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High-frequency pressure-control ventilation with high positive end-expiratory pressure in children with acute respiratory distress syndrome
High-frequency pressure,control ventilation with high positive end-expiratory pressure in children with acute respiratory distress syndrome Thomas E. Paulson, MD, Robert M. Spear, MD, Patricia D. Silva, and Bradley M. Peterson, MD From the Department of Pediatric Critical Care, San Diego Children's Hospital, San Diego, California
Objective: Animal models suggest that high-frequency ventilation with low tidal volumes and high positive end-expiratory pressure (PEEP) minimize secondary injury to the lung. We hypothesized that using a high-frequency pressure-control mode of ventilation with high PEEPin children with severe acute respiratory distress syndrome (ARDS) would be associated with improved survival. Design: The study was a retrospective and prospective clinical study at a 24-bed tertiary care pediatric critical care unit. Fifty-three patients with severe ARDS were studied during a 37-month period, 30 prospectively and 23 retrospectively. Severe ARDS was defined as (I) rapid onset of severe bilateral infiltrates of noncardiac origin, (2) partial pressure of oxygen (arterial)/fraction of inspired oxygen less than 200 on PEEPof 6 cm H2O or more for 24 hours or longer, and (3) Murray disease severity score greater than 2.5. All patients meeting these criteria underwent ventilation in the pressure-control mode; the protocol for ventilation had the following general guidelines: (I) fraction of inspired oxygen limited to 0.5, (2) mean airway pressure titrated with PEEPto maintain arterial partial pressure of oxygen at 55 mm Hg or greater (7.3 kPa), (3) peak inspiratory pressure minimized to allow hypercapnia (arterial partial pressure of carbon dioxide, 45 to 60 mm Hg [6.0 to 8.0 kPa]), and (4) ventilator rates of 40 to 120/min. Percutaneous thoracostomy and mediastinal tubes were placed for treatment of air leak. Results: The survival rate was 89% (47/53) in children with severe ARDS. Nonsurvivors had significantly higher peak inspiratory pressures (75 vs 40 cm H20, p = 0.0006), PEEP(23 vs 17 cm H2O, p = 0.0004), mean airway pressure (40 vs 28 cm H20, p = 0.04), alveolar-arterial oxygen gradient (579 vs 540 mm Hg, p = 0.03), and oxygenation index (43 vs 19, p = 0.0008) than survivors. Air leak was present in 5 I% of patients; there was no difference in the incidence of air leak between survivors and nonsurvivors (p = 0.42). Conclusions: The high-frequency positive-pressure mode of ventilation was safe and was associated with an improved survival rate (89%) for children with severe ARDS. Limitation of both inspired oxygen and tidal volume, along with aggressive treatment of air leak, may have contributed to the improved survival rate. (J Pediatr 1996;129:566-73) Submitted for publication Dec. 24, 1995; accepted June 6, 1996. Reprint requests: Thomas E. Paulson, MD, Pediatric Critical Care, Baptist Medical Center, Taylor at Marion Street, Columbia, SC 29220-0001. Copyright © 1996 by Mosby-Year Book Inc. 0022-3476/96/$5.00 + 0 9/21/75548 566
Recent studies of acute respiratory distress syndrome in children report a 60% to 75% mortality rate. 1-3 The 1991 multiinstitutional study of pediatric respiratory failure reported a mortality rate of 51% for 183 children with ARDS. 4 Conventional mechanical ventilatory techniques used in
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Table I. Volume control versus pressure control PEEP <6 cm H20 PEEP 6-9 cm H20 PIP <40 cm H20 or Paw <15 PEEP 6-9 cm H20 PIP ->40 cm H20 or Paw ->15 PEEP ->10 cm H20
Volume control Volume control Pressure control Pressure control
m
Paw, Mean airwaypressure. most studies of pediatric ARDS 1-3,5-7 employ volume-controlled ventilation with tidal volumes of approximately 10 to 12 cc/kg applied at relatively low frequencies (10 to 30 breaths/rain), resulting in low inspiratory/expiratory ratios. Animal and human research in normal and diseased lungs has shown t])at this type of ventilation produces a high incidence of secondary lung injury. 8 High-frequency modes of ventilation may prevent this injury by limiting tidal volume, peak inspiratory pressure, and vohitrauma. 9, 10 Since S)rstrand's initial description tl of high-frequency ARDS A-a FIO2 I/E OI Pao2 Paco2 PEEP PIP
Acute respiratory distress syndrome Alveolar-arterial [oxygenationgradient] Fraction of inspired oxygen Inspiratory/expiratory[ratio] Oxygenation index Partial pressure of oxygen, arterial Partial pressure of carbon dioxide, arterial Positive end-expiratorypressure Peak inspiratory pressure
positive-pressure ventilation in 1967, both high-frequency jet ventilation 12and high-frequency oscillation13have shown promising results in children with ARDS in comparison with conventional mechanical ventilatory techniques. We report the results of a combined retrospective and prospective study of children with severe ARDS who received high-frequency pressure-control ventilation with low tidal volumes, rapid rates, and high positive end-expiratory pressure. METHODS
Patients and entry criteria Retrospective phase. After institutional review board approval, w e examined the medical records of all patients with ARDS, respiratory failure, and respiratory insufficiency admitted to the pediatric intensive care unit at Children's Hospital, San DJ[ego, from Jan. 1, 1991, through June 30, 1992, and enrolled children who met the following criteria for the diagnosis of ARDS: (1) acute onset of diffuse, bilateral pulmonary infiltrates of noncardiac origin (pulmonary artery occlusion pressure -< 18 mm Hg when measured) and (2) severe hypoxemia defined by partial pressure of oxygen (arterial)/fraction of inspired oxygen of less than 200 during PEEP of 6 cm H20 or greater. 14 In addition to meeting the above general criteria for ARDS, the diagnosis of severe
567
Table II. Pressure-control protocol Mean airway pressure (cm H20)
liE r a t i o
Frequency (rate/rain)
<15 15-17 18-20 21-23 24-26 >26
1:3 1:2 t:1 1:1 1:1 1:l
10-30 20-40 30-60 40-80 60-i00 60-120
ARDS required a Murray disease severity score greater than 2.5 and Pao2/F~o2 less than 200 for a minimum of 24 hours. 15 The acute conditions associated with the development of ARDS, ventilator settings, blood gas analyses, inotropic support, incidence and treatment of air leak, duration of mechanical ventilation, and occurrence of end-organ failure were recorded. A daily median cardiac index was recorded in patients with a pulmonary artery thermodilution catheter. The cause of death was recorded in nonsurvivors. In 12 patients the lqo2 was increased to 1.0 to calculate alveolar-arterial oxygenation gradients and the oxygen index. The A-a gradient was calculated with the forlnula {[(Pbaro- PP H20) x FIO2] -Paco2/0.8} -Pao2, where Pbaro is 760 mm Hg and PpH20 is 47 mm Hg. The OI was calculated with the formula [(FIo2 x mean airway pressure)/Pao2] x 100. Prospective phase. After institutional review board approval and informed consent, we prospectively enrolled all patients with ARDS (same criteria as retrospective.phase) from June 30, 1992, to Jan. 30, 1994. In addition to the variables obtained in the retrospective phase, the A-a gradient and OI were calculated twice daily during the peak of disease severity with the use of arterial blood gas samples obtained after 10 minutes of FIO2 at 1.0. The same ventilatory technique was used in both the retrospective and the prospective study. Ventilator management. The Siemens 900C ventilator (Siemens Medical Systems Inc., Iselin, N.J.) was used in all children. Volume ventilation was used in some children initially; pressure-contro! ventilation was used in all patients once significant lung disease developed. Table I depicts the criteria for changing from volume to pressure-control ventilation. Table II outlines in stepwise fashion the ventilator rates and I/E ratios used as mean airway pressure requirements escalated. During recovery, weaning was also directed by means of the strategy outlined in Tables I and ti. The protocol for ventilator pressure adjustment related to blood gas analysis is shown in Table Ill. In the pressure-control mode of ventilation, mean airway pressure was titrated to maintain oxygenation (Pao2 55 to 75 mm Hg [7.3 to 10.0 kPa]); when oxygenation was inadequate, PEEP was increased until oxygenation improved (see Table l]I). Respiratory frequency and I/E ratio were increased as mean air-
