Severe acute respiratory distress syndrome complicating type A (H1N1) influenza treated with extracorporeal CO2 removal
*Jakub Śmiechowicz, Barbara Barteczko, Małgorzata Grotowska, Teresa Kaiser, Stanisław Zieliński, Andrzej Kübler
Department of Anaesthesiology and Intensive Therapy, Wrocław Medical University
Background. The influenza pandemic of 2009 was reported to be frequently associated with pulmonary complications, including ARDS. We report the case of a morbidly obese, 37-year-old, AH1N1-infected woman, who was admitted to a regional hospital because of rapidly progressing respiratory failure. She was treated successfully with high frequency oscillatory ventilation (HFOV) and low-flow extracorporeal CO2 removal.
Case report. The patient was admitted to a regional hospital because of severe viral infection, diabetes and hypertension that developed during pregnancy. On admission, she was deeply unconscious (GCS 5), hypotonic and anuric. Conventional ventilation, veno-venous haemofiltration, antibiotics and antiviral therapy (oseltamivir) did not improve the patient’s condition, and she was transferred to a tertiary referral centre. Immediately before the transfer, she suffered two cardiac arrest episodes. They were successfully reversed.
On admission, the patient was hypercapnic (PaCO2 150 mm Hg/20 kPa), acidotic (pH 6.92) and hyperkinetic (HR 120 min-1, CO 12.7 L min-1). Total lung compliance was 21 mL cm H2O-1, and SAP/DAP was 63/39 mm Hg). The PaO2/FIO2 index was 85. HFOV was instituted for 48 h, resulting in a marked improvement in gas exchange, however any manipulations caused immediate deterioration in the patient’s condition. Extracorporeal CO2 removal was commenced and continued for 120 h, resulting in gradual improvement and eventual weaning from artificial ventilation after 17 days. Further treatment was complicated by septic shock due to Pseudomonas aeruginosa infection of the vagina, treated with piperacillin/tazobactam. The patient eventually recovered and returned to her regional hospital after 24 days.
Discussion. During the 2009 pandemic, a high number of pulmonary complications were observed all over the world. Viral infections are especially difficult to treat and the CESAR study indicated that the use of ECMO or extracorporeal CO2 removal devices may result in a lower mortality when compared with standard therapy. We conclude that the use of a simple CO2 removal device can be beneficial in complicated cases of AH1N1 influenza.
The pandemic influenza A/H1N1 virus was first detected in Mexico and other countries of North America in April 2009 ; afterwards it spread to all continents. In the majority of cases, the course of this new influenza was mild, yet some patients required ITU therapy due to severe, life-threatening respiratory failure . The respiratory failure in pandemic influenza was rapidly progressing and required early intubation and mechanical ventilation. In many patients, gas exchange provided with conventional methods of lung ventilation was insufficient, which led to rapidly increasing hypoxia, hypercapnia and death. Depending on the technical options available, patients were administered with various rescue therapies.
We report the case of an AH1N1-infected woman with severe respiratory failure treated successfully with high frequency oscillatory ventilation (HFOV) and low-flow extracorporeal CO2 removal.
A 37-year-old, morbidly obese woman (118 kg, BMI 41 kg m-2) with the history of chronic nicotinism was admitted to a regional hospital with symptoms of acute respiratory failure and suspicion of A/H1N1 influenza. Five weeks earlier the patient underwent Caesarean section. During pregnancy she was diagnosed with diabetes and hypertension; for a week she was complaining of symptoms of upper respiratory tract infection and progressing dyspnoea. The chest angio-CT did not demonstrate features of pulmonary embolism yet ARDS-like changes were visible. The material for diagnostic tests was collected; the patient was transferred to the ITU of a tertiary referral hospital due to the shortage of beds. On admission, the patient was in extremely severe condition, deeply unconscious (GCS 5) and required artificial lung ventilation with 100% oxygen; HR was 115 min-1, SAP/DAP 69/37 mm Hg. Gasometry showed pH 7.06, PaCO2 114.9 mm Hg (15.32 kPa), PaO2 44.8 mmHg (5.97 kPa), SaO2 59.4%. Bi-level mechanical ventilation was used with PEEP 16 cm H2O (1.6 kPa), PIP 31 cm H2O (3.1 kPa), FIO2 1.0, f 22 min-1, I:E 1:2, which resulted in the following parameters: PaO2 51.8 mm Hg (6.91 kPa), PaCO2 70.1 mm Hg (9.35 kPa), pH 7.23, SaO2 76.2 %. The broad-spectrum antibiotic therapy with oseltamivir and catecholamine infusion was initiated. The biochemical findings revealed elevated transaminases, CRP and D-dimers; since renal failure was progressing, veno-venous haemofiltration was continued. Due to the shortage of beds, the patient could not have been transferred to the ward of a higher referral level. Her condition continuously deteriorated.
