292
failure (ARF) might be better treated by temporarily
Preliminary Communication
TREATMENT OF ACUTE RESPIRATORY
FAILURE WITH LOW-FREQUENCY
POSITIVE-PRESSURE VENTILATION AND
EXTRACORPOREAL REMOVAL OF CO2
L. GATTINONI* A. AGOSTONI†
A. PESENTI* A. PELIZZOLA*
G. P. ROSSI* M. LANGER*
S. VESCONI* L. UZIEL†
U. FOX‡ F. LONGONI‡
T. KOLOBOW§ G. DAMIA*
*Istituto di Anestesiologia e Rianimazione, †Istituto di Clinica
Medica VII, and ‡Istituto di Clinica Chirurgica III, Università di
Milano; and §National Institutes of Health, Bethesda, Maryland,
U.S.A.
Summary Terminal respiratory failure was reversed in
three patients with a combination of extra-
corporeal CO2 removal through a membrane lung and
oxygen diffusion into the diseased lungs between mechanical
breaths induced at a frequency of 2-3/min. The technique
seems to prevent the pulmonary barotrauma and extrapul-
monary derangements caused by conventional mechanical
ventilation.
INTRODUCTION
IN the past few years advances in extracerporeal oxygen-
ation had seemed to encourage the hope that acute respiratory
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shunting a portion of the cardiac output through such a
system. A multicentre trial was carried out in the U.S.A. to
determine whether a combination of conventional positive-
pressure ventilation with extracorporeal membrane oxygen-
ation (ECMO)I would be helpful. However, the outcome of
this trial was disappointing and led us to experiment in
normal2 and pathological models with an alternative
method, in which ventilation movement is eliminated or
greatly reduced when CO is extracted extracorporeally
while oxygen is supplied by diffusion through the natural
lungs either kept motionless or ventilated at 2 or 3 times per
minute5 (low-frequency positive-pressure ventilation with
extracorporeal C02 removal, LFPPV-ECC02R).
We have used this technique successfully in three patients
in refractory acute respiratory failure in whom conventional
therapy had failed. The three patients recovered from ARF
after 2 to 13 days’ treatment. The common pattern showed an
immediate gain in pulmonary gas exchange with reduced
right-to-left shunt, improved lung compliance, and pro-
gressive clearing of chest X-ray films.
This technique seems to overcome the ventilation/per-
fusion mismatching due to ventilation maldistribution in
stiff, non-homogeneous lungs and prevents the pulmonary
barotrauma and extrapulmonary derangements caused by
conventional mechanical ventilation.
LOW-FREQUENCY POSITIVE-PRESSURE VENTILATION WITH
EXTRACORPOREAL CO2 REMOVAL: THE CLINICAL
TECHNIQUE
During the procedure patients were kept paralysed with
pancuronium and anaesthetised with alphaxalone. After
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DC, Rees Smith B, Yeo PPB, Clark F, Hall R. Value of
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thyrotoxic relapse in Graves’ disease. Lancet 1977; i: 1181-82.
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stimulator. Lancet 1979; i: 693-95.
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1979; ii: 78-80.
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Autoimmune aspects of endocrine disorders. London: Academic Press,
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for human thyroid cells in culture. Proc Nat Acad Sci USA 1979; 76:
2022-26.
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anaesthesia and the injection ofa bolus of 1 mg/kg of heparin,
wire-reinforced polyurethane catheters were advanced into
the inferior vena cava through the femoral vein for blood
drainage and into the superior vena cava through the internal
jugular vein for venous return. The distal part of femoral and
internal jugular veins were also cannulated. The extra-
corporeal circuit was completed with a roller pump and two
Kolobow SciMed membrane lungs (surface area 3’55 m2x 2)
(fig. 1). Gas flow and blood flow in the membrane lung were
adjusted to clear the natural CO2 production (200-300
ml/min) and averaged 161/min and 1’31/min respectively. As
soon as ECC02R was started a polyvinyl catheter was
advanced through a side arm of the tracheal tube to the level
of the carina. This catheter was connected to a 100% oxygen
source adjusted to provide a flow of 200-300 ml/min. The
servo ventilator was set in intermittent-mandatory-ventila-
tion (IMV) mode at three breaths/min, with the peak-pressure
safety valve adjusted to 45 cm H20. The inspired oxygen
fraction (FI02) and positive end-expiratory pressure
(PEEP) levels of the ventilator were set according to the
clinical course, and since the patients were paralysed no
respiratory movements were observed between the three
mandatory tidal volumes/min.
During the end-expiratory pause (which lasted about 18 s)
the PEEP level (i.e., lung volume) was maintained by the
oxygen supplied thrpugh the carina catheter. As the only gas
exchanged during this time within the lungs is oxygen, the
amount of oxygen supplied to maintain lung volume equals
the oxygen consumed during the same time. Any excess of
oxygen delivered through the carina catheter such as to
increase the selected pressure within the lung is vented
through the PEEP valve.
