Novel pH1N1 viral requiring veno-venous extracorporeal membrane oxygenation

Sujata Subramanian, MD; Jonna D. Clark, MD; Howard E. Jeffries, MD, MBA; D. Michael McMullan, MD

Objective: To report a case of pH1N1 viral infection presenting Measurements and Main Results: Discovery of severe dilated as requiring mechanical extracorporeal life support. cardiomyopathy and respiratory failure. Design: Case report. Conclusions: Patients with pH1N1 may present in profound Setting: Pediatric intensive care unit at a regional children’s hospital. heart failure in addition to respiratory failure. Extracorporeal Patient: Obese 14-yr-old boy who presented with pH1N1-related membrane oxygenation may play an important role in manag- cardiomyopathy and respiratory failure that required extracorporeal ing these complex patients. (Pediatr Crit Care Med 2011; 12: membrane oxygenation. 000–000) Interventions: Extracorporeal membrane oxygenation, echo- KEY WORDS: pH1N1; swine flu; cardiomyopathy; extracorporeal cardiography, high-frequency oscillating ventilation. membrane oxygenation; obesity; children

ince the first North American presenting in acute heart failure due to phy. These findings prompted transtho- cases of novel pH1N1 influenza novel viral . racic echocardiography, which revealed A were described in April 2009 severe with an es- (1), the Centers for Disease Case Summary timated 15% to 20% left ventricular ejec- SControl estimates that, as of December tion fraction. Laboratory studies were 2009, there have been between 39–80 The Institutional Review Board of Se- significant for elevated serum creatinine million cases in the United States. The attle Children’s Hospital approved this (1.3 mg/dL), B-type natriuretic peptide clinical spectrum of novel pH1N1 infec- project and provided exemption to the (1031 pg/mL; normal, Ͻ100 pg/mL), and tion ranges from mild upper respiratory requirement of informed consent. white blood count (6900; 68% neutro- tract symptoms to fatal pneumonia. An A previously healthy, mildly obese phils, 13% bands). In the setting of pos- (body mass index, 28.3 kg/m2) 15-yr-old estimated 8,880 to 16,460 pH1N1-related sible viral myocarditis, the patient was boy presented to his primary careprovider deaths have occurred in the United States empirically treated with intravenous im- with a 2-wk history of , productive (2), whereas it is believed that Ͼ14,000 munoglobulin. Direct fluorescent anti- cough with blood-tinged sputum, and deaths have occurred worldwide. Al- body testing of nasopharyngeal fluid did shortness of breath. Review of symptoms though the global number of novel not reveal adenovirus, respiratory syncy- Ͼ was remarkable for abdominal with pH1N1 cases is not known, 440,000 lab- tial virus, influenza A or B, parainfluenza coughing, fatigue, and exposure to sib- oratory confirmed cases had been re- viruses, or human metapneumovirus. Ad- ported to the World Health Organization lings with upper respiratory tract infec- tion symptoms. After a brief trial of con- ditionally, coxsackie, enterovirus, cyto- by October 2009 (3). megalovirus, Epstein-Barr virus, parvovi- Although fever, sore throat, and upper servative therapy for presumed viral upper respiratory tract infection, he was rus, and herpes simplex virus were not respiratory tract symptoms are the pre- detected by polymerase chain reaction dominate features of most patients pre- empirically treated with oral amoxicillin (PCR) of airway secretions. senting with novel pH1N1 infection, and clavulanate for the presumptive diag- The patient was then transferred to vomiting and diarrhea have been re- nosis of pneumonia. Worsening symp- Seattle Children’s Hospital for further ported in up to 25% of patients (4). In toms over the next 24 hrs prompted an management and evaluation for cardiac this report, we describe the unusual case emergency department visit, at which transplantation candidacy. On admission of a child with novel pH1N1 infection time he was noted to be in febrile and in profound respiratory distress with sys- to the intensive care unit, he was febrile, temic oxygen saturation of 71%. After a diaphoretic, tachycardic, and mildly hy- failed trial of noninvasive positive pres- potensive. Diffuse hazy airspace opacities From the Divisions of Pediatric Cardiac Surgery were noted on chest radiography (Fig. 1). (MM) and Pediatric Critical Care Medicine (HEJ), Seat- sure ventilation, he underwent endotra- tle Children’s Hospital, Seattle, WA. cheal intubation and required significant A second echocardiogram