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Table Ill. Ventilator pressure strategy based on blood gas analysis Inadequate ventilation (Paco2 >60 mm Hg [8 kPa]) Inadequate oxygenation (Pao2 <55 mm Hg [7.3 kPa]) Adequate oxygenation (Pao2 55-75 mm Hg [7.3-10 kPa]) Excessive oxygenation (Pa02 >75 mm Hg [10 kPa])
Adequate ventilation (Paco2 45-60 mm Hg [6-8 kPa])
Excessive ventilation (Paco2 <45 mm Hg [6 kPa])
"]'PEEP; ?PIP
"['PEEP
"]'PEEP; ,[.PIP
"]'PIP
No change
,],PIP
+PEEP
SPEEP; +PIP
-J,ele; +PEEP
way pressure increased so that tidal volume could be minimized and mean airway pressure maximized at a given set PIP and PEEP (see Table II). In the pressure-control mode of ventilation, tidal volume is not preset and inherently varies with changes in dynamic compliance. Because of the very short inspiratory time at higher frequencies, a much smaller tidal volume (3 to 5 cc/kg) 16 is delivered than a tidal volume of 10 to 12 cc/kg, which is typical of conventional mechanical ventilation. Peak inspiratory pressure and therefore tidal volume were further limited, allowing mild hypercapnia (Paco2 45 to 60 mm Hg [6.0 to 8.0 kPa]). Oxygen was limited to FIO2 0.5 except during brief periods for data collection, tracheal suctioning, and acute deterioration. Management of air leak. Tube thoracostomy was performed at the bedside by the critical care physician for all pneumothoraces. Similarly, percutaneous placement of a mediastinal drainage tube was performed in any patient with mediastinal air visible in the substemal area on a lateral chest radiograph while requiring high ventilator settings.17 Outcome. Survival after ARDS was defined as successful tracheal extubation or complete clinical resolution of respiratory disease, with PEEP less than 5 cm H20, mean airway pressure less than 12 cm H20, FIo2 less than 0.5, and Pao2/FIo2 greater than 200 for more than 72 hours. Those patients from whom life support was withdrawn or limited because of neurologic futility before resolution of pulmonary disease were not included in the statistical analysis. Statistical analysis. The maximum values for PIP, PEEP, tidal pressure amplitude ( P I P - PEEP), mean airway pressure, A-a gradient, and OI collected at the peak of disease severity were compared in children with severe ARDS in the retrospective and prospective groups. Only ventilator settings used for 2 hours or more were used in data analysis. After analysis to determine the presence of a normal distribution, either the two-sample t test or the Mann-Whitney 13 test was used to compare groups. A p value of less than or equal to 0.05 was considered statistically significant. The retrospective and prospective data were then combined for further analysis because (1) there were no significant differences in respiratory variables between groups (p
>0.35; Table IV) and (2) the same ventilator protocol was used for both groups. The low number of nonsurvivors (one in the retrospective study; five in the prospective study) precluded statistical comparison of the nonsurvivor groups. The Fisher Exact Test was used to determine whether there was an association between outcome and the presence o f air leak or underlying chronic disease. The two-sample t test and the Mann-Whitney U test were used for a comparison of the use of PIP and PEEP between children with air leak and those without air leak. RESULTS
Patient selection. During the combined retrospective and prospective study period, 3826 children were admitted to the pediatric intensive care unit. There were 75 children with ARDS (39 retrospective and 36 prospective), representing 2% of all admissions. Parents of all children meeting entry criteria during the prospective phase gave consent for participation in the study. Therapy was withdrawn or limited because of brain death, or brain injury with futile prognosis, in 11 patients before resolution of ARDS. These patients were not included in statistical analysis because withdrawal of life support precluded accurate assessment of the experimental technique. Nevertheless, lung disease had improved in 8 of the 11 patients at the time support was withdrawn or limited. In no patient was therapy withdrawn or limited because of deterioration in pulmonary status, One patient (a survivor) was not included in the statistical analysis because of violation of the mechanical ventilation protocol. All other patients were managed according to the protocol. Therefore 63 patients were available for analysis (33 retrospective and 30 prospective), and 57 (90%) of the 63 survived. Ten of these patients did not have severe ARDS (i.e., Murray scores >2.5 and/or Pao2/FIo2 <200 for 24 hours) and were not included in further analysis. Severe ARDS: patient characteristics. Fifty-three patients met the criteria for severe ARDS. Murray disease severity scores were greater than 3 in all severe cases. The median age was 4 years (range, 0.1 to 16 years). Table IV compares the data for maximum PIP, PEEP, mean airway
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Table IV. Comparison of survivors in prospective and 60-
retrospective phases of study with severe ARDS
Survivor Nonsurvivor
50-
.=__ E <
Respiratory variables (maximum values)
o
O3
40o
30--
PIP (cm H20) PEEP (cm H20) Paw (cm H20) A-a gradient (mm Hg) OI
o
o
oOO~o o 0..
p-
0 0
Prospective (n = 25)
p~
40 (28-80) 16 (7-30) 28 (17-41) 520 (325-605) 20 (3-72)
40 (32-60) 16 (14-25) 28 (19-40) 543 (399-615) 18 (9-51)
0.72 0.36 0.77 0.96 0.96
dD
o
o o%O o
Retrospective (n = 22)
r
I
I
I
I
I
[
I
I
i0
20
30
40
50
60
70
80
90
Peak Inspiratory Pressure (cm H20) Figure. Scatter plot of highest peak inspiratory pressure and tidal pressure amplitude (PIP-PEEP) in survivors and nonsurvivors with severe ARDS. In univariate analysis, both mean PIP and mean tidal pressure amplitude were significantly different in survivors and nonsurvivors (p = 0.0006 and p = 0.002, respectively).
pressure, A-a gradient, and OI for the retrospective and prospective groups. Patient data and the acute clinical condition associated with the development of ARDS are shown in Table V. One third of patients had chronic illness. Multiple organ dysfunction syndrome, as defined by three or more concurrent organ system failures, was present in 15 (28%) children and occurred primarily (11/13) in children in whom ARDS developed during a period of shock. There were six patients who were immunocompromised before the development of ARDS, including four with malignancy.
