We read with interest the recent article by Niimi et al reporting low
levels of exhaled breath condensate (EBC) pH in patients with chronic
cough [1]. We and others have described low EBC pH in association with
airway inflammation in allergic asthma, cystic fibrosis and
COPD [2][3][4]. In these studies there is a relatively close association
between inflammation and low pH which is shown by the furth...
We read with interest the recent article by Niimi et al reporting low
levels of exhaled breath condensate (EBC) pH in patients with chronic
cough [1]. We and others have described low EBC pH in association with
airway inflammation in allergic asthma, cystic fibrosis and
COPD [2][3][4]. In these studies there is a relatively close association
between inflammation and low pH which is shown by the further fall in pH
during exacerbations [2]. However in non-asthmatic chronic cough whilst
there is a low grade inflammation present in some subjects this is much
less than would be required to invoke inflammation as the major cause of
airway acidification.
It is unclear from the description of the assessment protocol how
patients were allotted their individual diagnostic categories. A positive
methacholine challenge test is not infrequently found in patients with
reflux [5] and, even in classical asthma, reflux is a common phenomenon [6].
We would suggest that there has been a significant under diagnosis of
reflux disease in this cohort because of the lack of a structured history,
the non uniform application of investigations and the failure to perform
full oesophageal assessment, particularly manometry. We have shown that
when oesophageal manometry is not performed a significant number of
patients with reflux cough will be missed [7]. Proton pump inhibitors at
conventional doses only temporarily increase the pH of gastric reflux and
do not prevent reflux per se and, unsurprisingly, only improve symptoms in
a proportion of patients with reflux cough. A failure of cough to improve
with proton pump inhibitors does not therefore adequately rule out reflux
cough.
The simplest explanation for the low airway pH observed by Niimi et
al would be that a large proportion of the subjects have laryngopharyngeal
reflux. This would also explain the otherwise surprising finding of
similar EBC pH across the authors’ diagnostic categories.
References
(1) Niimi A, Nguyen LT, Usmani O, Mann B, Chung KF. Reduced pH and
chloride levels in exhaled breath condensate of patients with chronic
cough. Thorax 2004; 59: 608-612.
(2) Ojoo JC, Mulrennan S, Kastelik JA, Morice AH, Redington AE.
Exhaled breath condensate pH and exhaled nitric oxide in allergic asthma
and in cystic fibrosis. Thorax 2004; (In Press)
(3) Kostikas K, Papatheodorou G, Ganas K, Psathakis K, Panagou P,
Loukides S. pH in expired breath condensate of patients with inflammatory
airway diseases. Am J Respir Crit Care Med. 2002; 165: 1364-1370.
(4) Tate S, MacGregor G, Davis M, Innes JA, Greening AP. Airways in
cystic fibrosis are acidified: detection by exhaled breath condensate.
Thorax 2002; 57: 926-929.
(5) Bagnato GF, Gulli S, Giacobbe O, De Pasquale R, Purello DF.
Bronchial hyperresponsiveness in subjects with gastroesophageal reflux.
Respiration 2000; 67: 507-509.
(6) Vincent D, A.M., Leport J, et al. Gastro-oesophageal reflux
prevalence and relationship with bronchial reactivity in asthma. Eur
Respir J 1997; 10: 2255-2259.
(7) Kastelik JA, Redington AE, Aziz I, et al. Abnormal oesophageal
motility in patients with chronic cough. Thorax 2003; 58: 699-702.
Pearson et al [1] have failed to tease out any additional benefit of
vitamin E supplementation in mild-to-moderate asthmatics. Before
concluding that this is the case, it is relevant to highlight several
points in their study.
It is notable that the authors failed to measure any surrogate marker
of inflammation such as exhaled nitric oxide, sputum eosinophils or airway
hyperresponsiveness (AHR)...
Pearson et al [1] have failed to tease out any additional benefit of
vitamin E supplementation in mild-to-moderate asthmatics. Before
concluding that this is the case, it is relevant to highlight several
points in their study.
It is notable that the authors failed to measure any surrogate marker
of inflammation such as exhaled nitric oxide, sputum eosinophils or airway
hyperresponsiveness (AHR) to an indirect bronchoconstrictor stimulus.
Indeed, non-specific AHR to methacholine is only very tenuously linked to
underlying endobronchial inflammation and tends to be related to changes
in airway calibre [2,3]. In this respect, the use of adenosine
monophosphate or mannitol to assess AHR may have provided information
regarding the underlying inflammatory status as these agents which act
similarly [4], cause the release of inflammatory mediators rather than
directly causing contraction of airway smooth muscle. Use of these
bronchoconstrictor stimuli are also more akin to real life situations as
cold air and exercise also act in a similar physiological fashion.