revealed left The authors have not disclosed any potential con- mechanical ventilatory support with 0.8 ventricle dilation without hypertrophy flicts of interest. FIO2 and 20 cm H2O of positive end- and an estimated body mass index with For information regarding this article, E-mail: an ejection fraction of 18%. Working on a [email protected] expiratory pressure to maintain adequate Copyright © 2011 by the Society of Critical Care oxygenation. The patient was subse- presumed diagnosed of severe respiratory Medicine and the World Federation of Pediatric Inten- quently transferred to a regional medical failure, viral pneumonia, and a viral car- sive and Critical Care Societies center where patchy infiltrates and car- diomyopathy, he was empirically treated DOI: 10.1097/PCC.0b013e3181e327c9 diomegaly were noted by chest radiogra- with ceftriaxone and intravenous immu-

Pediatr Crit Care Med 2011 Vol. 12, No. 1 1 findings in the setting of presumed viral myocarditis, a course of high-dose corti- costeroid therapy was initiated. Endo- myocardial biopsy was not performed at that time because of the risks associated with transferring the patient to the cath- eterization suite. The patient’s respiratory and cardiovas- cular status improved over several days, and he was successfully extubated but still required inotropic support. A subsequent echocardiogram demonstrated slightly im- proved cardiac function with moderate left ventricle and left atrium dilation, moderate mitral regurgitation, and estimated ejec- tion fraction of 23%. He underwent diag- nostic cardiac catheterization, which re- vealed normal coronary anatomy, 7 mm Hg transpulmonary gradient, and 34 mm Hg left ventricular end-diastolic pressure. En- domyocardial biopsy obtained at that time revealed myocytolysis and myofibers with Figure 1. Chest radiograph demonstrating diffuse hazy airspace opacity throughout the right lung hypertophic changes. Electron microscopy and in the middle and lower left lung. The transverse diameter of the heart is greater than 1⁄2 the thoracic diameter. demonstrated clearing of the cytoplasm and autophagic vacuoles, suggestive of ba- sophilic degeneration consistent with novel noglobulin. He required intravenous do- Veno-arterial ECMO was considered in pH1N1 viral infection 4 wks before the time pamine, dobutamine, and milrinone infu- the setting of poor cardiac systolic func- of biopsy. In light of ongoing myocardial sions to maintain adequate blood tion; however, the patient had evidence of dysfunction, he is being evaluated for pos- pressure and lidocaine infusion to control adequate perfusion with the assistance of sible cardiac transplantation. frequent premature ventricular contrac- pharmacologic inotropic support. In ad- tions. PCR analysis of nasal washings dition, his serum B-type natriuretic pep- DISCUSSION identified coronavirus and influenza A tide was relatively low (136 pg/mL), and that was subsequently subtyped as novel his serum troponin I was in the normal Between April and December 2009, pH1N1. Enteral oseltamivir and rimanta- range. Veno-venous ECMO flows of ap- 793 patients with confirmed or suspected dine were administered for influenza A. proximately 3.6 L/min were achieved, novel pH1N1 viral infection were evalu- However, poor intestinal absorption providing mixed venous oxygen satura- ated or treated at Seattle Children’s Hos- prompted conversion to intravenous tions of 75% to 80%. He was transitioned pital. Thirty-eight of the 233 hospitalized peramivir, an investigational antiviral to a conventional ventilator (40% FIO2,28 patients with novel pH1N1 infection, in- agent which has received Emergency Use cm H2O peak inspiratory pressure, 15 cluding the patient described in this re- Authorization from the Food and Drug cm H2O positive end-expiratory pressure, port, were admitted to the intensive care Administration for the treatment of novel and 13 cm H2O pressure support). His unit. Seventeen of these patients required pH1N1 influenza (5). Respiratory cul- pulmonary status improved over the next mechanical ventilation, with the average tures did not detect a bacterial source of 5 days. ECMO was weaned and success- length of intensive care unit care being respiratory failure or evidence of bacterial fully discontinued after 6 days of support. 6.1 days. In addition to the patient de- superinfection. Because of the inability to Four days after ECMO decannulation, the scribed in this case report, ECMO support achieve adequate ventilation and oxygen- patient experienced an acute episode of was initially considered for an immuno- ation using conventional ventilation with ventricular , which responded suppressed bone marrow transplant re- high pressure at 36 hrs, he was converted to electrical cardioversion and intravenous cipient with aspergillus infection and se- to high-frequency oscillatory ventilation. amiodarone therapy. In addition, the pa- vere pH1N1 respiratory failure. However,

