- Email: [email protected]
Liquid ventilation in adults, children, and full-term neonates
RER status also allows clinical and pathological characteristics of HNPCC to be more sharply defined. These features could be used to develop simple diagnostic models for testing on other data sets. The data do not preclude the operation of other hereditary factors in families designated as A/RER-, B/RER+, or B/RER-. This work was funded by the Health Research Council and the Cancer Society of New Zealand.
References 1 Vasen HFA, Mecklin J-P, Khan PM, Lynch HT. The international collaborative group on hereditary non-polyposis colorectal cancer (ICG-HNPCC). Dis Colon Rectum 1991; 34: 424-24. 2 Aaltonen LA, Peltomäki P, Mecklin J-P, et al. Replication errors in benign and malignant tumours from hereditary nonpolyposis colorectal cancer patients. Cancer Res 1994; 54: 1645-48. 3 Weissenbach J, Gyapay G, Vignal A, Morissette J, Pillasseu P. A second-generation linkage map of the human genome. Nature 1992;
E, Vesa J, Alitalo K, Peltonen L. An Alu variable polyA repeat polymorphism upstream of Lymc at 1p32. Hum Mol Genet 1992; 1: 217. 5 Jones MH, Yamakawa K, Nakamura Y. Isolation and characterisation of 19 dinucleotide repeat polymorphisms on chromosome 3p. Hum Mol Genet 1992; 1: 131-33.
Liquid ventilation
in full-term neonates
adults, children, and
We evaluated the
and
safety
efficacy
Selection criteria and technique of ECLS are described elsewhere." Partial liquid ventilation was started 1-11 days after institution of extracorporeal support. The only exclusion criterion for the liquid ventilation protocol was active pulmonary airleak. During data collection, we used time-cycled, pressurecontrolled ventilation to generate a peak inspiratory pressure of
HO, peak end-expiratory rate
of Pathology (Prof J R Jass MD, D S Cottier MSc, P Jeevaratnam MSc, V Pokos MD, K M Holdaway MSc, M L Bowden BSc) and Molecular Medicine (N S Van de Water PhD, P J Browett FRCAP), School of Medicine, University of Auckland, Private Bag 92019, Auckland, New Zealand
of
pressure of 6-10
cm
H2O,
20-30/min, inspiratory:expiratory ratio of
Correspondence to:
Prof
Jeremy
R Jass
1:3, and fraction of inspired oxygen 1-0, depending
on the size. Perflubron (C8F27Br, LiquiVent, Alliance Pharmaceutical Corp, San Diego) was administered via the endotracheal tube at 2-5-10 mLJkg over 5-15 min. The dose of perflubron was repeated about every 30 min until a sustained meniscus was noted at the level of the sternum within the endotracheal tube. Mean initial dose of perflubron was 13-9 (SD 2-2) mL/kg (range 5-40). We redosed with perflubron daily with a mean cumulative dose of 36-3 (3-6) mLJkg (15-62-5) over 1-7
patient’s
Although liquid ventilation can improve gas exchange in animal models of respiratory failure, the only reported human experience involved three premature babies with surfactant deficiency and infant respiratory distress syndrome.1-3 At our institution we use extracorporeal life support (ECLS) to manage adults, children, and newborn infants with severe respiratory failure in whom mechanical ventilation is unsuccessful. We recognised an opportunity to enhance lung management in patients on ECLS while initiating studies on the technique of partial liquid ventilation, which consists of gas ventilation of the perfluorocarbon-filled lung. We report here our first clinical experience.
respiratory
Easton DF, Bishop DT, Ford D, Crockford GP, Consortium TBCL. Genetic linkage analysis in familial breast and ovarian cancer: results from 214 families. Am J Hum Genet 1993; 52: 678-701. 9 Kim H, Jen J, Vogelstein B, Hamilton SR. Clinical and pathological characteristics of sporadic colorectal carcinomas with DNA replication errors in microsatellite sequences. Am J Pathol 1994; 145: 148-56. 10 Nyström-Lahti M, Sistonen P, Mecklin J-P, et al. Close linkage to chromosome 3p and conservation of ancestral founding haplotype in hereditary nonpolyposis colorectal cancer families. Proc Natl Acad Sci USA 1994; 91: 6054-58. 11 Liu B, Farrington SM, Petersen GM, et al. Genetic instability occurs in the majority of young patients with colorectal cancer. Nature Med 1995; 1: 348-52.