Moreover, the use of adenosine monophosphate has been shown to be more
sensitive in detecting shifts in AHR than methacholine by approximately 1
doubling dilution [5].
It is important to point out in the present study [1] that patients
in both groups at baseline had neither demonstrable symptoms nor short
acting bronchodilator use. This in turn highlights the fact that these
patients were clinically stable and there was no actual signal from which
a discernable improvement in symptoms could be observed.
Before dietary manipulation with vitamin E is neglected, further
studies are required in symptomatic asthmatics evaluating other important
outcome parameters such as exacerbations and surrogate inflammatory
biomarkers.
Graeme P Currie
Department of Respiratory Medicine, Aberdeen Royal Infirmary, Foresterhill, Aberdeen AB25 2ZN, Scotland, United Kingdom
Wendy J Anderson
Department of Respiratory Medicine, Antrim Hospital, Bush Road, Antrim BT41 2QB, Northern Ireland, United Kingdom
Daniel K C Lee
Department of Respiratory Medicine, Ipswich Hospital, Heath Road, Ipswich IP4 5PD, England, United Kingdom
References
(1) Pearson PJK, Lewis SA, Britton J, Fogarty A. Vitamin E supplements in asthma: a parallel group randomised placebo controlled trial. Thorax 2004; 59: 652-6.
(2) Van Den Berge M, Meijer RJ, Kerstjens HA, et al. PC(20) adenosine 5'-monophosphate is more closely associated with airway inflammation in asthma than PC(20) methacholine. Am J Respir Crit Care Med 2001; 163: 1546-50.
(3) De Meer G, Heederik D, Postma, DS. Bronchial responsiveness to adenosine 5'-monophosphate (AMP) and methacholine differ in their relationship with airway allergy and baseline FEV(1). Am J Respir Crit Care Med. 2002, 165: 327-31.
(5) Wilson AM, Lipworth BJ. Dose-response evaluation of the therapeutic index for inhaled budesonide in patients with mild-to-moderate asthma. Am J Med 2000; 108: 269-75.
The paper by Kotecha et al reveals the important association between
delayed pulmonary neutrophil apoptosis and neonatal chronic lung disease.
This paper also raises several questions. Did the authors analyse the
effect of labour on the neutrophil counts? It would be useful to know the
mode of delivery as several papers have shown an effect on systemic
neutrophil function and survival. Neutrophil coun...
The paper by Kotecha et al reveals the important association between
delayed pulmonary neutrophil apoptosis and neonatal chronic lung disease.
This paper also raises several questions. Did the authors analyse the
effect of labour on the neutrophil counts? It would be useful to know the
mode of delivery as several papers have shown an effect on systemic
neutrophil function and survival. Neutrophil counts are higher in infants
born following vaginal delivery compared with elective caesarean section
with no labour [1-4]. In addition, several studies indicate that neonatal
neutrophil function is activated by labour [5-7].
Gender may be an additional confounding factor [8] as in females
neutrophil apoptosis is delayed compared with males. Differential
neutrophil counts would also be useful as there may be increased immature
neutrophils associated with both prematurity and steroids [9,10].
Progenitor neutrophils may have delayed apoptosis, extrapolating from
research in HL-60 cells [11]. Premature infants also have more
inflammatory conditions (e.g. necrotising enterocolitis, sepsis) therefore
details of co-morbidity would be interesting. In addition, duration of
ventilation and mean PIP, PEEP and MAP at one week would assess the
severity of the respiratory illness.
In adults, the systemic inflammatory response is associated with delayed
neutrophil apoptosis [12]. Therefore, the presence of maternal infection
such as chorioamnionitis may be relevant as infants may have altered
neutrophil survival at birth associated with a fetal inflammatory response
[13]. In this patient group were systemic and pulmonary neutrophil counts
inversely correlated? The systemic neutrophil counts in parallel with the
BAL results may give important information on the transmigration of
neutrophils in RDS and CLD [14]. Did infants with low Apgars, acidotic
cord pH or need for resuscitation have deranged neutrophil apoptosis? The
data on Apgars and cord pH would be interesting as the delay in apoptosis
is an early response and may be related to peripartum events [15,16].
Finally, measurement of IL-6 and GCSF would be relevant in this study
group as they have been shown to delay neutrophil apoptosis and both are
elevated in RDS [17,18].
References:
(1) Chirico G, Gasparoni A, Ciardelli L, Martinotti L, Rondini G. Leukocyte
counts in relation to the method of delivery during the first five days of
life. Biol Neonate. 1999;75(5):294-9
(2) Thilaganathan B, Meher-Homji N, Nicolaides KH. Labor: an
immunologically beneficial process for the neonate. Am J Obstet Gynecol.
