from Sweden with 14 000 post-operative patients where the incidence was measured to 0.09 % [41].
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However, these patients were given epidural morphine (4 mg), so the comparison has certain limitations. For post-operative patients in the United Kingdom the incidence was estimated to
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1 % [39].
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Heterogeneous prognoses
In a review article from 2008 Sosnowski [11] emphasises that there seems to be a correlation between the use of morphine and worsening of the patient's condition, based on five studies
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from 1987 to 2003 [10,21-24]. One of these is a small trial of prehospital treatment of
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pulmonary oedema. It showed that 38 % of patients treated with morphine and furosemide, experienced subjective deterioration compared with none of the patients who received
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nitroglycerin and furosemide [10]. These five studies are small, but the results suggested that
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there is a correlation between morphine and worsening of the condition but also that morphine was given to the sickest patients, which of course is a confounder in this analysis.
As mentioned above, Peacock and colleagues published data from the large (more than 147 000 patients) ADHERE registry [2]. Almost 21 000 patients received morphine and after adjusting for factors known to be associated with increased hospital mortality, including advanced age, troponin elevation and hypertension; morphine remained an independent predictor of mortality. In addition, significant correlations between morphine administration and increased intubation rate, more intensive care unit admissions and prolonged hospitalisation were found.
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In a similar but smaller study from 2003 to 2007 in UK, no significant correlation between
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morphine administration and mortality was observed [1]. However, there was neither any
patient perceived breathlessness over the first hour.
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correlation between the use of morphine and improvement in respiratory distress, measured in
In a retrospective study in Israel containing 2336 patients, morphine administration was
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associated with an increased mortality [25]. However, after propensity score matching this
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association became non-significant. Both in the European and the Israeli study, there was a tendency to aggravation associated with morphine treatment, but the results were not significant. None of the studies tended to demonstrate an improved prognosis when morphine
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was given.
When evaluating observational studies one must be aware of the confounding factors despite
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sophisticated statistical adjustment analysis. It is likely that morphine is given in a higher rate
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to those with a more pronounced acute heart failure situation. Neither is it possible, to evaluate if intubation was an “adverse effect” of receiving morphine or if the patient received morphine as a sedative in conjunction with the intubation in a retrospective registry study.
Based on the results mentioned above, it seems unlikely that serious respiratory depression is a widespread problem due to the use of morphine. Nausea, on the other hand, is a much more common adverse effect, which however may be corrected with antiemetics. Even though nausea is unpleasant, although not a dangerous adverse effect, it can be serious if the patient is receiving CPAP treatment. This illustrates how morphine has various benefits and risks in different subpopulations. The cardiodepressive effect that is described could equivalently be
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particularly crucial for hypertensive patients.
Benzodiazepines have been suggested as an alternative for morphine in treatment of
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pulmonary oedema [4,26]. However, these types of drugs have not been tested in this clinical situation properly. Nevertheless, this is interesting because benzodiazepines have shown to be efficient anxiolytics over a longer period of time, in addition to the fact that they have positive
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cardiovascular effects [42]. In a literature study, benzodiazepines were recommended in the
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treatment of chest pain due to these properties, and several aspects are presented suggesting
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that they could be an alternative in treatment of pulmonary oedema [42].
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Conclusion
Morphine is still used for pulmonary oedema in spite of relatively poor scientific background
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data. A randomised, controlled study is necessary in order to determine the effect – and
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especially the risk – when using morphine for pulmonary oedema. Since the positive effects are not sufficiently documented, and since the risk for increased mortality cannot be ruled out, one can advocate that the use should be avoided.
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Figure 1 Algorithm for treatment of acute pulmonary oedema, according to the guidelines from the European Society of Cardiology from 2012, which recommend that 4-8 mg of morphine i.v. may be
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considered and possibly repeated if needed by severe anxiety or distress [27]
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ACCEPTED MANUSCRIPT References
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Highlights
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Morphine may cause harm in patients with acute pulmonary oedema.
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The evidence for a vasodilatory effect is poor
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