Ventilator requirements, oxygenation index, and A-a gradient. Maximum ventilator requirements, A-a gradient, and OI for survivors and nonsurvivors are compared in Table VI. Nonsurvivors had significantly higher PIP, PEEP, tidal pressure amplitude, mean airway pressure, A-a gradient, and OI (Table VI). All nonsurvivors had an A-a gradient of 543 mm Hg or greater (range, 543 to 620), OI of 35 or greater (range, 35 to 110), and mean airway pressure of 29 cm H20 or greater (range, 29 to 55). There were 16 survivors with an A-a gradient of 543 mm Hg or greater, four survivors with an OI of 35 or greater, and 17 survivors with a mean airway pressure of 29 cm H20 or greater. The Pao2 values achieved in survivors were within the set goal of 55 to 75 mm Hg (7.3 to 10 kPa) during the peak of disease severity. The Paco2 values were maintained between 45 and 60 mm Hg (6-8 kPa); however, some patients had lower Pacoz values (35 to 45 mm Hg [4.6 to 6.0 kPa]) despite efforts to minimize PIP. The median ventilator frequency for both groups was 80 breaths/min (range, 40 to 120). The Figure shows the group as a function of their tidal pressure amplitude and PIP. Survivors had mechanical ventilation for a median of 17 days (range, 9 to 51), with a median duration
Data are reportedas median (range). Paw, Mean airwaypressure. *Mann-Whitney t test. of 10 days (range, 3 to 32), with PEEP of 6 cm H20 or greater. Nonsurvivors also had assisted ventilation for a median of 17 days (range, 7 to 30) before death and had received maximal ventilatory support until then. Air leak. Of 51 patients, 26 (51%) had either pneumothotax or pneumomediastinum. Two patients with blunt chest trauma who came to the emergency department with air leak were excluded from analysis. There was no difference in the incidence of air leak in survivors versus nonsurvivors (p = 0.42). Of the 51 patients, 20 (39%) had pneumothorax; all received tube thoracostomy. Of the 20 children with pneumothorax, 12 (60%) had bilateral pneumothoraces. Sixteen of the twenty patients with pneumothorax also had associated pneumomediastinum. Pneumomediastinum was present in a total of 22 patients, and a percutaneous mediasfinal tube was placed for drainage in 14 (64%) of them. Those children with air leak received higher median PIP of 48 cm H20 (range, 35 to 90) versus 38 cm H20 (range, 28 to 72; p = 0.002) and higher median PEEP of 19 cm H20 (range, 12 to 30) versus 16 cm H20 (range, 7 to 25; p = 0.03) than did those children without air leak. Inotropie support. Intravenously administered vasopressors other than dopamine (2.0 p/kg per minute) were used in 42 of 53 patients with severe ARDS. In 14 patients the addition of a single vasopressor was sufficient. Eighteen children, including five of six nonsurvivors, received three or more vasoactive medications. In 28 patients a thermodilution pulmonary artery catheter was used to measure cardiac function. The lowest daily median cardiac index was 4.0 L/rain per square meter (range, 2.8 to 7.0) in both survivors and nonsurvivors. Survivors. Of 53 children with severe ARDS, 47 (89%) survived; all 10 children with mild disease survived. One survivor required ventilatory support after resolution of ARDS. This infant had congenital nephrotic syndrome with end-stage renal failure and required minimal ventilator settings (FIo2 0.3, PEEP 3 cm H20) because of massive ascites. This child died of fulminant septic shock with Candida albicans infection 2 weeks after resolution of ARDS. Two
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Table V. Data in children with severe ARDS Patients
Acute disease associations
No.
(%)
Pneumonia--infectious
15
(28%)
8/15 NM disease (5) Malignancy (2) Renal failure (1)
Viral Mycoplasma Bacterial Fungal Pnettmonitis
8 4 2 1 13
(25%)
Gastric aspiration Near drowning/aspiration Shock
9 4 13
Septic Iron ingestion Trauma Pulmonary contusions Multiple trauma Other
12 1 7 5 2 5
Summary
53
Chronic illness
Air leak* (%)
MODS
Ventilation (days)'l"
Mortality rate
6/15
(40%)
1/15
18
2/15
5/13 NM disease (5)
8/13
(62%)
0/13
21
0/13
(25%)
2/13 NM disease (1) Malignancy (1)
6/13
(46%)
11/13
14
2/11
(12%)
0/7
4/55
(80%)
3/7
18
2/7
4/5 SEE (1) Malignancy (1) NM disease (2) 19/53 (36%)
2/5
0/5
19
0/5
15/53(28%)
17
6/53 (11%)
No.
26/51
(51%)
MODS, Multipleorgan dysfunctionsyndrome,definedas failureof three or more concurrentorgan systems (i.e., cardiac= ->3 pressors in the presence of shock; renal = creatinine->2;hepatic= bilimbin ->2;hematologic= platelets<100,000; neurologic= Glasgowcoma score <10; other organ systemsnot included);NM, neuromuscular;SLE, systemiclupus erythematosus. *Defined as pneumothoraxor pneumomediastinum. ?Expressed as median because of nonrandomdislributionof data. STwo patients with air leak caused by initial traumatic injury were excluded from analysis.
survivors were removed successfully from mechanical ventilatory support but died in the hospital of complications of their underlying neurologic disease (lissencephaly, near drowning) after "do not attempt resuscitation" orders were instituted. Of 15 children with multiple organ system dysfunction, 11 (73%) survived. Of 6 children with immunocompromise, 5 (83%) survived. TWO survivors with spinal muscular atrophy (Werdnig-Hoffmann disease) were discharged on a regimen of supplemental oxygen; no other children required supplemental oxygen after discharge from the hospital. Nonsurvivors. Of the six nonsurvivors, two patients had shown improvement in pulmonary function before death. One died of an air embolism resulting from staphylococcal pneumonia with multiple pneumatoceles, is and the other died of cardiac failure during an acute episode of septic shock. The four'remaining nonsurvivors received high levels of ventilatory support throughout their hospitalization and ultimately succumbed to cardiopulmonary failure, with two dying during a period of acute fungal septic shock, one
with acute air embolism related to pneumocystis and adenovirus pneumonitis, and the other with severe,, refractory pulmonary hypertension resulting from bilateral pulmonary contusions. DISCUSSION Our patients are representative of children with ARDS at a major pediatric referral center, with one third having chronic underlying illness, including 13 (25%) of 53 with neuromuscular disease and 6 (11%) of 53 with immunocompromise. Strict criteria were used for the diagnosis of ARDS, and the focus of our results was on those children with severe ARDS. By using both a Murray disease severity score greater than 2.5 and a 24-hour requirement for severe hypoxemia (PaoffFIo2 <200 with PEEP ->6 cm H20), we ensured that no patient with a rapid response to mechanical ventilation was included in the severe ARDS group. No prior study of children with ARDS required sustained hypoxemia for 24 hours as an entry criterion. Several studies had either no PEEP criteria for assessing hypoxemia 2, 3 or no Pao2/FIo2
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Table Vl. Ventilator pressures, A-a gradient, and oxygenation index for survivors and nonsurvivors with severe ARDS Respiratory variables
Survivors (n = 47)
Nonsurvivors (n = 6)
p*
PIP (cm H20) PEEP (cm H20) Paw (cm H20) Tidal pressure amplitude (cm H20) A-a gradient (mm Hg)'~ OPt
40 (28-80) 17 -+ 5 28 -+ 6 24 (12-50) 540 (325-629) 19 (3-72)
75 (44-90) 23 _+5 40 -+ 10 54 (24-60) 579 (543-620) 43 (35-110)
0.0006 0.0004 0.04 0.002 0.03 0.0008
Data are expressed as mean -+ SD or median (range) when variablesare not normallydistributed. Paw, Mean airway pressure. *Mann-Whitneytest (PIP, tidal pressure amplitude,A-a gradient, OI); two-sample t test (PEEP, Paw). ]'Data from 29 prospectiveand 12 retrospectivepatients (35 survivors,6 nonsurvivors). Table VR. Comparison of survivors in present study with survivors of prior studies of children with ARDS by means of conventional techniques Authors of study (No. of survivors) Paulson et al. (n = ,*7) Davis, et aL2 (n = 23) DeBruin et al.3 (n :28) Timmons et al.1 (n= ll) Pfenninger et al.6 (n= 12) Lyrene and Truog5 (n = 6)
Maximum F102
PIP (cm H2O)
PEEP (cm H20)
Pa-ff cm H20
Survival rate (%)
0.50
40*
17
28
89
0.87
65
12
26
38
>0.75
51
15
NA
28
>0.5
61
NA
21
25
>0.5
43
NA
NA
60
1.0
57
NA
NA
40
=
*Data are expressed as median because of nonrandomdistributionof data; all other data are expressed as mean. Paw, Mean airway pressure; NA, not available.
requirement for inclusion. 1, 5, 6 The Murray disease severity score and tlhe 24-hour hypoxemia criterion, combined with the ventilator mean airway pressure requirements, demonstrate that our patients were severely ill. Table VII compares maximum FI02, PIP, PEEP, and mean airway pressure in survivors in the current study versus survivors described in prior reports of ARDS in children in whom conventional mechanical ventilation was used. This comparison is useful in illustrating the differences in the use of ventilator pressure and inspired oxygen. Attempting to compare other physiologic measurements such as A-a gradient and OI in our study with measurements from other studies is more difficult and may be misleading because of the inherently physician- and strategy-directed nature of both of these measurements. 19 We used criteria similar to those of the recently published studies by Davis et al.2 and Timmons et al. 4 in excluding those patients with devastating brain injury, because premature withdrawal of therapy for nonpulmonary reasons did not allow a full evaluation of the ventilatory technique. In the 11 patients excluded from analysis because of withdrawal of life
support, improvement in respiratory function had occurred in 8 of 11 children at the time life support was withdrawn, suggesting that survival for this group would have been similar to that of patients who were included if life support had not been withdrawn. In the three survivors who died before hospital discharge, there had been complete resolution of ARDS before death, and therefore they were included as survivors using this technique of ventilation. Using high-frequency, pressure-control ventilation with an UE ratio of 1:1 and a higher mean airway pressure and PEEP than that reported thus far in treating children with ARDS, we were able to firnit FIo2 to 0.5 and still maintain relatively low PIP (see Table VII). Prior studies of children with ARDS using conventional techniques reported maximal PIP of 43 to 61 cm H20 and PEEP of 8 to 15 cm H20 in survivors. We achieved successful ventilation with a maximal median PIP of 40 cm H20 (range, 28 to 80) and a mean PEEP of 17 _+ 5 cm H20 in survivors. Not only was our PIP lower than other reports, but the PEEP was higher, resulting in a median tidal pressure amplitude of only 24 cm
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Paulson et al.
