advice we can offer is to never stop rethinking thepatient's problem.

Diffuse Homogeneous Lung Disease

Respiratory distress syndrome (RDS), pneumonia(especially Group B streptococcal), pulmonaryhemorrhage, and adult type respiratory distresssyndrome all may present with diffuse andhomogeneous radiographic lung disease. The mostcommon disease process producing diffusehomogeneous lung disease is RDS in the prematureinfant and pneumonia (especially that caused by GroupB streptococci) in the term infant. In our series of 67preterm infants with RDS and 45 term infants withpneumonia, we found that approximately 75% hadimprovements in gas exchange on HFO. In the terminfants who meet ECMO criteria, 80% could bemanaged with HFO alone. In addition, controlled trials(1,2) have demonstrated a reduction in barotraumawhen HFO is applied earlier in the course of respiratoryfailure. The pathophysiologic mechanisms common tothese disease processes are edema, atelectasis,decreased lung compliance, and ventilation/perfusionmismatch. The goals of assisted ventilation in thisgroup of patients are to improve lung inflation,compliance and ventilation/perfusion matching whileavoiding barotrauma or compromise of cardiac output.

Strategy in the management of diffuse homogeneous

lung disease.

Animal data (3,4,5) support the use of a HFO strategythat initially employs a high mean airway pressure torecruit collapsed alveoli, followed by judicious, butaggressive weaning of the mean airway pressureconcomitant with improvements in lung volumeand compliance.

Another strategy employs a sustained inflation (SI)maneuver to improve lung volume and oxygenation.(6,7) This SI maneuver provides pulsatile periods of

This is a summary of HFO strategies we use in themanagement of neonates. As with any newtechnology, the definition of optimal is dynamic andmany issues remain to be resolved. Our goal is tocommunicate one approach.

In providing HFO support to over 400 critically illneonates sent to Wilford Hall USAF Medical Center, weidentified four categories of patients. These fourgroups consist of patients with diffuse homogeneouslung disease, nonhomogeneous lung disease, lunghypoplasia syndromes, and airleak syndromes. Whilethese groups are distinct, several factors also play arole in determining the optimal HFO strategy to use inany specific patient. The three most important factorsare: airleak, pulmonary hypertension, and poorcardiac performance.

Management of patients with severe airleak requiresthat a low pressure approach be considered.Pulmonary hypertension may be responsive torespiratory alkalosis and relative hyperoxia(PaO2>80mmHg) and acceptable blood gas parametersmust be adjusted accordingly.

ECMO candidates with meconium aspiration syndromeor sepsis are often hypotensive due to poor cardiacfunction. Their limited cardiac reserve requires carefulassessment of the interaction between assistedventilation, venous return and pulmonary blood flow.Increasing end-expiratory pressure during conventionalmechanical ventilation (CMV) and increasing meanairway pressure during HFO can impede venous returnand increase pulmonary vascular resistance. As aresult, the patient with limited cardiac reserve can bemade even less stable. Optimizing these patients'intravascular volumes and vasopressor support iscritical before initiating HFO.

The guidelines discussed below are not meant toreplace individualized care. The most important

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High Frequency Oscillatory Ventilation:Clinical Management StrategiesReese H. Clark, MD and Donald M. Null, MD

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increased pressure during oscillation to re-expandatelectatic alveoli and to bring the lung onto thedeflation limb of the pressure volume curve. The safeuse of SI maneuvers in the management of infantswith RDS requires that they be carefully controlled.Intermittent hand ventilation with a short inspiratorytime is not a safe method of providing a SI. We preferto use gradual increases in the mean airway pressureto SI maneuvers as a method of recruiting collapsedalveoli and improving oxygenation.

Our current clinical strategy in the management ofinfants with diffuse homogeneous lung disease is toinitiate HFO at a mean airway pressure one to twocmH2O higher than that being used on CMV. Weincrease the mean airway pressure in one cmH2Oincrements until arterial oxygen improves by 20 to 30torr, or there is a rise in central venous pressure withsigns of decreased systemic blood flow, or until thechest radiograph shows evidence of normal lunginflation (eighth posterior rib level of expansion anddecreased radiopacification). Once there isimprovement in oxygenation, we hold the meanairway pressure constant and monitor the patient forclinical signs of decreased systemic perfusion. Capillaryrefill, blood pressure, central venous pressure, heartrate, and urine output are monitored hourly.Echocardiographic measurements of indices ofmyocardial performance are done daily.