1994 ;171(5):1271-2
(3) Herson VC, Block C, Eisenfeld LI, Maderazo E, Krause PJ. Effect of
labor and delivery on neonatal polymorphonuclear leukocyte number and
function. Am J Perinatol. 1992 ;9(4):285-8
(4) Hasan R, Inoue S, Banerjee A. Higher white blood cell counts and band
forms in newborns delivered vaginally compared with those delivered by
cesarean section. Am J Clin Pathol. 1993;100(2):116-8
(5) Gessler P, Dahinden C. Increased respiratory burst and increased
expression of complement receptor-3 (CD11b/CD18) and of IL-8 receptor-A in
neutrophil granulocytes from newborns after vaginal delivery. Biol
Neonate. 2003;83(2):107-12
(6) Weinschenk NP, Farina A, Bianchi DW. Neonatal neutrophil activation is
a function of labor length in preterm infants. Pediatr Res. 1998
;44(6):942-5
(7) Molloy EJ, O'Neill AJ, Grantham JJ, Sheridan-Pereira M, Fitzpatrick JM,
Webb DW, Watson RW. Labor Promotes Neonatal Neutrophil Survival and
Lipopolysaccharide Responsiveness. Pediatr Res 2004, Jul;56(1):99-103
(8) Molloy EJ, O’Neill AJ, Grantham J, Sheridan-Pereira M, Fitzpatrick JM,
Webb DW, Watson RWG. Gender-specific alterations in neutrophil apoptosis:
the role of estradiol and progesterone. Blood. 2003, 102:2653-2659
(9) Mouzinho A, Rosenfeld CR, Sanchez PJ, Risser R. Revised reference
ranges for circulating neutrophils in very-low-birth-weight neonates.
Pediatrics. 1994 Jul;94(1):76-82
(10) Peng CT, Lin HC, Lin YJ, Tsai CH, Yeh TF. Early dexamethasone therapy
and blood cell count in preterm infants. Pediatrics. 1999 Sep;104(3 Pt
1):476-81
(12) Jimenez, M.F. et al. 1997. Dysregulated expression of neutrophil
apoptosis in the systemic inflammatory response syndrome (SIRS). Arch.
Surg. 132:1263-1270
(13) Gomez R, Romero R, Ghezzi F, Yoon BH, Mazor M, Berry SM. The fetal
inflammatory response syndrome. Am J Obstet Gynecol. 1998 Jul;179(1):194-
202
(14) Sarafidis K, Drossou-Agakidou V, Kanakoudi-Tsakalidou F, Taparkou A,
Tsakalidis C, Tsandali C, Kremenopoulos G.Evidence of early systemic
activation and transendothelial migration of neutrophils in neonates with
severe respiratory distress syndrome. Pediatr Pulmonol. 2001 Mar;31(3):214
-9
(15) Drossou V, Kanakoudi F, Tzimouli V, Sarafidis K, Taparkou A,
Bougiouklis D, Petropoulou T, Kremenopoulos G. Impact of prematurity,
stress and sepsis on the neutrophil respiratory burst activity of
neonates. Biol Neonate. 1997;72(4):201-9
(16) Stanton K, Alam HB, Rhee P, Llorente O, Kirkpatrick J, Koustova
E.Human polymorphonuclear cell death after exposure to resuscitation
fluids in vitro: apoptosis versus necrosis. J Trauma. 2003 Jun;54(6):1065-
74; discussion 1075-6
(17) McLoughlin RM, Witowski J, Robson RL, Wilkinson TS, Hurst SM, Williams
AS, Williams JD, Rose-John S, Jones SA, Topley N. Interplay between IFN-
gamma and IL-6 signaling governs neutrophil trafficking and apoptosis
during acute inflammation. J Clin Invest. 2003 Aug;112(4):598-607
(18) Munshi UK, Niu JO, Siddiq MM, Parton LA. Elevation of interleukin-8
and interleukin-6 precedes the influx of neutrophils in tracheal aspirates
from preterm infants who develop bronchopulmonary dysplasia. Pediatr
Pulmonol. 1997 Nov;24(5):331-6
We agree with Anderson that age and significant co-morbidity might
reduce the chances of getting histology. In the population of our study
the proportion of patients with a clinical diagnosis was 7%. This
proportion varied from almost 3% for patients younger than 65 to 8% for
those aged 65-79 and 22% for those aged 80 or older. In patients younger
than 65 or in those aged 80 or older this proportio...