H20 (range, 12 to 50) during each ventilator cycle. The high frequency and high PEEP with I/E ratio of 1:1 enabled us to implement a "high lung volume" strategy without using high PIP, tidal pressure amplitude, or tidal volume. Using pressure and high frequency in this manner allows airway patency to be maintained throughout the ventilator cycle while avoiding the tidal opening and closing of gas exchange units, which causes shearing forces within the airway several magnitudes greater than the delivered PIP. 2° On the other hand, conventional mechanical ventilation at low frequency results in high peak pressures, large tidal volumes, and consistently large tidal pressure amplitudes. Computed tomographic studies have shown that the volume of lung participating in active gas exchange is significantly reduced in ARDS. 21 Therefore conventional tidal volumes in the range of 10 to 12 cc/kg may grossly overdistend and damage the ventilated portion of the lung. W e speculate that our results may also have been affected positively by the early use of high-frequency pressure-control ventilation, limitation of toxic effects of oxygen, and aggressive treatment of air leak. Pressure control and high frequencies were used from the earliest stages of progressive pulmonary dysfunction. Such early intervention may decrease the likelihood of excessive secondary lung injury. 9 Avoidance of the toxic effects of oxygen may also be a significant factor in the success of this form of mechanical ventilation. Prior studies of pediatric ARDS used high concentrations of oxygen to achieve optimal oxygenation. Alternatively, we have used mean airway pressure to achieve satisfactory oxygenation and have limited FIo2 to 0.5. Both animal and human studies have demonstrated pathologic changes in lung parenchyma on exposure to high concentrations Of oxygen, supporting the practice of using alternative methods such as mean airway pressure or high frequency to achieve adequate oxygenation while limiting FIo2. 22 It is plausible that the negative effects of oxygen toxicity from high FIo2 outweigh the positive effects of achieving satisfactory oxygenation with lower airway pressures. Early administration of high concentrations of oxygen may ultimately result in a downward spiral of worsening lung disease, driven in part by the toxic effects of oxygen itself. Finally, the incidence of air leak in this study was similar to that previously reported in children with ARDS despite our use of higher mean airway pressures. 1' 6 In our study there was a significantly higher median PIP of 48 (range, 35 to 90) versus 38 (range, 28 to 72) cm H20 and PEEP of 19 (range, 12 to 30) versus 16 (range, 7 to 25) cm H20 in those children in whom air leak developed. Nevertheless, air leak was not associated with a poor prognosis. This suggests that air leak is not evidence of irreversible, ongoing lung injury. Aggressive treatment, including percutaneous drainage of pneumomediastinum, may have played a role in the im-
The Journal of Pediatrics October 1996
proved survival rate. Drainage of pneumomediastinum frequently results in hemodynamic improvement, potentially decreasing the requirement for intravascular volume expansion and the administration of vasoactive medications. 17 These results suggest that high-frequency, pressure-control mechanical ventilation is safe for use in children with ARDS and may significantly improve survival rates (89%) for children with severe ARDS. However, the lack of a control group prevents us from making definitive judgments based on historical comparisons with earlier studies. Future controlled clinical studies comparing high-frequency, pressure-control ventilation with conventional mechanical ventilation will be required to define the superiority of either technique. Finally, many children with ARDS have complex, underlying disease including immunocompromised conditions. These and other children will remain susceptible to sepsis and multiple organ dysfunction syndrome. For these reasons alone, it is likely that a small percentage of children with ARDS will continue to succumb to the entities described above regardless of ventilator strategy. If future controlled clinical trials confmn our findings, further therapeuti c advances in pediatric ARDS may be better measured by their ability to reduce morbidity, including ventilator and intensive care days, with fewer complications and lower cost. We thank Dr. Carl G. M. Weigle for his thoughtful review of this manuscript. In addition, many thanks are extended to the wonderful nursing and respiratory care staff who assisted in the data collection. In particular, respiratory therapists Jack Mullany, RRT, Steve Leonard, RRT, and Paul Holbrook, RRT, of the dep~ment of respiratory care, deserve much credit for their incessant attention to detail and complete support of the study. REFERENCES
1. Timmons OD, Dean YM, Vernon DD. Mortality rates and prognostic variables in children with adult respiratory distress syndrome. J Pediatr 1991;119:896-9. 2. Davis SL, Furman DP, Costarino AT. ARDS in children: associated disease, clinical course, and predictors of death. J Pediatr 1993;123:35-45. 3. DeBruin W, Notterman DA, Magid M, Godwin T, Johnston S. Acute hypoxic respiratory failure in infants and children: clinical and pathologic characteristics. Crit Care Med 1992; 20:1223-33. 4. Timmons OD, Havens PL, Fackler JC. Predicting death in pediatric patients with acute respiratory failure. Chest 1995;108: 789-97. 5. Lyrene RK, Tmog WE. Adult respiratory distress syndrome in a pediatric intensivecare unit: predisposing conditions, clinical course, and outcome. Pediatrics 1981;67:790-5. 6. Pfenninger J, Gerber A, Tschgppeler H, Zimmermann A. Adult respiratory distress syndrome in children. J Pediatr 1982;101: 352-7. 7. Holbrook PR, Taylor G, Pollack MM, Fields AI. Adult respi- '
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ratory distress syndrome in children. Pediatr Clin North Am 1980;27:677-85. Hickling KG. Ventilatory management: can it affect the outcome? Intensive Care Med 1990;16:219-26. Lachmann B. Open the lung and keep it open. Intensive Care Med 1992;18:319-21. Marini JJ. New options for the ventilatory management of acute lung injury. New Horizons 1993;1:489-502. Sj6strand U. Review of the physiological rationale for and the development of high-frequency positive-pressure ventilation (HFPPV). Acta Anaesthesiol Scand 1977;Suppl 64:7-27. Smith DW, Frankel LR, Derish MT, et al. High-frequency jet ventilation in children with the adult respiratory distress syndrome complicated by pulmonary barotrauma. Pediatr Pulmonol lCO3;15:279-86. Arnold Jtt, Hanson JH, Toro-Figuero LO, Gutierz J, Berens RJ, Anglin DL. Prospective, randomized comparison of high-frequency oscillatory ventilation and conventional mechanical ventilation in pediatric respiratory failure. Crit Care Med 1994; 22:1530-9. Bernard GR, Artigas A, Brigham KL, Carlet J, Falke K, Hudson L, et al. The American-European consensus conference on ARDS. Am J Respir Crit Care Med 1994;149:818-24.