Using ventilatory settings of 0.1 FIO2,35 tient experienced an episode of severe pul- because data from the Extracorporeal Life cm H2O mean airway pressure of, 5 Hz monary hemorrhage, necessitating rein- Support Organization (ELSO) registry in- frequency, and 80 cm H2O amplitude, he stitution of high-frequency oscillatory dicated no immunocompromised bone was only able to achieve an oxygenation ventilation. A subsequent echocardio- marrow transplant recipient ECMO sur- index of 60 and a PaO2/FIO2 ratio of 58. gram demonstrated evidence of ongo- vivors (6), ECMO was not offered and this To improve oxygenation and maxi- ing severe dilated cardiomyopathy with patient subsequently died of respiratory mize gas exchange, he was placed on an estimated ejection fraction of 15% failure. With the exception of this patient, veno-venous extracorporeal membrane and moderate mitral regurgitation. Se- all novel pH1N1 patients treated at our oxygenation (ECMO), using a wire- rum B-type natriuretic peptide in- institution have survived to extubation or reinforced cannula (31F, Avalon Labora- creased to 1600 pg/mL. Repeat PCR of hospital discharge. tories, LLC, Rancho Dominguez, CA) nasal washings did not detect influenza A. The Centers for Disease Control and placed via the right internal jugular vein. Based on worsening echocardiographic Prevention has identified several risk fac-

2 Pediatr Crit Care Med 2011 Vol. 12, No. 1 tors for novel pH1N1-related complica- stolic function, or con- pediatric patients who received ECMO tions, including age Ͻ2 yrs and Ͼ65 yrs, tribute to myocardial dysfunction. Mortal- support for severe, acute myocarditis sur- pregnancy, chronic medical or immuno- ity approaches 20% with full recovery of vived to hospital discharge. These reports suppressive conditions, and long-term as- ventricular function seen in 45% of cases clearly demonstrate that ECMO can be an pirin therapy in persons Ͻ19 yrs of age with acute viral myocarditis (17). important and lifesaving therapy for chil- (7). There is growing evidence that obe- The treatment of viral myocarditis dren with either viral respiratory failure sity may be an independent risk factor for largely remains supportive, with hemody- or myocarditis. As of September 2009, 36 novel pH1N1-related complications (8). namic instability being managed with va- patients with novel pH1N1 viral illness Initial data from the ELSO registry indi- sopressors and inotropic agents. Addi- who required ECMO support had been cate that 38% of patients placed on tionally, intravenous immunoglobulin reported to the ELSO registry (9). The ECMO for novel pH1N1-related illness and corticosteroid therapy may play a median age of these patients is 19 yrs, Ͼ had a body mass index of 30 (9). Although role in managing these patients. We did with half of the patients being Ͻ18 yrs of the etiological relationship between obesity not observe any appreciable improvement age. Six (27%) of the 22 women in this and severe novel pH1N1 illness has not in myocardial function after initiation of group were pregnant. Overall survival been fully elucidated, there is evidence that peramivir therapy in the patient de- was approximately 59%, which is similar increased body mass index is associated scribed in this report. However, it is pos- to that recently reported for adults who with significantly increased influenza- sible that the observed improvement in were supported by ECMO for severe related mortality in an animal model of pulmonary function was related to the obesity (10). In the subject of our report, use of this investigational agent. Mechan- acute respiratory failure (22). A com- obesity is the only potential risk factor for ical circulatory support, including intra- prehensive review (23) of the initial increased complications from novel pH1N1 aortic counterpulsation, ventricular as- clinical experience on using ECMO to influenza. sist device, or ECMO, may be required to support patients with novel pH1N1 in- Initial myocardial biopsy was not per- support patients with severe, refractory fluenza respiratory failure in Australia formed to