After 2 days of treatment, the patient in critical condition was transferred to the ITU of an academic centre; however, before the transfer she experienced two short episodes of cardiac arrests in the mechanism of asystole.
After admission, the patient was analgosedated and did not respond to pain stimuli; her pupils were wide, symmetrical, with no reaction to light; due to respiratory failure, PCV with 100% oxygen was continued. Respiratory acidosis with marked carbon dioxide retention was observed: pH 6.92, PaCO2 150 mm Hg (20 kPa), PaO2 85 mm Hg (11.33 kPa), SaO2 91.4% (Table 1). The PaO2/FIO2 index during the first 4 hours ranged from 64 to 85 mm Hg/from 8.5 to 11.3 kPa; lung compliance was 21 mL cm H2O-1 (210 mL kPa-1). The circulation was stabilized with the infusion of noradrenaline (0.6 µg kg-1 min-1) and dobutamine (9 µg kg-1 min-1); HR was 120 min-1, SAP/DAP 110/60 mm Hg. Haemodynamic tests performed using the Swan-Ganz catheter demonstrated increased cardiac output (12.7 L min-1) and pulmonary artery pressure (63/39 mm Hg) (Table 1).
Despite the correction of parameters of mechanical lung ventilation, the patient was severely hypercapnic (PaCO2 90-100 mm Hg /12-13.3 kPa) and acidotic (pH 7.1) and required the infusion of bicarbonates. The treatment involved oseltamivir, meropenem, small doses of steroids and analgosedation with midazolam and fentanyl. HFOV was decided and started on day 5 of ITU stay. The patient’s clinical condition improved, which enabled gradual reduction in FIO2 from 1.0 to 0.55-0.6 and stabilization of PaCO2 at 50-70 mm Hg (6.7-9.3 kPa) as well as pH between 7.2 and 7.35. However, any nursing manipulations resulted in immediate deterioration of gas exchange parameters. Continuous veno-venous haemofiltration was administered with heparin for anticoagulation.
On day 3, the head CT was performed which demonstrated the presence of fluid in the left maxillary sinus and inflammatory changes in the ethmoid cells and the sphenoid sinus. During CT PCV was administered yet due to increasing hypercapnia and acidosis, HFOV was re-instituted. The influenza A/H1N1 infection was confirmed using the RT-PCR method. Another positive result was obtained in the swab collected on day 7 of ITU stay.
On day 4, conventional PCV was re-established at FIO2 = 0.55%. The change of ventilation mode resulted in another increase in PaCO2 to 68.5 mm Hg (9.13 kPa), decrease in pH to 7.23 and deteriorated blood oxygenation (PaO2 decrease to 58 mm Hg/7.73 kPa and SaO2 to 87.7%). The preparations for extracorporeal CO2 removal were started. The double-lumen dialysis catheter,14F, 20 cm long, was introduced to the internal jugular vein and the system for low-flow extracorporeal CO2 removal was attached (Decap, Hemodec, Italy). The procedure was carried out with the flow of 370 mL min-1 of heparinized blood. Using another catheter, continuous veno-venous haemofiltration was continued. During day 1 of extracorporeal CO2 removal, PaCO2 markedly decreased to 50-60 mm Hg (6.7-8 kPa), pH increased to 7.3-7.35 and blood oxygenation improved (PaO2 80 mm Hg/10.7 kPa, SaO2 96%). The bi-level mechanical ventilation was carried out according to the lung-sparing strategy − FIO2 55%, PEEP 14 cm H2O (1.4 kPa), PIP 30 cm H2O (3 kPa), obtaining the tidal volume of 4-6 mL kg-1.
Any nursing manipulations resulted in temporary deterioration of lung gas exchange, which required deeper analgosedation and muscle relaxants.