We agree with Anderson that age and significant co-morbidity might
reduce the chances of getting histology. In the population of our study
the proportion of patients with a clinical diagnosis was 7%. This
proportion varied from almost 3% for patients younger than 65 to 8% for
those aged 65-79 and 22% for those aged 80 or older. In patients younger
than 65 or in those aged 80 or older this proportion did not decrease with
significant co-morbidity. In patients aged 65-79, however, the proportion
of patients with a clinical diagnosis increased from 5% for patients
without co-morbidity to 7% for those with one co-morbid condition, and to
10% for those with at least two co-morbid conditions.
In our study we only included patients with non-small cell lung
cancer. In those with localized disease 3-year survival significantly
decreased with age.
However, the differences in lung cancer survival within Europe cannot
entirely be explained by differences in age distribution. In the EUROCARE
study [1,2] survival rates were standardised to a common age structure.
Furthermore, the rates were adjusted for the age-specific background
mortality to keep to a minimum the effect of age and competing causes of
death on the overall comparisons. In the United Kingdom the proportion of
microscopically verified lung cancer cases was rather low (about 60%) [3].
Therefore, differences in access to diagnostic care might be responsible
for variation in lung cancer survival, rather than differences in age
distribution or the prevalence of co-morbidity. Registration procedures
might also play a role, because we do not dispose on notifications from
death certificates. This problem becomes larger when access to care is
less optimal. The number of chest physicians in the Netherlands was 2 to 3
times as high as in the UK.
References
(1) Janssen-Heijnen ML, Gatta G, Forman D, et al. Variation in survival
of patients with lung cancer in Europe, 1985-1989. EUROCARE Working Group.
Eur J Cancer 1998;34:2191-6.
(2) Sant M, Aareleid T, Berrino F, et al. EUROCARE-3: survival of
cancer patients diagnosed 1990-94-results and commentary. Ann Oncol
2003;14 Suppl 5:V61-V118.
(3) Capocaccia R, Gatta G, Roazzi P, et al. The EUROCARE-3 database:
methodology of data collection, standardisation, quality control and
statistical analysis. Ann Oncol 2003;14 Suppl 5:V14-V27.
I read the article by Janssen-Heijnen et al with interest [1]. There are
large differences in the reported survival of patients presenting with
lung cancer. Those presenting in the United states and Spain are reported
to have up to twice the chance of surviving five years when compared to
those presenting in the United Kingdom [2-4]. This may be due to differences
in disease, differences in performanc...
I read the article by Janssen-Heijnen et al with interest [1]. There are
large differences in the reported survival of patients presenting with
lung cancer. Those presenting in the United states and Spain are reported
to have up to twice the chance of surviving five years when compared to
those presenting in the United Kingdom [2-4]. This may be due to differences
in disease, differences in performance status or co-morbidity, differences
in treatment, or differences in recording, but it demands a critical
analysis of current practice. This study informs the discussion suggesting
that age and co-morbidity do not significantly alter prognosis but it
includes only those with a histologically confirmed non small cell lung
cancer. It seems likely that age and significant co-morbidity might reduce
the chances of getting histology. Do the authors know the rate of
histological confirmation in the population described and, if so, is it
influenced by age or co-morbidity? It is hard to base any conclusion on
the role of these factors in outcomes for the whole population on those
with confirmed histology without first quantifying age and co-morbidity in
those without histological confirmation.
References
(1) Janssen-Heijnen MLG. Effect of comorbidity on the treatment and prognosis of elderly patients with non-small cell lung cancer. Thorax 2004; 59: 602-607
(2) Berrino F, Capocaccia R, Estève T, et al. Survival of cancer
patients in Europe- the EUROCARE 2 Study. (IARC Scientific Publications
No. 151) International Agency for Research on Cancer (Lyon: 1999)
(3) Sikora K. Cancer survival in Britain. BMJ 1999; 319: 461-2
(4) American Cancer Society, Inc. Cancer Facts and Figures 2002.
Surveillance Research (2002)
The paper by Fitzgerald et al [1] raises important questions as to
what patients should be advised to do during periods of less well
controlled asthma. In other words, the commonly advised practice of
doubling the inhaled corticosteroid dose is not backed up by a wealth of
evidence, in turn resulting in an embarassing paucity of clear guidance
for patients.
The paper by Fitzgerald et al [1] raises important questions as to
what patients should be advised to do during periods of less well
controlled asthma. In other words, the commonly advised practice of
doubling the inhaled corticosteroid dose is not backed up by a wealth of
evidence, in turn resulting in an embarassing paucity of clear guidance
for patients.