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15. Murray JF, Matthay MA, Luce JM. An expanded definition of the adult respiratory distress syndrome. Am Rev Respir Dis 1988;138:720-3. 16. Shitsky AS. Nonconventional methods of ventilation. AmRev Respir Dis 1988;138(1):175-83. 17. Turlapati KM, Spear RM, Peterson BM. Mediastinal tube placement in children: hemodynamic changes and description of technique. Crit Care Med 1995;23(l)Suppl:A192. 18. Zuhdi MK, Bradley JS, Spear RM, Peterson BM. Fatal air embolism as a complication of staphylococcal pneumonia with pneumatoceles. Pediatr Infect Dis 1995;14:8i 1-2. 19. Paulson TE, Spear RM, Peterson BM. New concepts in the treatment of children with acute respiratory distress syndrome. J Pediatr 1995;127:163-75. 20. Mead J, Takishima T, Leith D. Stress distribution in lungs: a model of pulmonary elasticity. J Appl Physio11970;28:596-608. 21. Gattinoni L, Pesenti A, Bombino M, Bagtioni S, et al. Relationships between lung computed tomographic density, gas exchange, and PEEP in acute respiratory failure. Anesthesiology 1988;69:824-32. 22. Jackson RM. Molecular, pharmacologic, and clinical aspects of oxygen-induced lung injury. Clin Chest Med Mar 1990;11(1): 73-86.
D o n ' t m i s s a s i n g l e i s s u e o f t h e j o u r n a l ! To e n s u r e p r o m p t s e r v i c e w h e n y o u c h a n g e y o u r a d d r e s s , please photocopy and complete the form below.
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Objective: Animal models suggest that high-frequency ventilation with low tidal volumes and high positive end-expiratory pressure (PEEP) minimize secondary injury to the lung. We hypothesized that using a high-frequency pressure-control mode of ventilation with high PEEPin children with severe acute respiratory distress syndrome (ARDS) would be associated with improved survival. Design: The study was a retrospective and prospective clinical study at a 24-bed tertiary care pediatric critical care unit. Fifty-three patients with severe ARDS were studied during a 37-month period, 30 prospectively and 23 retrospectively. Severe ARDS was defined as (I) rapid onset of severe bilateral infiltrates of noncardiac origin, (2) partial pressure of oxygen (arterial)/fraction of inspired oxygen less than 200 on PEEPof 6 cm H2O or more for 24 hours or longer, and (3) Murray disease severity score greater than 2.5. All patients meeting these criteria underwent ventilation in the pressure-control mode; the protocol for ventilation had the following general guidelines: (I) fraction of inspired oxygen limited to 0.5, (2) mean airway pressure titrated with PEEPto maintain arterial partial pressure of oxygen at 55 mm Hg or greater (7.3 kPa), (3) peak inspiratory pressure minimized to allow hypercapnia (arterial partial pressure of carbon dioxide, 45 to 60 mm Hg [6.0 to 8.0 kPa]), and (4) ventilator rates of 40 to 120/min. Percutaneous thoracostomy and mediastinal tubes were placed for treatment of air leak. Results: The survival rate was 89% (47/53) in children with severe ARDS. Nonsurvivors had significantly higher peak inspiratory pressures (75 vs 40 cm H20, p = 0.0006), PEEP(23 vs 17 cm H2O, p = 0.0004), mean airway pressure (40 vs 28 cm H20, p = 0.04), alveolar-arterial oxygen gradient (579 vs 540 mm Hg, p = 0.03), and oxygenation index (43 vs 19, p = 0.0008) than survivors. Air leak was present in 5 I% of patients; there was no difference in the incidence of air leak between survivors and nonsurvivors (p = 0.42). Conclusions: The high-frequency positive-pressure mode of ventilation was safe and was associated with an improved survival rate (89%) for children with severe ARDS. Limitation of both inspired oxygen and tidal volume, along with aggressive treatment of air leak, may have contributed to the improved survival rate. (J Pediatr 1996;129:566-73) Submitted for publication Dec. 24, 1995; accepted June 6, 1996. Reprint requests: Thomas E. Paulson, MD, Pediatric Critical Care, Baptist Medical Center, Taylor at Marion Street, Columbia, SC 29220-0001. Copyright © 1996 by Mosby-Year Book Inc. 0022-3476/96/$5.00 + 0 9/21/75548 566
Recent studies of acute respiratory distress syndrome in children report a 60% to 75% mortality rate. 1-3 The 1991 multiinstitutional study of pediatric respiratory failure reported a mortality rate of 51% for 183 children with ARDS. 4 Conventional mechanical ventilatory techniques used in
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Table I. Volume control versus pressure control PEEP <6 cm H20 PEEP 6-9 cm H20 PIP <40 cm H20 or Paw <15 PEEP 6-9 cm H20 PIP ->40 cm H20 or Paw ->15 PEEP ->10 cm H20
Volume control Volume control Pressure control Pressure control
m
Paw, Mean airwaypressure. most studies of pediatric ARDS 1-3,5-7 employ volume-controlled ventilation with tidal volumes of approximately 10 to 12 cc/kg applied at relatively low frequencies (10 to 30 breaths/rain), resulting in low inspiratory/expiratory ratios. Animal and human research in normal and diseased lungs has shown t])at this type of ventilation produces a high incidence of secondary lung injury. 8 High-frequency modes of ventilation may prevent this injury by limiting tidal volume, peak inspiratory pressure, and vohitrauma. 9, 10 Since S)rstrand's initial description tl of high-frequency ARDS A-a FIO2 I/E OI Pao2 Paco2 PEEP PIP
Acute respiratory distress syndrome Alveolar-arterial [oxygenationgradient] Fraction of inspired oxygen Inspiratory/expiratory[ratio] Oxygenation index Partial pressure of oxygen, arterial Partial pressure of carbon dioxide, arterial Positive end-expiratorypressure Peak inspiratory pressure
positive-pressure ventilation in 1967, both high-frequency jet ventilation 12and high-frequency oscillation13have shown promising results in children with ARDS in comparison with conventional mechanical ventilatory techniques. We report the results of a combined retrospective and prospective study of children with severe ARDS who received high-frequency pressure-control ventilation with low tidal volumes, rapid rates, and high positive end-expiratory pressure. METHODS
Patients and entry criteria Retrospective phase. After institutional review board approval, w e examined the medical records of all patients with ARDS, respiratory failure, and respiratory insufficiency admitted to the pediatric intensive care unit at Children's Hospital, San DJ[ego, from Jan. 1, 1991, through June 30, 1992, and enrolled children who met the following criteria for the diagnosis of ARDS: (1) acute onset of diffuse, bilateral pulmonary infiltrates of noncardiac origin (pulmonary artery occlusion pressure -< 18 mm Hg when measured) and (2) severe hypoxemia defined by partial pressure of oxygen (arterial)/fraction of inspired oxygen of less than 200 during PEEP of 6 cm H20 or greater. 14 In addition to meeting the above general criteria for ARDS, the diagnosis of severe
567
Table II. Pressure-control protocol Mean airway pressure (cm H20)
liE r a t i o
Frequency (rate/rain)
<15 15-17 18-20 21-23 24-26 >26
1:3 1:2 t:1 1:1 1:1 1:l
10-30 20-40 30-60 40-80 60-i00 60-120