Extracorporeal CO2 removal was used for 61 h changing the system of drains, oxygenator and haemofilter every 24 h. The therapy was discontinued on day 6 due to clotting of the system; however, after 36 h, on day 8, because of persisting CO2 retention (pH 7.29, PaCO2 59.3 mm Hg/7.9 kPa, PaO2 71.5 mm Hg/9.5 kPa, SaO2 94.2, PaO2/FIO2 143 mm Hg/19.1 kPa), extracorporeal CO2 removal was re-administered, continued for further 60 h and discontinued once the system clotted again. The ventilation parameters were reduced: FIO2 from 0.55 to 0.4, PEEP from 14 to 10 cm H2O (1.4 to 1,0 kPa) and PIP from 30 to 24 cm H2O (3.0 to 2.4 kPa). The conventional mechanical lung ventilation was started on day 11, initially using the bi-level mode with FIO2 0.4-0.5, PEEP 8-10 cm H2O (0.8-1 kPa), PIP 24-30 cm H2O (2.4-3.0 kPa), until the patient was fully conscious and extubated on day 17 of ITU therapy. After extubation, passive oxygen therapy with periodic non-invasive ventilation was used due to tendency to hypercapnia.
Catecholamines (noradrenaline and dobutamine) were administered until day 5; noradrenaline was re-started between day 11-16 of treatment when the patient was diagnosed with bacterial septic shock. Its source was the genital tract infection with leucorrhagia. The vaginal swab showed the presence of Pseudomonas aeruginosa, which was also found in the cultures from the throat and vascular catheter tip. The bacterial septic shock was accompanied by elevated body temperature to 38.50C and laboratory parameters of infection: leucocytosis, procalcitonine (to 13.69 ng mL-1) and CRP (to 121 mg L-1). Interestingly, already on day 7 of ITU stay, CPR rapidly increased (from 19 to 97 mg L-1) and Pseudomonas aeruginosa was detected in blood using the PCR method (SeptiFAST, Roche), yet other symptoms of generalized infection were not observed. After the development of septic shock, meropenem was replaced with cefepime, changed into imipenem with cilastatine due to skin reaction; once the antibiogram was available, piperacil lin with tazobactam were administered and the infection symptoms subsided. Oseltamivir was discontinued on day 17 when the test results for influenza virus were negative.
Renal replacement therapy (continuous veno-venous haemofiltration followed by haemodialysis) was continued until day 16 and resulted in gradual restoration of renal function; thanks to improved respiratory efficiency, the range of rehabilitation exercises was gradually widened. On day 24, the patient was discharged from ITU in good general condition.
In the epidemic season of 2009/2010, the influenza A/H1N1 virus constituted 82.4% of all the viruses. In some patients the virus caused pneumonia and severe acute respiratory distress syndrome.
The distinguishing feature characteristic of pandemic influenza of 2009 was a high percentage of hospitalized patients requiring ITU therapy. In Australia and New Zealand 722 (14.4%) of 5000 hospitalized patients were treated in ITUs; in Canada this percentage was 19.7%, in the USA – 25% [4, 5, 6]. In Canada, mortality among hospitalized patients was 5.2% and in the United States – 6.5%. In one of the studies performed, the development of ARDS during pandemic influenza was associated with the mortality rate of 52% .
High mortality in ARDS is likely to be related to adverse sequels of aggressive mechanical lung ventilation [8, 9, 10]. Patients with ADRS are treated with alternative methods of lung function support, e.g. respiratory mixture with addition of nitrogen oxide, oscillation ventilation and extracorporeal gas exchange, which is to enable ventilation according to the lung-sparing strategy and to prevent further damage caused by aggressive mechanical ventilation
Between 1.06.2009 and 31.08.2009 in 15 ITUs of Australia and New Zealand in which extracorporeal membrane oxygenation was available, 252 patients with the diagnosis of influenza were treated; 201 of them required mechanical ventilation. In 68 (33%), ECMO was necessary due to extremely severe respiratory failure. Before ECMO, in 81%, at least one type of rescue therapy was used, e.g. lung recruitment manoeuvres, prone ventilation, oscillation ventilation, ventilation with nitrogen oxide or inhalatory prostacyclin. Moreover, 68% of them received vasoconstricting drugs and renal replacement therapy was administered in 24% . In the group of 68 patients provided with ECMO, 17 died (25%) .
Extracorporeal membrane oxygenation is a recognized method of management for extremely severe respiratory failure in neonates; however, in adults it is considered controversial. To date, the CESAR study published in 2009 is the only study to demonstrate the tendency to better survival in the ECMO group (63% vs 47%; p=0.07) . During the latest influenza pandemic, ECMO was successfully used in specialized centres in Australia and New Zealand , United States  and some European countries yet the number of hospitalized patients was limited by low availability of beds in these centres.