It has become apparent in the management of chronic asthma, that
additional 2nd line controller therapy is generally more advantageous than
doubling the dose of inhaled corticosteroid. [2] In the treatment and
prevention of asthma exacerbations, a similar pharmacotherapeutic
rationale may also become the norm and be incorporated into individualised
asthma action plans. In other words, adding further 2nd line therapy for a
short period of time during deteriorating asthma control - while
maintaining the same inhaled corticosteroid dose - may be appropriate.
For example, the hybrid actions of leukotriene antagonism would
attenuate airway hyperresponsiveness and further dilate the airways, while
add on long acting ß2-agonist would maximally bronchodilate the airways
with the provision of an “airway stabilising effect”.[3] Indeed, Aalbers
et al demonstrated that the use of budesonide and eformoterol in
combination, with dose adjustment according to patients symptoms,
conferred benefit in terms of exacerbations, lung function and reliever
use. Perhaps in asthmatics already using an inhaled corticosteroid plus
long acting ß2-agonist, the addition of montelukast may be worthwhile, as
“triple therapy” has been shown to confer further benefit in terms of
surrogate inflammatory biomarkers and attenuating airway
hyperresponsiveness.[5]
In conclusion, studies evaluating the effects of “short bursts” of
leukotriene receptor antagonists or add-on long acting ß2-agonists
compared to doubling the inhaled corticosteroid dose during deteriorating
asthma control are urgently required.
Graeme P Currie
Daniel K C Lee †
Department of Respiratory Medicine, Aberdeen Royal Infirmary,
Foresterhill, Aberdeen AB25 2ZN, Scotland, United Kingdom
† Department of Respiratory Medicine, Ipswich Hospital, Heath Road,
Ipswich IP4 5PD, Suffolk, England, United Kingdom
References
1. FitzGerald JM, Becker A, Sears MR, et al. Doubling the dose of
budesonide versus maintenance treatment in asthma exacerbations. Thorax
2004;59:550–6
2. British Guideline on the Management of Asthma. Thorax 2003; 58
(Suppl 1):1-83.
3. Currie GP, Jackson CM, Ogston SA, Lipworth BJ. Airway-stabilising
effect of long-acting ß2-agonists as add-on therapy to inhaled
corticosteroids. QJM 2003;96: 435-40.
4. Aalbers R, Backer V, Kava TTK, et al. Adjustable maintenance
dosing with budesonide/formoterol compared with fixed-dose
salmeterol/fluticasone in moderate to severe asthma. Curr Med Research and
Opinion 2004; 20: 225-40.
5. Currie GP, Lee DKC, Haggart K, et al. Effects of montelukast on
surrogate inflammatory markers in corticosteroid treated patients with
asthma. Am J Respir Crit Care Med 2003; 167:1232-8.
Simler et al. raise an interesting possibility of the prognostic
value of plasma VEGF in interstitial lung disease. Meyer et al. in a
previous study [1] did not find any difference
in serum VEGF165 levels in patients with diffuse parenchymal lung disease.
It would have been interesting to know the BALF VEGF levels of these
patients as Meyer et al.and Koyama et al. [2] have shown reduced BAL fluid VEGF...
Simler et al. raise an interesting possibility of the prognostic
value of plasma VEGF in interstitial lung disease. Meyer et al. in a
previous study [1] did not find any difference
in serum VEGF165 levels in patients with diffuse parenchymal lung disease.
It would have been interesting to know the BALF VEGF levels of these
patients as Meyer et al.and Koyama et al. [2] have shown reduced BAL fluid VEGF levels in interstitial
lung disease. This might simply reflect damage to the alveolar epithelium
(a known major source) in this disease or indeed VEGF may have an
important role in the pathogenesis of interstitial disease. Interestingly,
VEGF receptor blockade has been shown to lead to an induction of apoptosis
and an emphysema-like histological appearance in rats but with no evidence
of fibrosis or inflammatory cells [3].
In addition, it is interesting to speculate the cellular source of
the elevated plasma VEGF in the more fibrotic patients? Could this
represent alveolar-capillary membrane damage with leakage of intra-
alveolar VEGF which is known to be compartmentalised [4] and hence lower BALF levels as described in the previous
studies? Or does it represent an inflammatory cell source of systemic VEGF
correlating with an inflammatory response that is here associated with a
poorer outcome? Or is there some other mechanism.
Finally, Koyama et al. have shown smokers also have reduced BAL VEGF
levels and this may be of relevance (if intrapulmonary VEGF is postuated
as having a role in this disease) given the DIP group had all smoked
compared to 50% of the NSIP, and only 20% of the controls.