8
to
of partial liquid ventilation in a series of 19 adults, children, and neonates who were in respiratory failure and on extracorporeal life support. During partial liquid ventilation, the alveolararterial oxygen difference decreased from 590 (SE 25) to 471 (42) mm Hg (p=0·0002) and static pulmonary compliance increased from 0·18 (0·04) to 0·29 (0·04) mL cm H2O-1 kg-1 (p=0·0002). 11 patients (58%) survived. These preliminary data suggest that partial liquid ventilation can be safely used in patients with severe respiratory failure and may improve lung function.
cm
DCC gene at chromosome 18q21. Hum Mol Genet 1991; 1: 657. Weber JL, Kwitek AE, May PE, Wallace MR, Collins FS, Ledbetter DH. Dinucleotide repeat polymorphisms at the D17S250 and D17S261 loci. Nucleic Acids Res 1990; 18: 4640.
7
Departments
359: 794-801. 4 Makela TP, Heilsten
30-45
Risinger JI, Boyd J. Dinucleotide repeat polymorphism in the human
6
1:1
days. The primary outcome measure was the alveolar-arterial oxygen difference ([A-a]DO2) during 10 min periods of discontinuation of ECLS. If, during discontinuation, Sa02 decreased to 80% or below ([A-a]DO2 approximately 620 mm Hg), a blood-gas sample was obtained and ECLS reinstituted. Three adult patients had insufficient data for calculation of (A-a)D02 at baseline due to inability to tolerate even transient periods of discontinuation of extracorporeal support. Therefore, 16 patients were included in (A-a)D02 analysis. Expired gas tidal volumes, corrected for ventilator tubing compliance and patient’s weight, were assessed by the ventilator and static pulmonary compliance calculated as the measured tidal volume divided by the difference between the peak inspiratory plateau pressure and the positive end-expiratory pressure in cm H20.
This series included 10 adults charcoal aspiration, capillary leak
(pneumonia 7, and syndrome, asthma 1 each), four children (pneumonia 2, hydrocarbon aspiration and capillary leak syndrome 1 each), and five neonates (congenital diaphragmatic hernia 4, pulmonary hypertension 1). (A-a)D02 decreased from 590 (SE 25) to 471 (42) mm Hg (figure 1) during temporary discontinuation of ECLS over the initial 3 days of partial liquid ventilation. Pulmonary compliance adjusted for weight also increased from 0-18 (0-04) to 0-29 (0-04) mL cm H20-’ kg-1 (p=0-0002 by repeated-measures ANOVA) over the same periods. Figure 2 shows the opaque perflubron-filled lungs of a 36-year-old adult with Legionnaire’s disease. All patients tolerated administration of perflubron without haemodynamic compromise. During partial liquid ventilation, pneumothoraces reaccumulated in six patients with previous ipsilateral pneumothoraces and new pneumothoraces occurred in three patients. Extravasation of perflubron into the pleural space was 1201
during partial liquid ventilation. In addition, all the data collected during transient discontinuation of ECLS. Therefore, our data demonstrate that gas exchange may be sustained during partial liquid ventilation in patients with severe respiratory failure. Gas exchange during partial liquid ventilation appears to be improved by several mechanisms. The high density (1-9 g/mL) and low surface tension (18 dyn/cm) of perfluorocarbons appear to enhance recruitment of atelectatic lung regions, especially in the dependent zones of the lung where atelectasis is most severe. 1,6,1 In addition, pulmonary blood flow, which is predominantly distributed to those same atelectatic, dependent lung regions, may simultaneously be redistributed to non-dependent zones because of the weight of the perfluorocarbon within the lungs." As such, ventilation/perfusion matching is enhanced. Finally, exudate in the peripheral airways and alveoli is effectively lavaged to the central airways, whence it may be removed via suctioning. Partial liquid ventilation was achieved with few related adverse events. Pneumothoraces occurred during partial liquid ventilation in nine patients, although six of these had ipsilateral pneumothoraces before initiation of the procedure. One neonate developed pulmonary haemorrhage about 2 days after discontinuation of ECLS and 4 days after administration of the last dose of perflubron. Several other complications of critical disease processes and ECLS were observed in these severely ill patients, but none seemed related to partial liquid ventilation. These were early studies without a control group. Therefore, we were unable to ascertain whether the improvements in gas exchange and pulmonary compliance were due to management with partial liquid ventilation. Randomised controlled studies are underway. Our initial studies suggest that partial liquid ventilation with perfluorocarbons is effective in sustaining and possibly improving gas exchange and pulmonary compliance in various patients with severe respiratory failure. were
Figure
1:
(A-a)D02 before and during partial liquid ventilation
Mean (SEM). p=0.0002
by repeated-measures ANOVA; *p=0-006, tp=0.003, and tp=0.002 by post-hoc paired t test with Bonferroni-corrected p=0.017.