confirm viral myocarditis in heart failure until recovery of ventricular and New Zealand was recently reported. this patient due to risks associated with function or heart transplantation. Al- The report is notable for the large per- transporting an ECMO-supported patient though extracorporeal biventricular me- centage (34%) of mechanically venti- to the cardiac catheterization suite. How- chanical support has been successfully lated pH1N1 patients who required ever, the patient’s clinical course, viral used to bridge an adult patient with in- ECMO support. The median age of load, and findings on subsequent myocar- fluenza A myocarditis to recovery (18), ECMO patients was 34 yrs, with only dial biopsy strongly suggest pH1N1- many of these patients ultimately die of three children requiring support. The induced cardiomyopathy. It may be ar- multiple organ system failure (19). Sim- median duration of ECMO support was gued that the patient’s nasal wash PCR ilarly, published reports (20) of the use of 10 days, with an overall survival of ap- was also positive for coronavirus; there- ECMO to support pediatric patients with proximately 75% at the end of the study fore, the observed myocarditis may have acute fulminate viral cardiomyopathy in- period. been causes by coronavirus infection. Al- clude successes and failures. A unique The rapid global spread of novel though coronavirus infection has been feature of the case described in this re- pH1N1 influenza has forced healthcare utilized in an animal model of viral myo- port is the successful use of veno-venous officials and providers to carefully review carditis (11), coronavirus has not been ECMO to support a patient with com- infection control policies, treatment identified by PCR of myocardial tissue bined cardiopulmonary failure rather strategies, and alternative hospital staff- specimens from patients suspected of than veno-arterial ECMO, which is the ing models. The burden of disease is so having viral myocarditis in a large re- most common modality (20). A recent significant that, in many settings, pa- ported series (12, 13). The only previously review (20) of international ELSO regis- tients being evaluated for symptoms of described association between coronavi- try data did not identify any infants, chil- acute respiratory illness are assumed to rus infection and myocarditis was de- dren, or young adults with acute myocar- be infected with novel pH1N1 influenza, scribed in a letter to the editor published ditis who have been supported with veno- and formal testing for definitive confir- in Lancet 30 yrs ago (14). Myocardial venous ECMO. We believe the use of mation of novel pH1N1 illness is not be- biopsies were not obtained in that case, veno-venous ECMO was appropriate in ing performed. Fortunately, severe life- and the relationship between coronavirus this case, because it reduces deoxygen- and myocardial dysfunction was based on ated coronary blood flow associated with threatening complications of novel circulating coronavirus antibodies. It is cervical veno-arterial ECMO cannulation. pH1N1 illness are uncommon and seem unlikely, therefore, that coronavirus was In addition, delivering oxygenated blood to be largely limited to specific high-risk the etiological agent of the myocarditis to the pulmonary circulation may facili- groups. The patient described in this case observed in our patient. Most cases of tate pulmonary , thereby re- presentation underscores the importance viral myocarditis are due to infection ducing myocardial stress of the right ven- considering unusual presenting symp- with enteroviruses or adenovirus (12, 15), tricle. Combined, these may improve toms, such as heart failure when evaluat- whereas myocarditis is an uncommonly re- myocardial recovery. ing patients at greatest risk for novel ported complication of influenza A infec- Over 2,000 children with nonbacterial pH1N1 complications. Furthermore, tion (16). The clinical presentation of acute pneumonia or acute respiratory failure ECMO support for novel pH1N1 patients viral myocarditis ranges from mild impair- have been supported by ECMO, with with refractory respiratory failure seems ment of myocardial function to cardiac to overall survival ranging from 50% to 63% to improve survival and should, there- severe heart failure and cardiogenic shock. (21). A recent review (20) of the ELSO fore, be considered early during clinical Dysrhythmia, impaired systolic and dia- registry revealed that 155 (61%) of 225 of course of these challenging patients.