Chest radiographs are obtained frequently to assessthe degree of lung inflation. If the PaO2 continues torise, the FiO2 is reduced until the level of support isless than 0. 60. When the FiO2 is less than 0.60, meanairway pressure is given equal priority in the weaningprocess. If at any time the chest radiograph shows lungoverinflation or there are signs of impaired cardiacoutput, weaning mean airway pressure is given priorityover FiO2. The goal is to maintain optimal lung inflationand the lowest level of FiO2 necessary to maintain anoxygen saturation of 90-95%. It is important torecognize that adjustments in the mean airwaypressure may not have an immediate effect onoxygenation. In the stable patient, make changesslowly and allow 30-60 minutes for the desired effectto occur.

We use an initial rate of 10-15 Hz with a fractionalinspiratory time of 0.33. Ventilation (PaCO2) is adjustedby changing the oscillatory pressure amplitude (power)

delivered by the ventilator. If adequate PaCO2 cannotbe achieved with the maximum power output, the rateis decreased to increase the tidal volume. If a patient isover ventilated at the lowest power setting, weincrease the rate to decrease the ventilator's tidalvolume output. The typical operation range is 5-15 Hzat a fractional inspiratory time of 0.33.

Nonhomogeneous Lung Disease

Patients with nonhomogeneous lung disease haveunilateral or patchy lung involvement. Meconiumaspiration syndrome (MAS) and focal pneumonia areexamples of this type of disease.

The pathophysiology shared by these diseases in non-uniform lung involvement where certain lung units arenearly normal while other areas are markedlyabnormal. As a result, ventilator management isdifficult. A strategy that is effective in openingdamaged areas may result in overinflation and traumato more normal areas of the lung.

Meconium Aspiration Syndrome

Patients with MAS are less responsive to HFO thanpatients with diffuse homogeneous lung disease. (8)In our series of 51 patients with severe respiratoryfailure secondary to MAS, only 30% responded to HFOwith an improvement in oxygenation. While theresponse rate was low, none of the patients who metECMO criteria, but responded to HFO, required ECMO.In contrast, 94% of the patients who failed to respondto HFO required ECMO to support adequate gasexchange. Poor responsiveness to HFO may be due tothe presence of meconium plugs within the airway.Patients least likely to respond to HFO are those withevidence of air trapping and overinflation on CMV.Currently employed strategies of HFO do not promoteairway clearance of meconium or mucous plugs. Focalgas trapping may be accentuated by HFO and result inairway rupture and pneumothorax.

Another important problem in infants with severe MASand respiratory failure is the presence of pulmonaryhypertension. Persistent pulmonary hypertension maybe associated with compromised cardiac output.

Lung volume changes substantially during tidalbreathing and CMV. During HFO, lung volume andpleural pressure remain relatively constant. Therelative absence of lung volume changes results innearly constant (and sometimes higher) intrathoracicpressure that may impede venous return and reduce

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cardiac output. In patients with limited reserve, thiscan lead to clinical deterioration. ECMO candidateswho do not respond to HFO have significantly worseindices of cardiac function. (9) While no specific indexhas a high positive predictive value in determiningwhich patients will need ECMO, it is important toassess cardiac performance before a trial on HFO. Theinjudicious adjustment of assisted ventilation (CMV orHFO) in infants with air trapping and/or signs of severepulmonary hypertension may cause pneumothoracesor cardiovascular compromise. These events may leadto severe irrecoverable hypoxemia and death. Close,readily available ECMO support is essential whenmanaging critically ill patients with MAS and severepulmonary hypertension.

