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European Review for Medical and Pharmacological Sciences 2019; 23: 7128-7134 Non-infarctual ST elevation and acute cardiopulmonary failure in carbon monoxide poisoning: a case report

Y. LONGHITANO1,2, M. CANDELLI3, H.A. MUIR1, A. AUDO4, S. MEDA4, P. DENNET LUMB1, J. MARSHALL BERGER1, G. PIGNATARO3, S. CICCHINELLI3, C. ZANZA1, F. FRANCESCHI3

1Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA 2San Giovanni Battista/Molinette Hospital, Turin, Italy 3University Hospital IRCCS – Fondazione Policlinico Gemelli, Rome, Italy 4SS Antonio e Biagio Hospital, Alessandria, Italy

Abstract. – OBJECTIVE: Carbon monoxide is (O2), Delayed Neurological Sequelae (DNS), carboxy- produced by the incomplete combustion of or- hemoglobin (COHb), The Italian Society of Emergency ganic fuel. In the United States, it is responsible Medicine-Urgency (SIMEU), The Italian Society of Un- for about 500 deaths annually. Increased car- derwater and Hyperbaric Medicine (SIMSI), hemoglobin boxyhemoglobin concentration and hypoxia dis- (Hb), peripheral oxygen blood saturation (SpO2), elec- rupt cardiac myocyte integrity and cause dys- trocardiogram (ECG), intensive care unit (ICU), Acute rhythmias, acute cardiac failure and coronary Heart Failure (AHF), transthoracic echocardiogram artery disease. We described a case of a patient (TTE), Acute Heart Failure (AHF), European Society with CO-poisoning and ST elevation at ECG pre- of Cardiology (ESC), creatine kinase (CK), creatine ki- cordial leads who developed severe transient nase-muscle/brain (CK-MB), amino-terminal fragment heart failure. of pro-brain natriuretic peptide (NT-proBNP), Emergen- CASE PRESENTATION: A 57-year-old man was cy Room (ER), pulseless electric activity (PEA), acute admitted to the emergency department for acute respiratory failure (ARF), ejection fraction (EF). carbon monoxide poisoning that led to respira- tory and cardiac failure. The electrocardiogram showed ST elevation in precordial leads, but the coronary angiography was normal. The patient was successfully treated and discharged. Three Introduction days later he was readmitted for similar symp- toms and subsequently died. We hypothesize Acute carbon monoxide (CO) intoxication is that the ECG findings were related to transient the most common type of accidental poisoning coronary vasospasm due to CO poisoning and in industrialized countries and is responsible that acute respiratory and cardiac failure related for 40-50,000 emergency department visits in to carbon monoxide toxicity caused death. 1,2 CONCLUSIONS: The management of patients the United States . CO is a colorless, odorless, poisoned by carbon monoxide requires ear- tasteless, and non-irritating gas produced by the ly identification and intensive treatment and a incomplete combustion of any type of organic careful evaluation of the home environment pri- fuel in conditions of oxygen deficiency3-8. Small or to discharge. ST elevation in such patients amounts of CO are physiologically produced by may be related to coronary vasospasm. enzymatic reactions, the most important of which Key Words: is catalyzed by heme oxygenase (HO)9,10. Its toxic Carbon monoxide, Cardiac failure, Coronary vaso- effects include inflammation, interruption of cel- spasm, STEMI. lular respiration, oxidative stress, and apoptosis with the activation of hypoxia-inducible 1α factor (HIF-1α) and neurologic and cardiac damage11. Abbreviations The main signs and symptoms mimic a gastroin- Carbon monoxide (CO), ST elevated myocardial infarc- testinal infectious disease and include headache, 12,14 tion (STEMI), not ST elevated myocardial infarction dizziness, nausea, and vomiting . Among its (NSTEMI), Central Nervous System (CNS), oxygen acute neurological manifestations, we find con-