ARDS required a Murray disease severity score greater than 2.5 and Pao2/F~o2 less than 200 for a minimum of 24 hours. 15 The acute conditions associated with the development of ARDS, ventilator settings, blood gas analyses, inotropic support, incidence and treatment of air leak, duration of mechanical ventilation, and occurrence of end-organ failure were recorded. A daily median cardiac index was recorded in patients with a pulmonary artery thermodilution catheter. The cause of death was recorded in nonsurvivors. In 12 patients the lqo2 was increased to 1.0 to calculate alveolar-arterial oxygenation gradients and the oxygen index. The A-a gradient was calculated with the forlnula {[(Pbaro- PP H20) x FIO2] -Paco2/0.8} -Pao2, where Pbaro is 760 mm Hg and PpH20 is 47 mm Hg. The OI was calculated with the formula [(FIo2 x mean airway pressure)/Pao2] x 100. Prospective phase. After institutional review board approval and informed consent, we prospectively enrolled all patients with ARDS (same criteria as retrospective.phase) from June 30, 1992, to Jan. 30, 1994. In addition to the variables obtained in the retrospective phase, the A-a gradient and OI were calculated twice daily during the peak of disease severity with the use of arterial blood gas samples obtained after 10 minutes of FIO2 at 1.0. The same ventilatory technique was used in both the retrospective and the prospective study. Ventilator management. The Siemens 900C ventilator (Siemens Medical Systems Inc., Iselin, N.J.) was used in all children. Volume ventilation was used in some children initially; pressure-contro! ventilation was used in all patients once significant lung disease developed. Table I depicts the criteria for changing from volume to pressure-control ventilation. Table II outlines in stepwise fashion the ventilator rates and I/E ratios used as mean airway pressure requirements escalated. During recovery, weaning was also directed by means of the strategy outlined in Tables I and ti. The protocol for ventilator pressure adjustment related to blood gas analysis is shown in Table Ill. In the pressure-control mode of ventilation, mean airway pressure was titrated to maintain oxygenation (Pao2 55 to 75 mm Hg [7.3 to 10.0 kPa]); when oxygenation was inadequate, PEEP was increased until oxygenation improved (see Table l]I). Respiratory frequency and I/E ratio were increased as mean air-
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Table Ill. Ventilator pressure strategy based on blood gas analysis Inadequate ventilation (Paco2 >60 mm Hg [8 kPa]) Inadequate oxygenation (Pao2 <55 mm Hg [7.3 kPa]) Adequate oxygenation (Pao2 55-75 mm Hg [7.3-10 kPa]) Excessive oxygenation (Pa02 >75 mm Hg [10 kPa])
Adequate ventilation (Paco2 45-60 mm Hg [6-8 kPa])
Excessive ventilation (Paco2 <45 mm Hg [6 kPa])
"]'PEEP; ?PIP
"['PEEP
"]'PEEP; ,[.PIP
"]'PIP
No change
,],PIP
+PEEP
SPEEP; +PIP
-J,ele; +PEEP
way pressure increased so that tidal volume could be minimized and mean airway pressure maximized at a given set PIP and PEEP (see Table II). In the pressure-control mode of ventilation, tidal volume is not preset and inherently varies with changes in dynamic compliance. Because of the very short inspiratory time at higher frequencies, a much smaller tidal volume (3 to 5 cc/kg) 16 is delivered than a tidal volume of 10 to 12 cc/kg, which is typical of conventional mechanical ventilation. Peak inspiratory pressure and therefore tidal volume were further limited, allowing mild hypercapnia (Paco2 45 to 60 mm Hg [6.0 to 8.0 kPa]). Oxygen was limited to FIO2 0.5 except during brief periods for data collection, tracheal suctioning, and acute deterioration. Management of air leak. Tube thoracostomy was performed at the bedside by the critical care physician for all pneumothoraces. Similarly, percutaneous placement of a mediastinal drainage tube was performed in any patient with mediastinal air visible in the substemal area on a lateral chest radiograph while requiring high ventilator settings.17 Outcome. Survival after ARDS was defined as successful tracheal extubation or complete clinical resolution of respiratory disease, with PEEP less than 5 cm H20, mean airway pressure less than 12 cm H20, FIo2 less than 0.5, and Pao2/FIo2 greater than 200 for more than 72 hours. Those patients from whom life support was withdrawn or limited because of neurologic futility before resolution of pulmonary disease were not included in the statistical analysis. Statistical analysis. The maximum values for PIP, PEEP, tidal pressure amplitude ( P I P - PEEP), mean airway pressure, A-a gradient, and OI collected at the peak of disease severity were compared in children with severe ARDS in the retrospective and prospective groups. Only ventilator settings used for 2 hours or more were used in data analysis. After analysis to determine the presence of a normal distribution, either the two-sample t test or the Mann-Whitney 13 test was used to compare groups. A p value of less than or equal to 0.05 was considered statistically significant. The retrospective and prospective data were then combined for further analysis because (1) there were no significant differences in respiratory variables between groups (p
>0.35; Table IV) and (2) the same ventilator protocol was used for both groups. The low number of nonsurvivors (one in the retrospective study; five in the prospective study) precluded statistical comparison of the nonsurvivor groups. The Fisher Exact Test was used to determine whether there was an association between outcome and the presence o f air leak or underlying chronic disease. The two-sample t test and the Mann-Whitney U test were used for a comparison of the use of PIP and PEEP between children with air leak and those without air leak. RESULTS
Patient selection. During the combined retrospective and prospective study period, 3826 children were admitted to the pediatric intensive care unit. There were 75 children with ARDS (39 retrospective and 36 prospective), representing 2% of all admissions. Parents of all children meeting entry criteria during the prospective phase gave consent for participation in the study. Therapy was withdrawn or limited because of brain death, or brain injury with futile prognosis, in 11 patients before resolution of ARDS. These patients were not included in statistical analysis because withdrawal of life support precluded accurate assessment of the experimental technique. Nevertheless, lung disease had improved in 8 of the 11 patients at the time support was withdrawn or limited. In no patient was therapy withdrawn or limited because of deterioration in pulmonary status, One patient (a survivor) was not included in the statistical analysis because of violation of the mechanical ventilation protocol. All other patients were managed according to the protocol. Therefore 63 patients were available for analysis (33 retrospective and 30 prospective), and 57 (90%) of the 63 survived. Ten of these patients did not have severe ARDS (i.e., Murray scores >2.5 and/or Pao2/FIo2 <200 for 24 hours) and were not included in further analysis. Severe ARDS: patient characteristics. Fifty-three patients met the criteria for severe ARDS. Murray disease severity scores were greater than 3 in all severe cases. The median age was 4 years (range, 0.1 to 16 years). Table IV compares the data for maximum PIP, PEEP, mean airway
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Table IV. Comparison of survivors in prospective and 60-
retrospective phases of study with severe ARDS
Survivor Nonsurvivor
50-
.=__ E <
Respiratory variables (maximum values)
o
O3
40o
30--
PIP (cm H20) PEEP (cm H20) Paw (cm H20) A-a gradient (mm Hg) OI
o
o
oOO~o o 0..
p-
0 0
Prospective (n = 25)
p~
40 (28-80) 16 (7-30) 28 (17-41) 520 (325-605) 20 (3-72)
40 (32-60) 16 (14-25) 28 (19-40) 543 (399-615) 18 (9-51)
0.72 0.36 0.77 0.96 0.96
dD
o
o o%O o
Retrospective (n = 22)
r
I
I
I
I
I
[
I
I
i0
20
30
40
50
60
70
80
90
Peak Inspiratory Pressure (cm H20) Figure. Scatter plot of highest peak inspiratory pressure and tidal pressure amplitude (PIP-PEEP) in survivors and nonsurvivors with severe ARDS. In univariate analysis, both mean PIP and mean tidal pressure amplitude were significantly different in survivors and nonsurvivors (p = 0.0006 and p = 0.002, respectively).
pressure, A-a gradient, and OI for the retrospective and prospective groups. Patient data and the acute clinical condition associated with the development of ARDS are shown in Table V. One third of patients had chronic illness. Multiple organ dysfunction syndrome, as defined by three or more concurrent organ system failures, was present in 15 (28%) children and occurred primarily (11/13) in children in whom ARDS developed during a period of shock. There were six patients who were immunocompromised before the development of ARDS, including four with malignancy.