References
(1) J Lab Clin Med 2000;135:332-8.
(2) Am J Resp Crit Care Med 2002;166: 382-5.
(3) Kasahara et al. J Clin Invest. 2000
Dec;106(11):1311-9.
We read with interest the recent article from Simler et al in Thorax
investigating angiogenic cytokines in patients with idiopathic
interstitial pneumonia [1]. We were surprised by their reported high
levels of plasma VEGF in the normal control group. Previously, several
other groups, including the manufacturers of the ELISA (R&D systems)
quote normal plasma VEGF levels in the range of 36-76 pg/...
We read with interest the recent article from Simler et al in Thorax
investigating angiogenic cytokines in patients with idiopathic
interstitial pneumonia [1]. We were surprised by their reported high
levels of plasma VEGF in the normal control group. Previously, several
other groups, including the manufacturers of the ELISA (R&D systems)
quote normal plasma VEGF levels in the range of 36-76 pg/ml[2, 3]. Indeed
one of the authors of the paper previously quoted normal VEGF levels as 76
pg/ml using a matched pair ELISA [4]. It is clear, therefore that the
levels quoted of 648 pg/ml for normal controls are nearly 10 fold higher
than reported previously.
One possible explanation for this finding is the low centrifugal
force used for preparation of plasma (300g for 12 minutes). The
manufacturer of the ELISA recommends 1000 g for 15 minutes as a way to
reduce platelet contamination of plasma. Platelet secretion of VEGF is the
reason for elevated serum levels of VEGF when compared to plasma and might
therefore explain the extraordinarily high levels of VEGF found in these
normal subjects [4]. Interestingly 14/49 (28.5%) of patients included were
on immunosuppressant drugs that potentially reduce platelet count. This
offers an alternative explanation as to why there was no difference
between normal patients and those with pulmonary fibrosis in contrast to
earlier reports in connective tissue disease related pulmonary fibrosis
from 1998 [5].
Although the plasma levels of VEGF correlated with fibrosis based
upon CT score it is difficult to fully appreciate the relevance of this
finding, without knowing the concentration of VEGF actually within the
lung compartment. This is because in the normal individual, epithelial
lining fluid levels of VEGF at 9-11 ng/ml are several orders of magnitude
greater than that found in the circulation [6, 7]. Furthermore, previous
investigators have reported reduced levels of alveolar VEGF in patients
with IPF [8]. Low BALF VEGF levels are also seen in patients with acute
lung injury, sarcoidosis, emphysema and the transplanted lung. Thus it
would appear that a reduced alveolar level of VEGF is a common feature of
diseases associated with alveolar epithelial damage. Indeed, in ARDS,
alveolar levels of VEGF are lowest in those with the worst lung injury.
This is probably a result of reduced epithelial cell secretion of VEGF and
increased expression of its soluble receptor sVEGFR-1, which acts as a
natural inhibitor to the bioactivity of VEGF. The trophic role of VEGF
within the lung is supported by the fact that VEGF acts as a proliferative
factor for fetal pulmonary epithelial cells (9) and because lung-targeted
VEGF inactivation leads to an emphysema phenotype in mice[10]. These
studies suggest that reduced alveolar levels of VEGF may inhibit
epithelial repair in a wide variety of lung diseases.
To summarize, we have some concerns about the
validity/reproducibility of the VEGF levels reported in this study.
Furthermore, based upon the available evidence, we believe it is
inappropriate to suggest that antagonizing VEGF would be a successful
potential therapy for patients with pulmonary fibrosis. To the contrary we
believe this would hasten epithelial cell apoptosis and promote alveolar
septal cell loss with resultant honeycombing and functional deterioration.
References
(1) Simler, N. R., P. E. Brenchley, A. W. Horrocks, S. M. Greaves, P.
S. Hasleton, and J. J. Egan. 2004. Angiogenic cytokines in patients with
idiopathic interstitial pneumonia. Thorax 59(7):581-585.
(2) Thickett, D. R., L. Armstrong, S. J. Christie, and A. B. Millar. 2001.
Vascular endothelial growth factor may contribute to increased vascular
permeability in acute respiratory distress syndrome. Am J Respir Crit Care
Med 164(9):1601-5.
(3) Himeno, W. 2001. Angiogenic growth factors in patients with cyanotic
congenital heart disease and in normal children. Kurume Med J 48(2):111-6.
(4) Webb, N. J., M. J. Bottomley, C. J. Watson, and P. E. Brenchley. 1998.
Vascular endothelial growth factor (VEGF) is released from platelets
during blood clotting: implications for measurement of circulating VEGF
levels in clinical disease. Clin Sci (Lond) 94(4):395-404.