The ventilation FI02and FI02 of the gases ventilating the
membrane lung were progressively reduced according to the
clinical course. During the weaning period patients were
decurarised and anaesthesia was suspended. C02 removal by
the membrane lung was progressively reduced, and the
patient was allowed to breathe on IMV. The patients were
disconnected when able to maintain a normal PC02 on IMV
or continuous positive airways pressure (CPAP) without any
extracorporeal support.
During the procedure heparin was given by continuous
infusion to maintain the activated clotting time between 90
and 120 s (generally less than 0’22 mg/kg/h). Platelet count,
fibrinogen, and coagulation tests during bypass were
routinely done at least twice a day, according to the clinical
course. After the bypass was discontinued and the catheters
Fig. l-Low-frequency positive-pressure ventilation Iwith extra-
corporeal removal of CO 2 .
F=flowmeter, H=humidifier, T=transducers, CDML=carbon-dioxide
membrane lung, BP=blood pump, RB=reservoir bag, VC=vacuum,
C=water trap, WV =water vale, OX=oxymeter, V= ventilator.
293
HAEMODYNAMIC CHANGES DURING BYPASS
had been removed heparin was maintained for a further 4
days at aprogressively decreasing dose level to protect the
repair of jugular and femoral veins.
Intensive monitoring was carried out throughout the
procedure, in particular continuous surveillance of
haemodynamic, respiratory, and haematological states. The
haemodynamic changes are summarised in the table.
CASE-REPORTS
Patient 1
A 25-year-old woman was admitted to hospital with aplastic
anaemia (Hb 3 g/dl). She was 5 months pregnant. Blood transfusion
restored the haemoglobin level to normal, but a laparotomy had to be
carried out to remove a dead fetus. 3 days later she became pro-
gressively dyspnoeic, tachypnoeic, and cyanotic, and a chest X-ray
showed "white lungs" typical of adult respiratory-distress
syndrome. She had a fever of39°C. She was transferred to intensive
care and treated with continuous positive-pressure ventilation
(CPPV). CPPV progressively failed to provide adequate respiration
and a decision to connect the patient was taken after 50 h, when the
PaC02and Pa022 had fallen to 42 -7 and 46 -mm Hg respectively,
Qva/Q was 0’ 6, deadspace/tidal-volume ratio(VD/VT) 0’ 67, lung
compliance 25 ml/cm H2O. CPPV was at that time at 16
breaths/min, FI02 0-8, PEEP 10 cm H20, and pulmonary
ventilation 141/min. The extracorporeal circulation was established
at 1-5 5 1/min, with CO2 removal averaging 210 ml/min. The 02
supplied extracorporeally was less than 20% ofVO 2’ PaCOand pH
were very stable at 35 · 2±0 · 4 mm Hg and 7-40±0-01.
After 35 h, weaning was started. The patient was decurarised,
woken up, and then allowed to breathe spontaneously between the
three mandatory tidal volumes. The CO2 through the membrane
lung was progressively diminished and she was found to be able to
tolerate IMV at 3 breaths/min, FIO 0 - 4, and PEEP ofl0cmH20.
4 h after extracorporeal CO2 removal was discontinued, the
perfusion was stopped and the patient was disconnected. An hour
after disconnection Pa02and PaC02were 98 - 7 and 31’00 mm Hg
respectively at a total ventilation of 8 t/min, 15 breaths/min, FI02
O’ 4, and PEEP 10 cm H20. Qva/Q was then O’ 18, lung compliance
555 mi/cm H 20, and VD/VT 0 -3. 7 days after termination of bypass
the patient suffered a dehiscence of the laparotomy wound and
Pseudomonas xruginosa peritonitis. She died of septic shock 7 days
later with no worsening of pulmonary function until a few hours
before death.
Patient 2
A very obese woman aged 55 was admitted with severe thoracic
trauma after a traffic accident. Bilateral atelectasis developed, and
294
Fig. 2-Patient 2: ventilator FIO, (top), PaO,. total static com-
pliance, and venous admixture (Qva/Q) during bypass.
Pa0 2 and Qva/Q values are averaged over each 24 h period.
she was treated with CPPV. Pulmonary function progressively
deteriorated over the next 5 days as the lung fields opacified. On the
6th day of CPPV she developed a pneumomediastinum and sub-
cutaneous emphysema, and the Pa02 fell to below 50 mm Hg
despite an FloofO-8, PEEP 15 cm H 20, and VE 221/min. When
she was connected to the LFPPV-ECC02R the ventilatory
parameters were as follows: PaO 47-0, PaC02 34-7, Qva/Q 0-6,
VD/VT 0 - 8, lung compliance 11 ml/cm H2O. CPPV was at that
time at 22 bmp, Floz 0 · 8, PEEP 15 cm H 20, and pulmonary
ventilation 251/min. Fig. 2 plots the course of the Pao 2, Qva/Q, and
lung compliance throughout the bypass. Pa02 rose despite a
reduction in ventilator FI02from 1 -0to 0 -3, and a fall in Qva/Q.