Ventilator requirements, oxygenation index, and A-a gradient. Maximum ventilator requirements, A-a gradient, and OI for survivors and nonsurvivors are compared in Table VI. Nonsurvivors had significantly higher PIP, PEEP, tidal pressure amplitude, mean airway pressure, A-a gradient, and OI (Table VI). All nonsurvivors had an A-a gradient of 543 mm Hg or greater (range, 543 to 620), OI of 35 or greater (range, 35 to 110), and mean airway pressure of 29 cm H20 or greater (range, 29 to 55). There were 16 survivors with an A-a gradient of 543 mm Hg or greater, four survivors with an OI of 35 or greater, and 17 survivors with a mean airway pressure of 29 cm H20 or greater. The Pao2 values achieved in survivors were within the set goal of 55 to 75 mm Hg (7.3 to 10 kPa) during the peak of disease severity. The Paco2 values were maintained between 45 and 60 mm Hg (6-8 kPa); however, some patients had lower Pacoz values (35 to 45 mm Hg [4.6 to 6.0 kPa]) despite efforts to minimize PIP. The median ventilator frequency for both groups was 80 breaths/min (range, 40 to 120). The Figure shows the group as a function of their tidal pressure amplitude and PIP. Survivors had mechanical ventilation for a median of 17 days (range, 9 to 51), with a median duration
Data are reportedas median (range). Paw, Mean airwaypressure. *Mann-Whitney t test. of 10 days (range, 3 to 32), with PEEP of 6 cm H20 or greater. Nonsurvivors also had assisted ventilation for a median of 17 days (range, 7 to 30) before death and had received maximal ventilatory support until then. Air leak. Of 51 patients, 26 (51%) had either pneumothotax or pneumomediastinum. Two patients with blunt chest trauma who came to the emergency department with air leak were excluded from analysis. There was no difference in the incidence of air leak in survivors versus nonsurvivors (p = 0.42). Of the 51 patients, 20 (39%) had pneumothorax; all received tube thoracostomy. Of the 20 children with pneumothorax, 12 (60%) had bilateral pneumothoraces. Sixteen of the twenty patients with pneumothorax also had associated pneumomediastinum. Pneumomediastinum was present in a total of 22 patients, and a percutaneous mediasfinal tube was placed for drainage in 14 (64%) of them. Those children with air leak received higher median PIP of 48 cm H20 (range, 35 to 90) versus 38 cm H20 (range, 28 to 72; p = 0.002) and higher median PEEP of 19 cm H20 (range, 12 to 30) versus 16 cm H20 (range, 7 to 25; p = 0.03) than did those children without air leak. Inotropie support. Intravenously administered vasopressors other than dopamine (2.0 p/kg per minute) were used in 42 of 53 patients with severe ARDS. In 14 patients the addition of a single vasopressor was sufficient. Eighteen children, including five of six nonsurvivors, received three or more vasoactive medications. In 28 patients a thermodilution pulmonary artery catheter was used to measure cardiac function. The lowest daily median cardiac index was 4.0 L/rain per square meter (range, 2.8 to 7.0) in both survivors and nonsurvivors. Survivors. Of 53 children with severe ARDS, 47 (89%) survived; all 10 children with mild disease survived. One survivor required ventilatory support after resolution of ARDS. This infant had congenital nephrotic syndrome with end-stage renal failure and required minimal ventilator settings (FIo2 0.3, PEEP 3 cm H20) because of massive ascites. This child died of fulminant septic shock with Candida albicans infection 2 weeks after resolution of ARDS. Two
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Table V. Data in children with severe ARDS Patients
Acute disease associations
No.
(%)
Pneumonia--infectious
15
(28%)
8/15 NM disease (5) Malignancy (2) Renal failure (1)
Viral Mycoplasma Bacterial Fungal Pnettmonitis
8 4 2 1 13
(25%)
Gastric aspiration Near drowning/aspiration Shock
9 4 13
Septic Iron ingestion Trauma Pulmonary contusions Multiple trauma Other
12 1 7 5 2 5
Summary
53
Chronic illness
Air leak* (%)
MODS
Ventilation (days)'l"
Mortality rate
6/15
(40%)
1/15
18
2/15
5/13 NM disease (5)
8/13
(62%)
0/13
21
0/13
(25%)
2/13 NM disease (1) Malignancy (1)
6/13
(46%)
11/13
14
2/11
(12%)
0/7
4/55
(80%)
3/7
18
2/7
4/5 SEE (1) Malignancy (1) NM disease (2) 19/53 (36%)
2/5
0/5
19
0/5
15/53(28%)
17
6/53 (11%)
No.
26/51
(51%)
MODS, Multipleorgan dysfunctionsyndrome,definedas failureof three or more concurrentorgan systems (i.e., cardiac= ->3 pressors in the presence of shock; renal = creatinine->2;hepatic= bilimbin ->2;hematologic= platelets<100,000; neurologic= Glasgowcoma score <10; other organ systemsnot included);NM, neuromuscular;SLE, systemiclupus erythematosus. *Defined as pneumothoraxor pneumomediastinum. ?Expressed as median because of nonrandomdislributionof data. STwo patients with air leak caused by initial traumatic injury were excluded from analysis.
survivors were removed successfully from mechanical ventilatory support but died in the hospital of complications of their underlying neurologic disease (lissencephaly, near drowning) after "do not attempt resuscitation" orders were instituted. Of 15 children with multiple organ system dysfunction, 11 (73%) survived. Of 6 children with immunocompromise, 5 (83%) survived. TWO survivors with spinal muscular atrophy (Werdnig-Hoffmann disease) were discharged on a regimen of supplemental oxygen; no other children required supplemental oxygen after discharge from the hospital. Nonsurvivors. Of the six nonsurvivors, two patients had shown improvement in pulmonary function before death. One died of an air embolism resulting from staphylococcal pneumonia with multiple pneumatoceles, is and the other died of cardiac failure during an acute episode of septic shock. The four'remaining nonsurvivors received high levels of ventilatory support throughout their hospitalization and ultimately succumbed to cardiopulmonary failure, with two dying during a period of acute fungal septic shock, one
with acute air embolism related to pneumocystis and adenovirus pneumonitis, and the other with severe,, refractory pulmonary hypertension resulting from bilateral pulmonary contusions. DISCUSSION Our patients are representative of children with ARDS at a major pediatric referral center, with one third having chronic underlying illness, including 13 (25%) of 53 with neuromuscular disease and 6 (11%) of 53 with immunocompromise. Strict criteria were used for the diagnosis of ARDS, and the focus of our results was on those children with severe ARDS. By using both a Murray disease severity score greater than 2.5 and a 24-hour requirement for severe hypoxemia (PaoffFIo2 <200 with PEEP ->6 cm H20), we ensured that no patient with a rapid response to mechanical ventilation was included in the severe ARDS group. No prior study of children with ARDS required sustained hypoxemia for 24 hours as an entry criterion. Several studies had either no PEEP criteria for assessing hypoxemia 2, 3 or no Pao2/FIo2
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Table Vl. Ventilator pressures, A-a gradient, and oxygenation index for survivors and nonsurvivors with severe ARDS Respiratory variables
Survivors (n = 47)
Nonsurvivors (n = 6)
p*
PIP (cm H20) PEEP (cm H20) Paw (cm H20) Tidal pressure amplitude (cm H20) A-a gradient (mm Hg)'~ OPt
40 (28-80) 17 -+ 5 28 -+ 6 24 (12-50) 540 (325-629) 19 (3-72)
75 (44-90) 23 _+5 40 -+ 10 54 (24-60) 579 (543-620) 43 (35-110)
0.0006 0.0004 0.04 0.002 0.03 0.0008
Data are expressed as mean -+ SD or median (range) when variablesare not normallydistributed. Paw, Mean airway pressure. *Mann-Whitneytest (PIP, tidal pressure amplitude,A-a gradient, OI); two-sample t test (PEEP, Paw). ]'Data from 29 prospectiveand 12 retrospectivepatients (35 survivors,6 nonsurvivors). Table VR. Comparison of survivors in present study with survivors of prior studies of children with ARDS by means of conventional techniques Authors of study (No. of survivors) Paulson et al. (n = ,*7) Davis, et aL2 (n = 23) DeBruin et al.3 (n :28) Timmons et al.1 (n= ll) Pfenninger et al.6 (n= 12) Lyrene and Truog5 (n = 6)
Maximum F102
PIP (cm H2O)
PEEP (cm H20)
Pa-ff cm H20
Survival rate (%)
0.50
40*
17
28
89
0.87
65
12
26
38
>0.75
51
15
NA
28
>0.5
61
NA
21
25
>0.5
43
NA
NA
60
1.0
57
NA
NA
40
=
*Data are expressed as median because of nonrandomdistributionof data; all other data are expressed as mean. Paw, Mean airway pressure; NA, not available.