The use of ECMO is related to the risk of severe complications; the procedure is invasive, complex and requires trained medical personnel, including perfusionists, and may be applied only in specialized centres. In recent years, simpler and easier to apply methods of extracorporeal gas exchange were introduced, which can be used outside the specialized centres.
For one of such techniques, the Decap (Hemodec, Italy) is needed (Fig. 1) based on the system described by Livigni and colleagues . The procedure technique is similar to continuous veno-venous haemofiltration. The venous access is provided by a double-lumen vascular catheter 14F routinely used for veno-venous haemofiltration. The catheter is attached to the low-flow system of lines, oxygenator and haemofilter. The serum filtrated in the haemofilter is returned to the oxygenator where CO2 is re-removed. Such a design enables substantial CO2 removal at the blood flow of 300-400 mL min-1, i.e. markedly lower compared to the devices used to date in which the blood flow required for CO2 elimination (3-6 mL kg-1 min-1) is about 25% of cardiac output . Effective CO2 removal enables lung ventilation with lower tidal volumes, which reduces the risk of ventilator-induced lung injury [15, 17, 18]. Terragni and co-workers , who used this type of therapy in patients with severe ARDS, could reduce the tidal vol
umes from 6.3 to 4.2 mL kg-1 and plateau pressure from 29.1 to 25.0 cm H2O (2.9 do 2.5 kPa). This resulted in improved morphologic parameters of lungs on CT (reduced lung weight, decreased hyperinflation, and improved lung aeration), better blood oxygenation (PaO2/FIO2 increased from 136 to 221 mm Hg/18.1 to 29.4 kPa), and decreased levels of inflammatory cytokines in bronchial tree secretion obtained by BAL. Our observations confirm that the method enables lung sparing mechanical ventilation with the tidal volume of 6 mL kg-1 and plateau pressure <30 cm H2O (3 kPa), maintenance of PaCO2 at the level of 45-60 mm Hg (6-8 kPa), pH above 7.3 and PaO2/FIO2 between 110 and 190 mm Hg/14.6 – 25.3 kPa during the first days of therapy.
A/H1N1 influenza of 2009 is susceptible to neuraminidase inhibitors, i.e. oseltamivir or zanamivir and resistant to amantadine and rimantadine . During influenza AH1N1 pandemic, oseltamivir was most frequently used in the standard dose 2x75 mg for 5 days. For patients with severe influenza, i.e. with pneumonia of progressing disease, higher doses of oseltamivir (2x150 mg) and longer administration (e.g. 10 days) were recommended . In our case, oseltamivir treatment was started during the first hospitalization day, 2x75 mg, increased to 2x150 mg and continued until the culture results were negative and clinical improvement was observed, in total for 17 days.
The treatment was complicated by septic shock caused by bacterial superinfection with Pseudomonas aeruginosa. The source of infection was the genital tract. Meropenem used empirically since the admission to ITU was ineffective against the cultured species of Pseudomonas; the infection subsided after piperacillin with tazobactam. According to other literature findings, bacterial superinfections usually occurred in the form of bacterial pneumonia, diagnosed in 20-24% of patients with pandemic influenza treated in ITUs . The commonest pathogens found were Streptococcus pneumoniae, Streptococcus pyogenes and Staphylococcus aureus .
In each country affected by influenza pandemic of 2009, ITUs were faced with the problem of rapidly increasing number of new admissions at limited availability of beds. In many countries, almost 100% of such beds have been permanently occupied . In Mexico, where in March 2009, pandemic AH1N1 influenza started, four patients died in the admissions department before transfer to ITU was possible . In the case described, lack of vacancies delayed the transfer of the patient to ITU of higher referral level, which resulted in two episodes of cardiac arrest. In extremely severe respiratory failure during A/H1N1 influenza, alternative methods of lung support should be available in the selected intensive therapy units. One of such methods is extracorporeal CO2 removal using the Decap, which however cannot fully replace pulmonary gas exchange. In the most severe cases of hypoxaemia (PaO2/FIO2 <70 mm Hg/9.3 kPa, at PEEP ≥10 cm H2O/1 kPa), the use of extracorporeal blood oxygenation may be necessary .
In conclusions, A/H1N1 influenza may be complicated by rapidly progressing ARDS with systemic symptoms. Such complications should be treated using advanced methods of respiratory support, including extracorporeal gas exchange. Extracorporeal CO2 removal can be successfully used for the treatment of selected cases of respiratory failure during A/H1N1 influenza.
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