observed in three patients with pneumothoraces and was noted on subsequent radiographs to resolve slowly without deleterious effects. Mucus plugs, which compromised gas exchange, formed in one patient and resolved with aggressive suctioning and bronchoscopy. Complications that occurred after partial liquid ventilation and which did not appear to be related to the performance of such ventilation included bleeding (6), hyperbilirubinaemia (4), renal failure (3), and brain death (3). Of the 19 patients, 14 were successfully weaned from ECLS and 11 (58%) survived to discharge. The causes of death were irreversible lung disease in four patients, cerebrovascular accident in one, ischaemic encephalopathy after cardiac arrest in one, and multiorgan system failure in two. The 11 survivors are well and without evidence of pulmonary or systemic adverse effects from administration of perflubron after 2-12 months of follow-up. Although our patients’ age and size, and causes and pathophysiology of respiratory failure were diverse, gas exchange and pulmonary compliance improved overall
We acknowledge the critical contribution of all the additional physicians and nurses, respiratory therapists, critical care diagnostic personnel, and ECLS specialists involved in this project. Specifically, we thank Diane Shaltis, Marilyn Purple, Jon Elliott, and Carl Haas. The perflubron was given by the Alliance Pharmaceutical Corporation. This study was funded in part by NIH grant R01HD15434.
References 1 2
3
4 5
6
7
8
Shaffer TH, Wolfson MR, Clark LC Jr. State of the art review: liquid ventilation. Pediatr Pulmonol 1992; 14: 102-09. Greenspan JS, Wolfson MR, Rubenstein D, Shaffer TH. Liquid ventilation of human preterm neontates. J Pediatr 1990; 117: 106-11. Hirschl RB, Tooley R, Parent A, Johnson K, Bartlett RH. Partial liquid ventilation improves gas exchange in the setting of respiratory failure during extracorporeal life support (ECLS). Chest 1995; 108: 500-08. Bartlett R. Extracorporeal life support for cardiopulmonary failure. Curr Prob Surg 1990; 27: 621-705. Fuhrman BP, Paczan PR, DeFrancis M. Perfluorocarbon-associated gas exchange. Crit Care Med 1991; 19: 712-22. Gattinoni L, D’Andrea L, Pelosi P, Vitale G, Pesenti A, Furnagalli R. Regional effects and mechanism of positive end-expiratory pressure in early adult respiratory distress syndrome. JAMA 1993; 269: 2122-27. Hirschl RB, Overbeck MC, Parent A, et al. Liquid ventilation provides uniform distribution of perfluorocarbon in the setting of respiratory failure. Surgery 1994; 116: 159-68. Lowe C, Shaffer T. Pulmonary vascular resistance in the fluorocarbonfilled lung. Appl J Physiol 1986; 60: 154-59.
Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA (R B Hirschl MD, T Pranikoff MD, P Gauger MD, R J Schreiner MD, R Dechert MS, R H Bartlett MD)
Figure 2: Anteroposterior chest radiograph in 36-year-old adult showing perflubron-filled lungs 1202
Correspondence to: Dr Ronald B Hirschl, Section of Pediatric Surgery, F3970 Mott, Box 0245, Ann Arbor, Ml 48109, USA
References 1 Vasen HFA, Mecklin J-P, Khan PM, Lynch HT. The international collaborative group on hereditary non-polyposis colorectal cancer (ICG-HNPCC). Dis Colon Rectum 1991; 34: 424-24. 2 Aaltonen LA, Peltomäki P, Mecklin J-P, et al. Replication errors in benign and malignant tumours from hereditary nonpolyposis colorectal cancer patients. Cancer Res 1994; 54: 1645-48. 3 Weissenbach J, Gyapay G, Vignal A, Morissette J, Pillasseu P. A second-generation linkage map of the human genome. Nature 1992;
E, Vesa J, Alitalo K, Peltonen L. An Alu variable polyA repeat polymorphism upstream of Lymc at 1p32. Hum Mol Genet 1992; 1: 217. 5 Jones MH, Yamakawa K, Nakamura Y. Isolation and characterisation of 19 dinucleotide repeat polymorphisms on chromosome 3p. Hum Mol Genet 1992; 1: 131-33.
Liquid ventilation
in full-term neonates
adults, children, and
We evaluated the
and
safety
efficacy
Selection criteria and technique of ECLS are described elsewhere." Partial liquid ventilation was started 1-11 days after institution of extracorporeal support. The only exclusion criterion for the liquid ventilation protocol was active pulmonary airleak. During data collection, we used time-cycled, pressurecontrolled ventilation to generate a peak inspiratory pressure of
HO, peak end-expiratory rate
of Pathology (Prof J R Jass MD, D S Cottier MSc, P Jeevaratnam MSc, V Pokos MD, K M Holdaway MSc, M L Bowden BSc) and Molecular Medicine (N S Van de Water PhD, P J Browett FRCAP), School of Medicine, University of Auckland, Private Bag 92019, Auckland, New Zealand
of
pressure of 6-10
cm
H2O,
20-30/min, inspiratory:expiratory ratio of
Correspondence to:
Prof
Jeremy
R Jass
1:3, and fraction of inspired oxygen 1-0, depending
on the size. Perflubron (C8F27Br, LiquiVent, Alliance Pharmaceutical Corp, San Diego) was administered via the endotracheal tube at 2-5-10 mLJkg over 5-15 min. The dose of perflubron was repeated about every 30 min until a sustained meniscus was noted at the level of the sternum within the endotracheal tube. Mean initial dose of perflubron was 13-9 (SD 2-2) mL/kg (range 5-40). We redosed with perflubron daily with a mean cumulative dose of 36-3 (3-6) mLJkg (15-62-5) over 1-7
patient’s
Although liquid ventilation can improve gas exchange in animal models of respiratory failure, the only reported human experience involved three premature babies with surfactant deficiency and infant respiratory distress syndrome.1-3 At our institution we use extracorporeal life support (ECLS) to manage adults, children, and newborn infants with severe respiratory failure in whom mechanical ventilation is unsuccessful. We recognised an opportunity to enhance lung management in patients on ECLS while initiating studies on the technique of partial liquid ventilation, which consists of gas ventilation of the perfluorocarbon-filled lung. We report here our first clinical experience.
respiratory
Easton DF, Bishop DT, Ford D, Crockford GP, Consortium TBCL. Genetic linkage analysis in familial breast and ovarian cancer: results from 214 families. Am J Hum Genet 1993; 52: 678-701. 9 Kim H, Jen J, Vogelstein B, Hamilton SR. Clinical and pathological characteristics of sporadic colorectal carcinomas with DNA replication errors in microsatellite sequences. Am J Pathol 1994; 145: 148-56. 10 Nyström-Lahti M, Sistonen P, Mecklin J-P, et al. Close linkage to chromosome 3p and conservation of ancestral founding haplotype in hereditary nonpolyposis colorectal cancer families. Proc Natl Acad Sci USA 1994; 91: 6054-58. 11 Liu B, Farrington SM, Petersen GM, et al. Genetic instability occurs in the majority of young patients with colorectal cancer. Nature Med 1995; 1: 348-52.