requirement for inclusion. 1, 5, 6 The Murray disease severity score and tlhe 24-hour hypoxemia criterion, combined with the ventilator mean airway pressure requirements, demonstrate that our patients were severely ill. Table VII compares maximum FI02, PIP, PEEP, and mean airway pressure in survivors in the current study versus survivors described in prior reports of ARDS in children in whom conventional mechanical ventilation was used. This comparison is useful in illustrating the differences in the use of ventilator pressure and inspired oxygen. Attempting to compare other physiologic measurements such as A-a gradient and OI in our study with measurements from other studies is more difficult and may be misleading because of the inherently physician- and strategy-directed nature of both of these measurements. 19 We used criteria similar to those of the recently published studies by Davis et al.2 and Timmons et al. 4 in excluding those patients with devastating brain injury, because premature withdrawal of therapy for nonpulmonary reasons did not allow a full evaluation of the ventilatory technique. In the 11 patients excluded from analysis because of withdrawal of life
support, improvement in respiratory function had occurred in 8 of 11 children at the time life support was withdrawn, suggesting that survival for this group would have been similar to that of patients who were included if life support had not been withdrawn. In the three survivors who died before hospital discharge, there had been complete resolution of ARDS before death, and therefore they were included as survivors using this technique of ventilation. Using high-frequency, pressure-control ventilation with an UE ratio of 1:1 and a higher mean airway pressure and PEEP than that reported thus far in treating children with ARDS, we were able to firnit FIo2 to 0.5 and still maintain relatively low PIP (see Table VII). Prior studies of children with ARDS using conventional techniques reported maximal PIP of 43 to 61 cm H20 and PEEP of 8 to 15 cm H20 in survivors. We achieved successful ventilation with a maximal median PIP of 40 cm H20 (range, 28 to 80) and a mean PEEP of 17 _+ 5 cm H20 in survivors. Not only was our PIP lower than other reports, but the PEEP was higher, resulting in a median tidal pressure amplitude of only 24 cm
572
Paulson et al.
H20 (range, 12 to 50) during each ventilator cycle. The high frequency and high PEEP with I/E ratio of 1:1 enabled us to implement a "high lung volume" strategy without using high PIP, tidal pressure amplitude, or tidal volume. Using pressure and high frequency in this manner allows airway patency to be maintained throughout the ventilator cycle while avoiding the tidal opening and closing of gas exchange units, which causes shearing forces within the airway several magnitudes greater than the delivered PIP. 2° On the other hand, conventional mechanical ventilation at low frequency results in high peak pressures, large tidal volumes, and consistently large tidal pressure amplitudes. Computed tomographic studies have shown that the volume of lung participating in active gas exchange is significantly reduced in ARDS. 21 Therefore conventional tidal volumes in the range of 10 to 12 cc/kg may grossly overdistend and damage the ventilated portion of the lung. W e speculate that our results may also have been affected positively by the early use of high-frequency pressure-control ventilation, limitation of toxic effects of oxygen, and aggressive treatment of air leak. Pressure control and high frequencies were used from the earliest stages of progressive pulmonary dysfunction. Such early intervention may decrease the likelihood of excessive secondary lung injury. 9 Avoidance of the toxic effects of oxygen may also be a significant factor in the success of this form of mechanical ventilation. Prior studies of pediatric ARDS used high concentrations of oxygen to achieve optimal oxygenation. Alternatively, we have used mean airway pressure to achieve satisfactory oxygenation and have limited FIo2 to 0.5. Both animal and human studies have demonstrated pathologic changes in lung parenchyma on exposure to high concentrations Of oxygen, supporting the practice of using alternative methods such as mean airway pressure or high frequency to achieve adequate oxygenation while limiting FIo2. 22 It is plausible that the negative effects of oxygen toxicity from high FIo2 outweigh the positive effects of achieving satisfactory oxygenation with lower airway pressures. Early administration of high concentrations of oxygen may ultimately result in a downward spiral of worsening lung disease, driven in part by the toxic effects of oxygen itself. Finally, the incidence of air leak in this study was similar to that previously reported in children with ARDS despite our use of higher mean airway pressures. 1' 6 In our study there was a significantly higher median PIP of 48 (range, 35 to 90) versus 38 (range, 28 to 72) cm H20 and PEEP of 19 (range, 12 to 30) versus 16 (range, 7 to 25) cm H20 in those children in whom air leak developed. Nevertheless, air leak was not associated with a poor prognosis. This suggests that air leak is not evidence of irreversible, ongoing lung injury. Aggressive treatment, including percutaneous drainage of pneumomediastinum, may have played a role in the im-
The Journal of Pediatrics October 1996
proved survival rate. Drainage of pneumomediastinum frequently results in hemodynamic improvement, potentially decreasing the requirement for intravascular volume expansion and the administration of vasoactive medications. 17 These results suggest that high-frequency, pressure-control mechanical ventilation is safe for use in children with ARDS and may significantly improve survival rates (89%) for children with severe ARDS. However, the lack of a control group prevents us from making definitive judgments based on historical comparisons with earlier studies. Future controlled clinical studies comparing high-frequency, pressure-control ventilation with conventional mechanical ventilation will be required to define the superiority of either technique. Finally, many children with ARDS have complex, underlying disease including immunocompromised conditions. These and other children will remain susceptible to sepsis and multiple organ dysfunction syndrome. For these reasons alone, it is likely that a small percentage of children with ARDS will continue to succumb to the entities described above regardless of ventilator strategy. If future controlled clinical trials confmn our findings, further therapeuti c advances in pediatric ARDS may be better measured by their ability to reduce morbidity, including ventilator and intensive care days, with fewer complications and lower cost. We thank Dr. Carl G. M. Weigle for his thoughtful review of this manuscript. In addition, many thanks are extended to the wonderful nursing and respiratory care staff who assisted in the data collection. In particular, respiratory therapists Jack Mullany, RRT, Steve Leonard, RRT, and Paul Holbrook, RRT, of the dep~ment of respiratory care, deserve much credit for their incessant attention to detail and complete support of the study. REFERENCES
1. Timmons OD, Dean YM, Vernon DD. Mortality rates and prognostic variables in children with adult respiratory distress syndrome. J Pediatr 1991;119:896-9. 2. Davis SL, Furman DP, Costarino AT. ARDS in children: associated disease, clinical course, and predictors of death. J Pediatr 1993;123:35-45. 3. DeBruin W, Notterman DA, Magid M, Godwin T, Johnston S. Acute hypoxic respiratory failure in infants and children: clinical and pathologic characteristics. Crit Care Med 1992; 20:1223-33. 4. Timmons OD, Havens PL, Fackler JC. Predicting death in pediatric patients with acute respiratory failure. Chest 1995;108: 789-97. 5. Lyrene RK, Tmog WE. Adult respiratory distress syndrome in a pediatric intensivecare unit: predisposing conditions, clinical course, and outcome. Pediatrics 1981;67:790-5. 6. Pfenninger J, Gerber A, Tschgppeler H, Zimmermann A. Adult respiratory distress syndrome in children. J Pediatr 1982;101: 352-7. 7. Holbrook PR, Taylor G, Pollack MM, Fields AI. Adult respi- '
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15. Murray JF, Matthay MA, Luce JM. An expanded definition of the adult respiratory distress syndrome. Am Rev Respir Dis 1988;138:720-3. 16. Shitsky AS. Nonconventional methods of ventilation. AmRev Respir Dis 1988;138(1):175-83. 17. Turlapati KM, Spear RM, Peterson BM. Mediastinal tube placement in children: hemodynamic changes and description of technique. Crit Care Med 1995;23(l)Suppl:A192. 18. Zuhdi MK, Bradley JS, Spear RM, Peterson BM. Fatal air embolism as a complication of staphylococcal pneumonia with pneumatoceles. Pediatr Infect Dis 1995;14:8i 1-2. 19. Paulson TE, Spear RM, Peterson BM. New concepts in the treatment of children with acute respiratory distress syndrome. J Pediatr 1995;127:163-75. 20. Mead J, Takishima T, Leith D. Stress distribution in lungs: a model of pulmonary elasticity. J Appl Physio11970;28:596-608. 21. Gattinoni L, Pesenti A, Bombino M, Bagtioni S, et al. Relationships between lung computed tomographic density, gas exchange, and PEEP in acute respiratory failure. Anesthesiology 1988;69:824-32. 22. Jackson RM. Molecular, pharmacologic, and clinical aspects of oxygen-induced lung injury. Clin Chest Med Mar 1990;11(1): 73-86.
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