(5) Kikuchi, K., M. Kubo, T. Kadono, N. Yazawa, H. Ihn, and K. Tamaki.
1998. Serum concentrations of vascular endothelial growth factor in
collagen diseases. Br J Dermatol 139(6):1049-51.
(6) Kaner, R. J., and R. G. Crystal. 2001. Compartmentalization of vascular
endothelial growth factor to the epithelial surface of the human lung. Mol
Med 7(4):240-6.
(7) Thickett, D. R., L. Armstrong, and A. B. Millar. 2002. A role for
vascular endothelial growth factor in acute and resolving lung injury. Am
J Respir Crit Care Med 166(10):1332-7.
(8) Koyama, S., E. Sato, M. Haniuda, H. Numanami, S. Nagai, and T. Izumi.
2002. Decreased level of vascular endothelial growth factor in
bronchoalveolar lavage fluid of normal smokers and patients with pulmonary
fibrosis. Am J Respir Crit Care Med 166(3):382-5.
(9) Brown, K. R., K. M. England, K. L. Goss, J. M. Snyder, and M. J.
Acarregui. 2001. VEGF induces airway epithelial cell proliferation in
human fetal lung in vitro. Am J Physiol Lung Cell Mol Physiol 281(4):L1001
-10.
(10) Tang, K., H. B. Rossiter, P. D. Wagner, and E. C. Breen. 2004. Lung-
targeted VEGF inactivation leads to an emphysema phenotype in mice. J Appl
Physiol.
Lung-protective ventilation with low tidal volume (6 ml/Kg of ideal
body weight) and maintenance of the plateau airway pressure below 30 cm
H2O has now become the standard ventilatory strategy for patients with
acute respiratory distress syndrome (ARDS). The ARDS Network trial
demonstrated significant reduction of mortality among patients with low
tidal volume (6 ml/kg of IBW) as compared wi...
Lung-protective ventilation with low tidal volume (6 ml/Kg of ideal
body weight) and maintenance of the plateau airway pressure below 30 cm
H2O has now become the standard ventilatory strategy for patients with
acute respiratory distress syndrome (ARDS). The ARDS Network trial
demonstrated significant reduction of mortality among patients with low
tidal volume (6 ml/kg of IBW) as compared with those with traditional
tidal volume ventilation (12 ml/kg of IBW).[1] Low tidal volume
ventilation may be associated with hypercapnia and respiratory acidosis
(permissive hypercapnia).[2] Respiratory acidosis shifts the oxygen
dissociation curve to the right, decreases haemoglobin affinity for oxygen
and increases O2 delivery to the tissues, in spite of the relatively lower
arterial O2 saturation (SaO2). For a given arterial partial pressure of O2
(PaO2), arterial O2 saturation is lower than would be expected at a normal
pH of 7.4. Almost all ventilatory strategies focus on maintaining
satisfactory arterial oxygenation rather than tissue oxygenation, with the
goal of an arterial O2 saturation of 90 % or more. Many ARDS patients with
low tidal volume ventilation develop significant respiratory acidosis (pH
<7.2) that may render SaO2 less reliable as an indicator of oxygen
delivery (DO2) and tissue oxygenation. I may suggest that - at least in
the setting of permissive hypercapnia with significant respiratory
acidosis- it may be more appropriate to use O2 extraction ratio (O2 ER)
instead of arterial O2 saturation as a marker of tissue oxygenation. O2 ER
= SaO2 – SvO2 /SaO2, where SvO2 is mixed venous O2 saturation – of blood
taken from pulmonary artery with Swan-Ganz catheter. In conclusion, as a
result of respiratory acidosis and right shift of O2 dissociation curve
during permissive hypercapnia of ARDS patients, arterial O2 saturation may
be relatively low in spite of improved O2 delivery rendering SaO2 less
reliable marker of tissue oxygenation as compared with O2 extraction
ratio.
References
1. Ventilation with lower tidal volumes as compared with traditional
tidal volumes for acute respiratory distress syndrome. The Acute
Respiratory Distress Syndrome Network. N Eng J Med 2000; 342: 1301.
2. Tuxen, Dv. Permissive hypercapnic ventilation. Am L Respir Crit
Care Med 1994; 150:870.
I would like to thank Dr M Ghrew for his interest in my letter. I
agree that a restrictive strategy of red-cell transfusion, in which
haemoglobin is maintained at 7–9 g per deciliter, is at least as
effective as and possibly superior to a liberal transfusion strategy, in
which haemoglobin is maintained at 10–12 g per deciliter. Hebert and his
colleagues in the Canadian Critical Care Trials Group reporte...