8
to
of partial liquid ventilation in a series of 19 adults, children, and neonates who were in respiratory failure and on extracorporeal life support. During partial liquid ventilation, the alveolararterial oxygen difference decreased from 590 (SE 25) to 471 (42) mm Hg (p=0·0002) and static pulmonary compliance increased from 0·18 (0·04) to 0·29 (0·04) mL cm H2O-1 kg-1 (p=0·0002). 11 patients (58%) survived. These preliminary data suggest that partial liquid ventilation can be safely used in patients with severe respiratory failure and may improve lung function.
cm
DCC gene at chromosome 18q21. Hum Mol Genet 1991; 1: 657. Weber JL, Kwitek AE, May PE, Wallace MR, Collins FS, Ledbetter DH. Dinucleotide repeat polymorphisms at the D17S250 and D17S261 loci. Nucleic Acids Res 1990; 18: 4640.
7
Departments
359: 794-801. 4 Makela TP, Heilsten
30-45
Risinger JI, Boyd J. Dinucleotide repeat polymorphism in the human
6
1:1
days. The primary outcome measure was the alveolar-arterial oxygen difference ([A-a]DO2) during 10 min periods of discontinuation of ECLS. If, during discontinuation, Sa02 decreased to 80% or below ([A-a]DO2 approximately 620 mm Hg), a blood-gas sample was obtained and ECLS reinstituted. Three adult patients had insufficient data for calculation of (A-a)D02 at baseline due to inability to tolerate even transient periods of discontinuation of extracorporeal support. Therefore, 16 patients were included in (A-a)D02 analysis. Expired gas tidal volumes, corrected for ventilator tubing compliance and patient’s weight, were assessed by the ventilator and static pulmonary compliance calculated as the measured tidal volume divided by the difference between the peak inspiratory plateau pressure and the positive end-expiratory pressure in cm H20.
This series included 10 adults charcoal aspiration, capillary leak
(pneumonia 7, and syndrome, asthma 1 each), four children (pneumonia 2, hydrocarbon aspiration and capillary leak syndrome 1 each), and five neonates (congenital diaphragmatic hernia 4, pulmonary hypertension 1). (A-a)D02 decreased from 590 (SE 25) to 471 (42) mm Hg (figure 1) during temporary discontinuation of ECLS over the initial 3 days of partial liquid ventilation. Pulmonary compliance adjusted for weight also increased from 0-18 (0-04) to 0-29 (0-04) mL cm H20-’ kg-1 (p=0-0002 by repeated-measures ANOVA) over the same periods. Figure 2 shows the opaque perflubron-filled lungs of a 36-year-old adult with Legionnaire’s disease. All patients tolerated administration of perflubron without haemodynamic compromise. During partial liquid ventilation, pneumothoraces reaccumulated in six patients with previous ipsilateral pneumothoraces and new pneumothoraces occurred in three patients. Extravasation of perflubron into the pleural space was 1201
during partial liquid ventilation. In addition, all the data collected during transient discontinuation of ECLS. Therefore, our data demonstrate that gas exchange may be sustained during partial liquid ventilation in patients with severe respiratory failure. Gas exchange during partial liquid ventilation appears to be improved by several mechanisms. The high density (1-9 g/mL) and low surface tension (18 dyn/cm) of perfluorocarbons appear to enhance recruitment of atelectatic lung regions, especially in the dependent zones of the lung where atelectasis is most severe. 1,6,1 In addition, pulmonary blood flow, which is predominantly distributed to those same atelectatic, dependent lung regions, may simultaneously be redistributed to non-dependent zones because of the weight of the perfluorocarbon within the lungs." As such, ventilation/perfusion matching is enhanced. Finally, exudate in the peripheral airways and alveoli is effectively lavaged to the central airways, whence it may be removed via suctioning. Partial liquid ventilation was achieved with few related adverse events. Pneumothoraces occurred during partial liquid ventilation in nine patients, although six of these had ipsilateral pneumothoraces before initiation of the procedure. One neonate developed pulmonary haemorrhage about 2 days after discontinuation of ECLS and 4 days after administration of the last dose of perflubron. Several other complications of critical disease processes and ECLS were observed in these severely ill patients, but none seemed related to partial liquid ventilation. These were early studies without a control group. Therefore, we were unable to ascertain whether the improvements in gas exchange and pulmonary compliance were due to management with partial liquid ventilation. Randomised controlled studies are underway. Our initial studies suggest that partial liquid ventilation with perfluorocarbons is effective in sustaining and possibly improving gas exchange and pulmonary compliance in various patients with severe respiratory failure. were
Figure
1:
(A-a)D02 before and during partial liquid ventilation
Mean (SEM). p=0.0002
by repeated-measures ANOVA; *p=0-006, tp=0.003, and tp=0.002 by post-hoc paired t test with Bonferroni-corrected p=0.017.