An important subgroup of patients with MAS hasclinical and radiographic finding more consistent withRDS. These patients tend to be older (>2 days) andusually have been exposed to prolonged high levels ofoxygen and ventilator support. The chest radiographtypically shows lung underinflation and morehomogeneous reticulogranular pattern. In theseinfants, echocardiographic evaluation oftendemonstrates normal myocardial performance, andthey frequently respond well to HFO.

Lung Hypoplasia Syndromes

The most common associated diagnosis in thispopulation of infants is congenital diaphragmatichernia (CDH). Other less common associateddiagnoses include Potters’ syndrome, prolongedrupture of membranes and hydrops fetalis. Thecommon variable in this group of infants is small, oftenabnormal lungs. The theoretic advantage that HFOoffers over CMV is a less traumatic method ofsupporting carbon dioxide elimination. In our series of15 ECMO candidates with CDH, 27% responded to HFOand did not require ECMO.

Infants with lung hypoplasia are similar to those withMAS in that they frequently fail to have a sustainedresponse to HFO. While gas exchange frequentlyimproves on initiation of rescue therapy, theimprovement is usually transient.(10, 11) There are twopossible explanations for the poor response. The first isthat patients with lung hypoplasia have inadequatelung tissue to support adequate gas exchange. Despiteaggressive medical management (CMV or HFO), someinfants die shortly after birth. These infants are usuallynot offered ECMO because they are felt to have

inadequate lung tissue to support life or because theydie before ECMO can be initiated. However, someinfants with radiographic evidence of profoundpulmonary hypoplasia on the first day of life haveradiographs that show much less severe lunghypoplasia after several days of HFO. While it isunlikely that their lungs have grown in this time frame,it is possible that lung capacity improved because ofadaptive factors and avoidance of lung injury.Therefore, we are aggressive in the early managementof all infants with lung hypoplasia syndromes who donot have other lethal congenital anomalies.

The second explanation for the failure of HFO toproduce an improvement in gas exchange in patientswith pulmonary hypoplasia is the presence of profoundpulmonary hypertension. As described in patients withMAS, HFO may compromise cardiac output. In thepatient with limited cardiac reserve, any change thateffects cardiac output (e.g., agitation, pneumothorax,increasing end-expiratory pressure) can cause acuteirreversible deterioration. It is exceedingly important tohave immediate access to ECMO therapy for the infantwith pulmonary hypoplasia and marginal gasexchange. Acute deterioration can be associated withsevere irreversible hypoxemia.

While HFO has not been a very effective mode ofrescue for infants with lung hypoplasia who are failingCMV, it may be an effective ventilatory strategy in theearly management of these infants. HFO improvesventilation and allows the use of lower pressureamplitudes. The use of HFO early in the managementof lung hypoplasia could reduce ventilator associatedbarotrauma and improve pulmonary recoverability andlong term outcome. This hypothesis is currently beingstudied. Until further data are available, the use of HFOearly in the management of patients with CDH must beconsidered investigational.

Strategy in the management of non-homogeneous

lung disease and pulmonary hypoplasia syndromes

Initiation of HFO in this group of infants must be donewith care. Evaluation of the degree of lung inflation onchest radiograph, degree of lability in gas exchange,the severity of existing pulmonary hypotension and theadequacy of cardiac performance must be performedbefore starting HFO. In addition, these patients musthave access to ECMO. In our own nurseries weaccomplish this by notifying the ECMO team before weoffer a trial of HFO.

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The goal of HFO in these patients is to improveoxygenation at the lowest possible mean airwaypressure. Care must be taken to avoid lungoverinflation. Estimating optimal lung inflation is moredifficult in this group of infants than in patients withhomogeneous lung disease. In initiating HFO in thesepatients, we start at the same mean airway pressurethat was being used on CMV. Central venous pressure,oxygen saturation and systemic blood pressure aremonitored continuously during the trial of HFO. If thepatient remains stable for five minutes, an arterialblood gas is obtained. If oxygenation has notimproved, the mean airway pressure is increased byone cmH2O increments every five to ten minutes untilthe arterial oxygen tension improves. Once there is animprovement in PaO2, the mean airway pressure isheld constant at that level. In general, onceoxygenation begins to improve it will continue toimprove, and increasing the mean airway pressurefurther can result in lung overinflation. If at any pointduring the trial there is a significant increase in thecentral venous pressure, a decrease in the systemicarterial pressure, or a drop in the arterial oxygensaturation, the infant is returned to CMV at the samesettings as were present before the trial of HFO. Wheninitiating a second trial of HFO in these patients, westart at a mean airway pressure one to two cmH2Olower than that required on CMV and then follow thesame protocol.