7128 Corresponding Author: Yaroslava Longhitano, MD; e-mail: [email protected] Non-infarctual ST elevation and acute cardiopulmonary failure in carbon monoxide poisoning fusion, concentration deficit, initial irritability ible ventricular dysfunction, which occurs when followed by lethargy and coma14. The delayed reperfusion follows a short ischemic event40. The manifestations, also known as Delayed Neuro- cardiac damage most commonly displays with logical Sequelae (DNS), are seen in about 30% of tachycardia41, dysrhythmias and electrocardio- cases and can sometimes occur a long time after graphic alterations42, myocardial infarction43,44, exposure15-18. The cardiac manifestations assume pulmonary edema, and cardiogenic shock45. The great clinical significance since the cardiocytes electrocardiographic changes are not correlated are highly sensitive to hypoxia and ischemia to COHb concentration46. The CO can unmask caused by the disruption of mitochondrial oxida- an unknown coronary arterial disease leading tive reactions by elevated CO levels19. Since CO to a myocardial ischemia33. Myocardial ischemia intoxication frequently presents with non-specific and necrosis have been described even in patients signs and symptoms, it may not be diagnosed rap- with healthy coronary arteries43. Therefore, when idly20 and is frequently confused with other acute CO intoxication is suspected, coronary angiog- diseases21,22. In most of the cases, the determina- raphy should be considered in order to rule out tion of the plasma levels of carboxyhemoglobin undiagnosed coronary artery disease47. A few (COHb) confirms the diagnosis23. Plasma levels cases of ST elevation without significant coronary of COHb are not predictive of the severity of stenosis has been described and related to coro- intoxication unless levels are 40-50% higher than nary spasm and variant angina48,49. the baseline24. This depends on time elapsed be- tween exposure and subsequent determination of Case Report plasma COHb and on the ability of the lungs and A 57-year-old Caucasian man was admitted kidneys to eliminate carbon monoxide from the to the Emergency Department due to anxiety, organism25,26. The Italian Society of Emergency confusion, tachycardia, and dyspnea. The pa- Medicine-Urgency (SIMEU) has proposed a se- tient did not report any significant past medical verity grading based on clinical manifestations27. history. The patient did not take any medi- CO cardiotoxicity is well documented. CO-in- cation, did not consume alcohol, and did not duced cardiac toxicity was reported for the first smoke. Admission vital signs were noted: reg- time in 1865, when Klebs et al28 described dif- ular radial pulse with an average heart rate fused hemorrhagic spots in the cardiac tissue. of 110 beats per minute, arterial pressure of CO is cardiotoxic and the damage can be revers- 180/90 mmHg and peripheral oxygen blood 29-31 ible or permanent . CO toxicity derives from saturation (SpO2) of 90% in ambient air and the combination of tissue hypoxia and direct spontaneous breathing with an average respira- CO-mediated cellular damage32. It competes with tory rate of 25 breaths per minute. The axillary molecular oxygen (O2) for hemoglobin (Hb) bind- temperature was normal. Cardiac examination ing sites, with an affinity 200-250 times higher revealed a regular rate and rhythm with normal than O2. The binding of Hb with CO forms heart sounds and a holosystolic murmur at the COHb, which reduces the hemoglobin available apex. Chest examination noted symmetrical for oxygen transport to the tissues33. Moreover, thoracic activity, normal expansion, and bilat- the release of O2 to the tissues is altered because eral basal end-inspiratory crackles. Abdominal of COHb shifts the oxyhemoglobin dissociation examination was normal; no swelling of the curve to the left, making its shape more hyper- feet or legs was detected but the extremities bolic34. Free dissolved CO damages the heart were cold. The patient was alert, answered sim- 35,36 directly: it competes O2 for cytochrome-a ple questions accurately and was able to exe- and inhibits cardiac cytochrome-oxidase activity cute simple tasks; the pupils were equal, round interfering with mitochondrial cell respiration37; and normally reactive to light; the neurological it also binds intracardiac myoglobin heme, by examination was normal. The patient lived in 38 inhibiting myoglobin-dependent O2 uptake . An the countryside and used a pellet stove to heat additional element of cardiotoxicity of CO results his bedroom without any aeration system. An from the oxidative stress: the overproduction of arterial blood gas analysis showed respiratory oxygen free radicals overwhelms antioxidant de- acidosis with hyperlactatemia, increased anion fensive capacity, resulting in cell damage15. These gap, and a concentration of COHb above 15%. observations support the hypothesis that CO poi- CXR detected pulmonary edema. The ECG soning causes a stunned myocardial syndrome39. showed sinus tachycardia with ST-segment ele- This syndrome consists of transient and revers- vation in the precordial V1-V6 leads.

7129 Y. Longhitano, M. Candelli, H.A. Muir, A. Audo, S. Meda, et al.

Figure 1. ST-elevation is correlated with myocardial infarction, pericarditis, and myocarditis. Probably the acute myocarditis that occurred in this patient is due to chemical damage of CO on myositis or to vasospasm.

The patient rapidly decompensated with the He was admitted to the Intensive Care Unit onset of hypotension (systolic BP < 90 mmHg), (ICU). Acute Heart Failure (AHF) with cardio- worsening hypoxemia, and respiratory acidosis. genic shock and respiratory failure was suspect-

Figure 2. Mutual effects of the CO poisoning on the cardiac and pulmonary function. The carbon monoxide (CO) displays direct toxicity on the myocardiocytes leading to acute heart failure (AHF) and thus to pulmonary edema and to acute respiratory failure (ARF) type I (lung failure). Little is known about a direct effect of this toxic gas on the pneumocytes. The CO is also responsible for indirect effects by establishing a hypoxic condition that is multifactorial (leftward shift of the oxyhemoglobin dissociation curve, unconsciousness, tissue hypoperfusion) and a mixed acidosis. The hypoxia exacerbates the AHF by affecting the contractile function of the myocardiocytes and sustains an ARF type II (pump failure) by causing the fatigue of the respiratory muscles.