observed in three patients with pneumothoraces and was noted on subsequent radiographs to resolve slowly without deleterious effects. Mucus plugs, which compromised gas exchange, formed in one patient and resolved with aggressive suctioning and bronchoscopy. Complications that occurred after partial liquid ventilation and which did not appear to be related to the performance of such ventilation included bleeding (6), hyperbilirubinaemia (4), renal failure (3), and brain death (3). Of the 19 patients, 14 were successfully weaned from ECLS and 11 (58%) survived to discharge. The causes of death were irreversible lung disease in four patients, cerebrovascular accident in one, ischaemic encephalopathy after cardiac arrest in one, and multiorgan system failure in two. The 11 survivors are well and without evidence of pulmonary or systemic adverse effects from administration of perflubron after 2-12 months of follow-up. Although our patients’ age and size, and causes and pathophysiology of respiratory failure were diverse, gas exchange and pulmonary compliance improved overall
We acknowledge the critical contribution of all the additional physicians and nurses, respiratory therapists, critical care diagnostic personnel, and ECLS specialists involved in this project. Specifically, we thank Diane Shaltis, Marilyn Purple, Jon Elliott, and Carl Haas. The perflubron was given by the Alliance Pharmaceutical Corporation. This study was funded in part by NIH grant R01HD15434.
References 1 2
3
4 5
6
7
8
Shaffer TH, Wolfson MR, Clark LC Jr. State of the art review: liquid ventilation. Pediatr Pulmonol 1992; 14: 102-09. Greenspan JS, Wolfson MR, Rubenstein D, Shaffer TH. Liquid ventilation of human preterm neontates. J Pediatr 1990; 117: 106-11. Hirschl RB, Tooley R, Parent A, Johnson K, Bartlett RH. Partial liquid ventilation improves gas exchange in the setting of respiratory failure during extracorporeal life support (ECLS). Chest 1995; 108: 500-08. Bartlett R. Extracorporeal life support for cardiopulmonary failure. Curr Prob Surg 1990; 27: 621-705. Fuhrman BP, Paczan PR, DeFrancis M. Perfluorocarbon-associated gas exchange. Crit Care Med 1991; 19: 712-22. Gattinoni L, D’Andrea L, Pelosi P, Vitale G, Pesenti A, Furnagalli R. Regional effects and mechanism of positive end-expiratory pressure in early adult respiratory distress syndrome. JAMA 1993; 269: 2122-27. Hirschl RB, Overbeck MC, Parent A, et al. Liquid ventilation provides uniform distribution of perfluorocarbon in the setting of respiratory failure. Surgery 1994; 116: 159-68. Lowe C, Shaffer T. Pulmonary vascular resistance in the fluorocarbonfilled lung. Appl J Physiol 1986; 60: 154-59.
Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA (R B Hirschl MD, T Pranikoff MD, P Gauger MD, R J Schreiner MD, R Dechert MS, R H Bartlett MD)
Figure 2: Anteroposterior chest radiograph in 36-year-old adult showing perflubron-filled lungs 1202
Correspondence to: Dr Ronald B Hirschl, Section of Pediatric Surgery, F3970 Mott, Box 0245, Ann Arbor, Ml 48109, USA