Within an hour of initiation of HFO, a chest radiographis obtained to look for signs of lung overinflation. Forpatients without lung hypoplasia, lung overinflation isdiagnosed when the lung fields are expanded to a levelof more than eight posterior ribs, or are hyperlucent, orwhen the diaphragms are flattened. Assessment oflung overinflation in neonates with lung hypoplasia ismore subjective. If there are sings of lung overinflation,attempts are made to decrease the mean airwaypressure. If lung overinflation persists, the rate beingused on HFO is decreased by one to two Hz. Byreducing the rate, the lung is allowed more time toempty and problems with gas trapping are reduced.The patient is returned to CMV if these procedures failto result in resolution of lung overinflation.

Ventilation is controlled by adjusting oscillatorypressure amplitude and ventilator rate. As in patientswith homogeneous lung disease, we initiate HFO at arate of 10-15 Hz, a pressure amplitude that produces

perceptible chest wall movement and a fractionalinspiratory time of 0.33. If the infant remains stable, anarterial blood gas is obtained. If ventilation isinadequate and the chest x-ray shows normal inflation,the pressure amplitude is increased. If the chest x-rayshows overinflation, the ventilator rate is decreasedallowing increased times for exhalation. If adequateventilation cannot be achieved at five Hz andmaximum power output, the infant is returned to CMV.Faster rates, larger tidal volumes, and longerinspiratory times all increase the propensity for gas tobecome trapped within the lung. Avoidance of thiscomplication is crucial to the safe use of HFO ininfants with heterogeneous lung disease and/orpulmonary hypoplasia.

Airleak Syndromes

Airleak syndromes (pneumothoraces,pneumopericardium, pneumoperitoneum,pneumomediastinum, and pulmonary interstitialemphysema) are a common complication of CMV inthe management of respiratory failure. In thepremature infant, the most common airleak syndromeassociated with severe respiratory failure is pulmonaryinterstitial emphysema (PIE). The most common airleaksyndrome in the near-to-term infant is pneumothorax.The occurrence of airleak usually results in furtherdeterioration of the patient. In patients with intractableairleak, a significant portion of the volume deliveredduring a positive pressure breath can be lost throughthe leak. If this air accumulates in a closed space, it cancompromise vital structures and cause death. Ventingthe airleak can restore function by decompressing thetrapped gas. However, evacuation of the airleak mayalso result in the loss of delivered tidal volume throughthe vent. A cycle can develop whereby adequate gasexchange requires the use of higher ventilator settingsthat, in turn, increases the airleak and reduces theamount of gas available to participate in gas exchange.If this cycle is not interrupted, gas exchange becomesineffective. Frequently, HFO achieves adequateventilation at lower peak and/or mean intrapulmonarypressure than CMV and can break the cycle of airleakand need for high pressures on assisted ventilation.In our series of 127 preterm infants with PIE,78% responded to HFO with an improvement ingas exchange.

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Strategy in patients with airleak syndromes

In the management of PIE, we have found two distinctgroups of patients based on their clinical presentationand response to HFO. The first group of infants haschest radiographic changes consistent with small focalbubbles surrounded by diffuse atelectasis representedby dense radiopacification and low lung volumes. Thepathologic correlates in these infants are dilated distalbronchioles and diffuse alveolar collapse. (12) Themanagement of these infants is the same as thatoutlined for patients with homogeneous lung diseases.Again, the goal is to improve lung inflation and avoidlung overinflation that may cause rupture of the dilateddistal airway and produce PIE and/or pneumothorax.