7130 Non-infarctual ST elevation and acute cardiopulmonary failure in carbon monoxide poisoning ed. A transthoracic echocardiogram (TTE) was Discussion performed and demonstrated globally reduced left ventricular contractile function with ejec- As described in the literature and confirmed tion fraction of 20-25% and a severe mitral by our clinical case, blood COHb concentra- regurgitation; the pericardium was normal. The tion is not a reliable prognostic marker in the patient was treated with ventilatory and circu- CO-poisoned patient. In this case, the patient latory support. He underwent an orotracheal outcome was deadly, despite the normalization intubation under sedation with subsequent lung of COHb concentration after the hyperbaric protective mechanical ventilation and inotropic oxygen therapy and the initial recovery. This support. The patient responded quickly, and pe- can be explained by the accumulation of large ripheral perfusion was restored. As the patient amounts of CO in the tissues and its subsequent was confused and had cardiovascular failure and release, which can lead to coma and fulminant acidosis, hyperbaric oxygen therapy was start- cardiorespiratory failure51. In addition to the ed and maintained until COHb concentration toxic mechanisms described so far, we hypothe- was reduced to normal values (<3%)25,50. Blood size that acute heart failure and acute respiratory cell count, electrolytes, renal, liver, and thy- failure induced by CO worsen one another. We roid function were all within the normal range. can reasonably state that the initial impairment Creatine kinase (CK), creatine kinase-muscle/ in both lung and heart function is sustained by brain (CK-MB), troponin and lactate dehydro- hypoxia which depends on two main factors: the genase (LDH) were higher than the normal val- leftward shift of the oxyhemoglobin dissociation ue. The amino-terminal fragment of pro-brain curve and the interruption of cellular respiration natriuretic peptide (NT-proBNP) was slightly due to inhibition of the mitochondrial IV com- elevated. The ECG showed a pattern indicating plex17. In addition, CO-poisoned patients may be an Acute Coronary Syndrome (ACS). Given the unconscious this leading to impaired ventilation ECG findings and the increased concentration and thus to acute respiratory failure (ARF) type of myocardial necrosis markers, a coronary an- II (pump failure). Pump failure causes carbon giography was performed but it did not detect dioxide (CO2) retention with respiratory acido- any stenosis or other abnormalities of the coro- sis; at the same time, the interruption of cellular nary arteries. It was supposed that ECG finding respiration due to inhibition of the mitochon- was related to coronary vasospasm related to drial IV complex causes metabolic acidosis52. CO intoxication. After 12 hours of mechanical The hypoxia and the acidosis are responsible for support, lung function improved, and no fur- myocardial damage and subsequent reduced EF ther evidence of cardiopulmonary failure was heart failure with high capillary wedge pressure observed. The subsequent arterial blood gas (PCWP). The increase of PCWP explains the analysis was normal, and the radiogram of the onset of pulmonary edema which itself sustains chest showed no further evidence of pulmonary a type I acute respiratory failure (ARF-I) also edema. The cardiac necrosis markers decreased known as lung failure. The ARF-I maintains the to normal levels. The TTE was repeated and de- hypoxia that causes the fatigue of respiratory tected an improved EF to 50-60% with no global muscles that is itself a cause of ARF-II. More- dysfunction; mitral regurgitation was no longer over, severe acidosis is known to increase the documented. The patient was extubated and effects of parasympathetic nervous activity. It is discharged to the Internal Medicine (IM) ward possibly due to interfering with the hydrolysis of for monitoring and care. He remained hemo- acetylcholine by acetylcholinesterase that will dynamically stable for the following two days result in a depression of the respiration12. While and discharged. Three days later, he was re-ad- the CO direct toxicity on the cardiac and ner- mitted to the Emergency Room (ER) with the vous cells is well described in the literature32-34, same cardiovascular condition. He had the same little is known about a possible direct damage on TTE pattern of the previous admission with the pneumocytes. Reilly et al53 have investigated decreased ejection fraction (EF) and global left the role of air pollution on lungs and have con- ventricular dysfunction. The measured COHb cluded that long-term low-to-moderate air pol- level was higher than 20%. He died from acute lutants exposure is associated with an increased cardiac failure and cardiac arrest with pulseless risk of Acute Respiratory Distress Syndrome electric activity (PEA) despite prompt treatment after severe trauma. Althaus et al54 have stud- and resuscitative measures. ied the effects of CO on the alveolo-capillary

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