Lung compliance, however, did not change for 10 days and
improved only moderately on the 1lth day. Weaning began on the
1 lth day and was completed on the 13th day. The technique was
similar to that used in case 1, except that progress was more gradual.
When she was able to maintain normal gas exchange on CPAP with
an FI02 of0’4 4 and PEEP of 5 cm H2O she was disconnected from
extracorporeal support. Subsequently she was able to breathe room
air without support. 15 days later she was discharged and is now in
good health.
Patient 3 .
A 33-year-old woman was admitted with cystopyelitis. 5 days later
she became hyperthermic with urine and blood cultures positive for
Escherichia coli. On the 7th day she became dyspnceic, tachypnoeic,
and cyanotic, with progressive opacification of the chest X-ray. 3
days later she was transferred to an intensive-care unit with acute
renal and respiratory failure. She was treated with CPPV for 11
days, but pulmonary function progressively deteriorated and she
was referred to our unit for extracorporeal support. Before the con-
nection the respiratory parameters were as follows: Pa02 57 mm
Hg, PaC02 43 mm Hg, Qva/Q 0 - 6, VD/VT 0 - 7, lung compliance
10 ml/cm H2O. CPPV was 20 bpm, FI02 0-8, PEEP 15 cm H2O,
and pulmonary ventilation 18 1/min. The patient also had
pulmonary hypertension (mean pulmonary-artery pressure [PAP]
50 mm Hg). During the first 2 h of bypass PAP fell to 22 mm Hg.
Urine output rose dramatically in the first 6 h of bypass from an
hourly mean of 70 ml to 500 ml before becoming normal. On the 4th
day weaning was started with progressive reduction of extra-
corporeal CO2 removal, allowing the patient to breathe on CPAP.
On the 5th day she was disconnected and kept on CPAP (5 cm H 20
of PEEP). 6 days later she was able to breathe room air PQ!1:...
taneously. A week later she was discharged and is now in goo3"
health.
DISCUSSION
The comparative failure of the ECMO trial stimulated us to
devise an alternative technique to conventional CPPV
associated with supplementary extracorporeal oxygenation.
We chose to rest the lung with diffusion oxygenation (3
breaths/min), avoiding possible pulmonary and extra-
pulmonary complications of CPPV, and removed CO2
through a membrane lung by low-flow veno-venous bypass to
make lung rest feasible. In pathological models3 this form of
treatment resulted without exception in a common
pattern-rise in Pa02> a fall in Qva/Q, an improvement in
lung compliance, and clearing of the chest X-ray. Our
patients showed a similar pattern. Whereas the
improvements in natural lung gas-exchange as judged by
Pa02 and Qva/Q trends were almost immediate, the rise in
compliance and X-ray clearing were observed in our patients
at different intervals (10 h, 11 days, and 15 h). The different
times required for the immediate fall in Qva/Q and the later
lung-compliance improvement probably reflect respectively
the functional and the anatomopathological improvement. It
is possible that lowering total ventilation from 15-20 1/min
(20 breaths/min) to 0 -7— 1’ 51/min (3 breaths/min) results in a
better distribution of gases in highly diseased lungs in which
compliance distribution is not homogeneous.
Although entry criteria of our patients in this study were
the same as in the ECMO trial, the weaning criteria were
completely different. In every patient we treated the ECMO
weaning criteria were met after only a few hours of LFPPV-
ECC02R. However, ECMO criteria are based on gas
exchange alone, which can be misleading when dissociated
from a parallel improvement in lung compliance. In our view,
patients should be weaned when they can be ventilated at
normal volume and pressure or, as in the second and third
cases, when they can maintain spontaneous breathing.
The technique immediately improves local conditions
within the diseased lung (PCO, P02, pH), overcomes the
problems of ventilation of stiff and non-homogeneous lung,
provides an even gas distribution, and prevents the pulmon-
ary barotrauma and extrapulmonary complications of high-
pressure, high-volume CPPV. It is possible that all these
factors together combined to provide a better environment
for lungs to heal, without compromising the general cir-
culation or increasing lung damage. This allows prolongation
of extracorporeal support until complete resolution of the
disease.
LFPPV-ECCO 2R with increasing experience appears to be
safe and easy, and the only common complication observed
(bleeding) can be easily controlled by blood transfusion. It is
hoped that this technique can eventually be applied as a
partial support in earlier stages of the disease as an alternative
to high-volume, high-pressure mechanical ventilation. In
such circumstances much simpler vascular access similar to
that used in renal dialysis will probably be sufficient.
We thank Prof. D. G. Melrose for his help in preparing the manuscript; the
Transplantation, Immunology and Blood Transfusion Service, Policlimco,
Milan, for continuous support; and the medical and nursing staff for their
generous help. This work was supported in part by Special Project on
Biomedical Engineering, contracts 78.00474.86 and 78.00452.86, from
CNR, Rome.
Requests for reprints should be addressed to L.G., Istituto di Anestesiologia
e Rianimazione, University of Milan, Via F. Sforza 35, 20122 Milan, Italy.
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