The second group of patients has chest radiographsthat show large tortuous cysts. Lung involvement maybe focal or diffuse, unilateral or bilateral. Pathologicalexamination of lungs from these infants shows trueinterstitial collections of gas. (12) As the cysts dilate,they may compress surrounding lung tissue and actlike a tension pneumothorax. Our goal in themanagement of these patients is to allow reabsorptionof the interstitial air. In these patients, every attempt ismade to use the lowest possible ventilator settings andto accept low arterial oxygen (45-60 torr) and highcarbon dioxide (50-65 with pH> 7.25) levels. The infantis placed on HFO at a mean airway pressure equal toor less than that being used on CMV. The mean airwaypressure is reduced in one cmH2O increments until thetarget PaO2 is reached or the chest radiographdemonstrates normal inflation and signs of airleakresolution. In these infants weaning mean airwaypressure is given priority over weaning FiO2.

Ventilation is adjusted as discussed previously. Theuse of low oscillatory pressure amplitudes (comparedto PIP or CMV) often leads to resolution of the airleakwithout requiring great reductions in mean airwaypressures. The most severely affected lung is placed inthe dependent position to increase resistance to gasdelivery to that lung. We avoid hand bagging and SImaneuvers in these patients because they can beassociated with worsening of the PIE. (13, 14)

Another important issue in treating infants with PIE iswhen to wean back to CMV. In patients who resolvetheir PIE, we continue HFO for an additional 24 - 48hours. We feel this allows for the completereabsorption of interstitial air and decreases thepossibility of the recurrence of PIE. In patients whose

PIE fails to resolve or evolves into a radiographicpicture of bronchopulmonary dysplasia, we attempt towean back to CMV once the patient is on less than 50%oxygen, and can be supported on peak pressures lessthan 30 cmH2O and a rate less than 30 breaths perminute. Most patients will improve following theirswitch to CMV. This improvement is often temporarilyassociated with mobilization of pulmonary edema andclearance of airway secretions.

Our approach to the infant with gross airleak (recurrentpneumothoraces) is the same as that employed tomanage the preterm infant with PIE. As in patientswith PIE, we first decide if the predominant problem ispoor lung inflation or airleak. In patients whoseprimary problem is poor lung inflation, our goal is toimprove inflation. Therefore when switching fromCMV to HFO, we use a higher mean airway pressure toaccomplish this goal. In infants whose primaryproblem is severe airleak, our goal is to allowresolution of the airleak. In these patients, we use thelowest mean pressure that will allow adequate gasexchange. In either case, it should be reiterated thatthe oscillatory pressures are substantially lower thanthe peak inspiratory pressures of CMV.

Concluding Remarks

As with any new therapy, this technology has alearning curve. The safe introduction of HFO requirescareful education of all those involved with itsapplication. This includes, but is not limited to, nurses,respiratory therapists, physicians and ECMOspecialists. We would like to emphasize all thecomplications seen during CMV can be seen on HFO.Hospital in-services reduce the learning curve’s effecton these complications. While adjusting this HFO issimple, defining optimal lung volume and patientspecific ventilatory strategies can be difficult. Weencourage animal laboratory experience beforeclinical use.

We believe that HFO is an important adjunct to CMV inthe management of neonates with respiratory failure.However, its optimal application requires continuedresearch into the definition of disease-specific HFOstrategies. We hope this paper, based on our clinicalexperience and animal experiments, has helped clarifythe current state-of-the-art.

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REFERENCES

1 Clark RH, Gerstmann DR, Null DM, Jr., deLemos RA.A prospective randomized comparison of highfrequency oscillatory ventilation and conventionalventilation in respiratory distress syndrome. Pediatrics1992; 89: 5-12.

2 HiFO Study Group. High frequency oscillatoryventilation using a variable inspiratory timedecreases the incidence of airleak syndrome ininfants with severe respiratory distress syndrome. Am Rev Respir Dis 1991; 143: A 723.

3 Truog WE, Standaert TA. Effect of high-frequencyventilation on gas exchange and pulmonaryvascular resistance in lambs. J Appl Physiol 1985;59: 104-9.