I would like to thank Dr M Ghrew for his interest in my letter. I
agree that a restrictive strategy of red-cell transfusion, in which
haemoglobin is maintained at 7–9 g per deciliter, is at least as
effective as and possibly superior to a liberal transfusion strategy, in
which haemoglobin is maintained at 10–12 g per deciliter. Hebert and his
colleagues in the Canadian Critical Care Trials Group reported that
mortality rate was significantly lower with the restrictive transfusion
strategy among patients with less severe illness (those with an APACHE
score <or = 20) and among patients who were <55 years of age, but
not among patients with clinically significant cardiac disease. The in-
hospital mortality rate was significantly lower in the restrictive
strategy group, although the 30-day mortality was similar.[1] Therefore,
further studies are required to decide if the restrictive strategy of red-
cell transfusion is still beneficial to the subgroups of patients with
cardiac disease [2], COPD [3], ARDS, more severe illness as well as older
patients. Unfortunately, O2 delivery (DO2) and O2 uptake (VO2) were not
calculated or measured in this trial, making it difficult to evaluate the
usefulness of the restrictive transfusion strategy in critically-ill
patients with hypoxemia and / or low cardiac output. A clinical setting in
which the arterial O2 content, O2 delivery and tissue oxygenation are all
reduced. I believe that many intensivists may be unwilling to use a
haemoglobin level of <7 g per deciliter as a threshold for transfusion
of red blood cells to critically-ill patients with ARDS or cardiogenic
shock, particularly if there is evidence of tissue hypoxia. Several
randomized controlled trials in which hemodynamic therapy (including
inotropic and vasopressor agents, volume expansion, packed RBCs and
vasodilators) aimed at achieving supranormal values of cardiac output (QT)
and O2 delivery failed to improve survival and may actually have been
detrimental [4, 5, 6]. On the contrary, I hypothesized that maintaining
adequate tissue oxygenation- by supranormal cardiac output – may enable
intensivists to use more protective ventilatory strategy (lower levels of
PEEP, FIO2 and I:E ratio) and to accept lower values of arterial O2
saturation (SaO2) aiming at minimizing the risks of pulmonary O2 toxicity,
barotrauma and lung injury that may be difficult to identify in the
clinical setting of ARDS. According to this hypothesis, SaO2 may be
allowed to decrease below 90 % (permissive hypoxemia) as long as no
evidence of tissue hypoxia (such as increased O2 extraction ratio and
elevated arterial blood lactate) is present.
DO2 = 1.34 x SaO2 x Hb x QT. According to this equation, I suggested that
O2 delivery could be maintained within normal or near-normal (not
supranormal) levels by augmenting cardiac output, if SaO2 is relatively
low. It should be noted that supranormal cardiac output is not a target in
itself, but is considered a compensatory mechanism to maintain adequate
tissue perfusion if 'permissive hypoxemia' has resulted in tissue hypoxia.
Finally, this tissue oxygenation-oriented approach remains hypothetical
waiting for further outcome studies to evaluate its impact on mortality of
patients with ARDS.
References
1. Hébert PC, Wells G, Blajchman MA, et al. A multicenter,
randomized, controlled clinical trial of transfusion requirements in
critical care. N Engl J Med 1999; 340:409-417.
2. Carson JL, Duff A, Poses RM, et al. Effect of anaemia and
cardiovascular disease on surgical mortality and morbidity. Lancet 1996;
348: 1055-1060.
3. Schönhofer B, Wenzel M, Geibel M, Köhler D. Blood transfusion and
lung function in chronically anemic patients with severe chronic
obstructive pulmonary disease. Crit Care Med 1998; 26:1824-1828.
4. Palazzo M, Hinds C, Watson D. Elevation of systemic oxygen
delivery in the treatment of critically ill patients. N Engl J Med 1994;
330:1717-1722.
5. Gattinoni L, Brazzi L, Pelosi P, et al. A trial of goal-oriented
hemodynamic therapy in critically ill patients. N Engl J Med 1995;
333:1025-1032.
6. Heyland DK, Cook DJ, King D, Kernerman P, Brun-Buisson C.
Maximizing oxygen delivery in critically ill patients: a methodologic
appraisal of the evidence. Crit Care Med 1996; 24:517-524
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I would like to thank Dr M Ghrew for his interest in my letter. I agree that a restrictive strategy of red-cell transfusion, in which haemoglobin is maintained at 7–9 g per deciliter, is at least as effective as and possibly superior to a liberal transfusion strategy, in which haemoglobin is maintained at 10–12 g per deciliter. Hebert and his colleagues in the Canadian Critical Care Trials Group reporte...
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