Pediatr Crit Care Med 2011 Vol. 12, No. 1 3 REFERENCES influenza A (H1N1) virus infection—Michigan, during influenza A infection. Pediatr Infect June 2009. Available at http://www.cdc.gov/ Dis J 2006; 25:660–661 1. Ginsberg M, Maroufi A, Dunne G: Swine influ- MMWR/preview/mmwrhtml/mm58d0710a1. 17. McCarthy RE 3rd, Boehmer JP, Hruban RH, enza A (H1N1) infection in two children— htm. Accessed October 2, 2009 et al: Long-term outcome of fulminant myo- Southern California, March–April 2009. Avail- 9. Park P: H1N1 and ECMO: Review of ELSO carditis as compared with acute (nonfulmi- able at http://www.cdc.gov/mmwr/preview/ influenza experience 1990–2000. In: 20th nant) myocarditis. N Engl J Med 2000; 342: mmwrhtml/mm58d0421a1.htm. Accessed Annual ELSO Conference Proceedings. Ann 690–695 October 2, 2009 Arbor, MI, September 16, 2009 18. McGovern PC, Chambers S, Blumberg EA, et 2. CDC: CDC estimates of 2009 H1N1 influenza 10. Smith AG, Sheridan PA, Harp JB, et al: Diet- al: Successful explantation of a ventricular cases, hospitalizations and deaths in the induced obese mice have increased mortality assist device following fulminant influenza United States, April–December 12, 2009. and altered immune responses when infected type A-associated myocarditis. J Heart Lung Available at http://www.cdc.gov/h1n1flu/ with influenza virus. J Nutr 2007; 137: Transplant 2002; 21:290–293 estimates_2009_h1n1.htm. Accessed Octo- 1236–1243 19. Miura M, Asaumi Y, Wada Y, et al: A case of ber 2, 2009 11. Alexander LK, Keene BW, Small JD, et al: influenza subtype A virus-induced fulminant 3. WHO: Global Alert and Response (GAR): State- Electrocardiographic changes following rab- myocarditis: An experience of percutaneous ment by Dr Keiji Fukuda on behalf of WHO at bit coronavirus-induced myocarditis and di- cardio-pulmonary support (PCPS) treatment the Council of Europe hearing on pandemic lated cardiomyopathy. Adv Exp Med Biol and immunohistochemical analysis. Tohoku (H1N1) 2009. Available at http://www.who.int/ 1993; 342:365–370 J Exp Med 2001; 195:11–19 csr/disease/swineflu/coe_hearing/en/index. 12. Bowles NE, Ni J, Kearney DL, et al: Detection 20. Rajagopal SK, Almond CS, Laussen PC, et al: html Accessed October 2, 2009 4. Dawood FS, Jain S, Finelli L, et al: Emer- of viruses in myocardial tissues by polymer- Extracorporeal membrane oxygenation for gence of a novel swine-origin influenza A ase chain reaction. Evidence of adenovirus as the support of infants, children, and young (H1N1) virus in humans. N Engl J Med 2009; a common cause of myocarditis in children adults with acute myocarditis: A review of 360:2605–2615 and adults. J Am Coll Cardiol 2003; 42: the Extracorporeal Life Support Organiza- 5. Birnkrant D, Cox E: The emergency use au- 466–472 tion registry. Crit Care Med 2009; 38: thorization of peramivir for treatment of 13. Jin O, Sole MJ, Butany JW, et al: Detection of 382–387 2009 H1N1 influenza. N Engl J Med 2009; enterovirus RNA in myocardial biopsies from 21. Extracorporeal Life Support Organization In- 361:2204–2207 patients with myocarditis and cardiomyopa- ternational Registry Report. Ann Arbor, MI, 6. Gupta M, Shanley TP, Moler FW: Extracor- thy using gene amplification by polymerase July 2009 poreal life support for severe respiratory fail- chain reaction. Circulation 1990; 82:8–16 22. Peek GJ, Mugford M, Tiruvoipati R, et al: ure in children with immune compromised 14. Riski H, Hovi T, Frick MH: Carditis associ- Efficacy and economic assessment of conven- conditions. Pediatr Crit Care Med 2008; ated with coronavirus infection. Lancet tional ventilatory support versus extracorpo- 9:380–385 1980; 2:100–101 real membrane oxygenation for severe adult 7. CDC: Updated interim recommendations for 15. Bowles NE, Rose ML, Taylor P, et al: End- respiratory failure (CESAR): A multicentre the use of antiviral medications in the treat- stage dilated cardiomyopathy. Persistence of randomised controlled trial. Lancet 2009; ment and prevention of influenza for the enterovirus RNA in myocardium at cardiac 374:1351–1363 2009–2010seasonH1N1flu.Availableathttp:// transplantation and lack of immune re- 23. Davies A, Jones D, Bailey M, et al: Extracor- www.cdc.gov/h1n1flu/recommendations. sponse. Circulation 1989; 80:1128–1136 poreal membrane oxygenation for 2009 in- htm. Accessed October 2, 2009 16. Harre B, Nashelsky M, Douvoyiannis M, et al: fluenza A (H1N1) acute respiratory distress 8. CDC: Intensive-care patients with severe novel Fatal group A streptococcal myopericarditis syndrome. JAMA 2009; 302:1888–1895

4 Pediatr Crit Care Med 2011 Vol. 12, No. 1