4 Meredith KS, deLemos RA, Coalson JJ, King RJ,Gerstmann DR, Kumar R, Kuehl TJ, Winter DC,Taylor A, Clark RH, Null DM, Jr., Role of lung injuryin the pathogenesis of hyaline membrane disease inpremature baboons. J Appl Physiol 1989; 66:2 150-8.

5 Kinsella JP, Gerstmann DR, Clark RH, Null DM, Jr.,Morrow WR, Taylor AF, deLemos RA. HFO vs IMV:Early hemodynamic effects in the prematurebaboon with HMD. Pediatr Res 1991; 29: 160-166.

6 Kolton M, Cattran CB, Kent G, Volgysi G, Froese AB,Bryan AC. Oxygenation during high-frequencyventilation compared with conventional mechanicalventilation in two models of lung injury. AnesthAnalg 1982; 61:323-32.

7 Froese A. Personal communication. 1990.

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ABOUT THE AUTHORS...

Reese H. Clark, MDDr. Clark is a leading clinical researcher for the care of critically ill newborns, the Director of Research for Pediatrix Medical Group,Inc. and a Consulting Associate Professor at Duke University in Durham, NC. As a board-certified pediatrician and neonatologist,he has held positions at Emory University School of Medicine in Atlanta, GA and as a Director of Neonatal Research at WilfordHall United States Air Forces Medical Center in San Antonio, TX. Dr. Clark’s success as a leader in clinical research has beenrecognized by his FDA appointment as an advisor to the Anesthesiology and Respiratory Therapy Devices Panel of the MedicalDevices Committee. In addition, he was elected by the membership of the Extracorporeal Life Support Organization to chair thecommittee that develops new clinical studies involving ECMO.

Donald M. Null, Jr., MDDr. Null is the Medical Director, Newborn Intensive Care at Primary Children’s Medical Center and Professor of PediatricsUniversity of Utah School of Medicine in Salt Lake City, Utah. Previously, he was the Director of Neonatology at Allegheny GeneralHospital in Pittsburgh, PA and before going to Pennsylvania, Dr. Null was the Chief of Neonatology and Director of the NeonatalFellowship Program at Wilford Hall Air Force Base Hospital in San Antonio, TX. For more than 15 years, he has been a leadingresearcher in high frequency ventilation, was a key investigator in the development of the 3100 HFOV, and a founder of the annualSnowbird High Frequency Ventilation Conference.

8 Carter JM, Gerstmann DR, Clark RH, Snyder G,Cornish JD, Null DM Jr, deLemos RA. Highfrequency oscillatory ventilation and extracorporealmembrane oxygenation for the treatment of acuteneonatal respiratory failure. Pediatrics 1990; 85: 159-64.

9 McCurnin DC, Kinsella JR, Clark RH, Morrow WR,Null DM, Jr. Cardiac performance in ECMO candidates: Echocardiographic predictors for ECMO.Clin Res 1990; 38: 47A.

10 Bohn D, Tamura M, Perrin D, Barker G, RabinovitchM. Ventilatory predictors of pulmonary hypoplasiain congenital diaphragmatic hernia, confirmed bymorphologic assessment. J Pediatr 1987; 111: 423-31.

11 Ortega M, Ramos AD, Platzker ACG, Atkinson JB,Bowman CM. Early prediction of ultimate outcome in newborn infants with severe respiratory failure. J Pediatr 1988; 113: 744-7.

12 Swischuk LE. Bubbles in hyaline membrane disease. Differentiation of three types. Radiology 1977; 122: 417-26.

13 Clark RH, Gerstmann DR, Null DM, Yoder BA, Cornish JD, Glasier CM, Ackerman NB, Bell RE, deLemos RA. Pulmonary interstitial emphysema treated with high-frequency oscillatory ventilation. Crit Care Med 1986; 14: 926-30.

14 Ackerman NB Jr, Coalson JJ, Kuehl TJ, Stoddard R,Minnick L, Escobedo MB, Null DM, Jr., Robotham, JL, deLemos R. Pulmonary interstitial emphysema in the premature baboon with hyaline membrane disease. Crit Care Med 1984; 12: 512-16.