Spring 2004

Chair & Editor
Timothy R. Myers, BS, RRT-NPS
Clinical Studies Coordinator, Dept. of Pediatrics
Rainbow Babies & Children's Hospital
Case Western Reserve University
11100 Euclid Avenue Suite 3001
Cleveland, OH 44106
(216) 844-7429
Fax (216) 844-5246
timothy.myers@uhhs.com

Co-Editors
Melissa K. Brown RCP, RRT-NPS
Instructor
Respiratory Therapy Program
Health Sciences Department
Grossmont Community College
8800 Grossmont College Dr.
El Cajon, CA 92020
619-743-4032
mkbrown@ucsd.edu

Kathleen Deakins, RRT-NPS
Rainbow Babies and Children's Hospital
11100 Euclid Ave
Cleveland OH 44110
(216) 844-1954
Fax: 216-844-5246
kathleen.deakins@uhhs.com

As with most decisions in health care today, the basic goal in selecting the best mode of ventilation is to find a way to maximize the benefit/cost ratio. Thus, the first step is to identify the potential benefits and costs of a mode:

Benefits

Clinical

• Maintenance of adequate gas exchange
• Reduced work of breathing
• Optimum machine-patient synchrony (i.e., patient comfort)

Technical

• “Learnability” (easy to understand)
• Efficiency (minimum setup and maintenance time)
• Low error rate (minimum risk of inappropriate settings)

Costs

 Clinical

• Adverse reactions (i.e., under/over ventilation, volutrauma)
• Associated complications (i.e., blood loss, pneumonia)

Technical

• Hospital charges to patient
• Hospital costs to provide care

Mode comparisons

While there are dozens of named modes of ventilation, they can all be grouped logically according to their engineering control characteristics. There is, in fact, a natural progression from simple to more complex modes based on the sophistication of the ventilator's feedback control type (see Figure 1). Commercially available modes fall into one of five control type categories:

1. Set point control

Examples: all the basic volume and pressure control modes providing continuous mandatory ventilation, intermittent mandatory ventilation, or continuous spontaneous ventilation (i.e., CPAP and pressure support).

2. Auto set point control

Example: dual control within breaths, such as Pmax on the Draeger Evita 4.

3. Servo control

Examples: Proportional Assist and Automatic Tube Compensation.

4. Adaptive control

Examples: dual control between breaths, such as Pressure Regulated Volume Control on the Siemens Servo or CMV + Autoflow on the Draeger Evita 4.

5. Optimum Control

Example: Adaptive Pressure Ventilation on the Hamilton Galileo.

Figure 1. Summary of control system hierarchy. Note that as the mode becomes more sophisticated, the operator is less involved with the selection of intra-breath characteristics and at the highest levels (intelligent control), may be eliminated altogether.

Tactical Control (within breaths)
 Static set points
   1. set point
   2. auto set point
   3. servo


Stategic Control (between breaths)
 Dynamic set points
 Static models
   4. adaptive
   5. optimal



Intelligent Control (between patients)
 Dynamic set points
 Dynamic models
 Ability to learn from experience
   6. knowledge based
   7. artificial neural networks

Figure 1 shows that simpler modes employ tactical control, or control of pressure, volume, and flow within each breath. The ventilator has no knowledge of how one breath relates to another and no knowledge of the patient's response much beyond triggering and cycling (i.e., breath starting and ending) purposes. Thus, the burden of selecting appropriate breath parameters falls to the operator.

More sophisticated modes employ strategic control as well as tactical control. Strategic control implies at least minimal knowledge of the patient's condition. In adaptive control, the ventilator knows the compliance and resistance of the respiratory system and makes tactical control adjustments accordingly. In optimal control, the ventilator also knows the patient's weight and hence predicted minute ventilation requirement. Strategic control employs mathematical modeling to supplement or replace the operator's need to select appropriate breath parameters. The practical result is that the goals of ventilation are achieved more efficiently. That is, the patient spends more time in physiologically appropriate breathing patterns with less operator-ventilator interaction.

Modes for neonatal mechanical ventilation

Historically, neonates (particularly with RDS) have been ventilated with PC-IMV (pressure controlled intermittent mandatory ventilation) for the simple reason that it was technologically impractical to provide any other mode (other than CPAP). In the mid-1990s, technology advanced to provide patient-triggered breaths, making PC-IMV possible. Patient triggering provides better machine-patient synchrony, which stabilizes tidal volume delivery and gas exchange. It may also reduce the risk of intracranial hemorrhage.

Because PC-IMV is such a primitive mode, increasing and decreasing the level of ventilatory support has for decades been viewed as simply a matter of adjusting frequency and pressure limit. That paradigm has not changed, even though much more sophisticated modes are now available.

In the late 1990s, pressure support (i.e., patient-triggered, pressure-limited, flow-cycled breaths) became available on infant ventilators. While pressure support provides assisted ventilation for spontaneous breaths, there is always the problem of how much support to provide. On one hand, full ventilatory support can be set if the pressure limit is high enough to deliver a normal tidal volume. On the other, pressure support has been used in an attempt to support only the resistive work of breathing through the endotracheal tube. This leaves a wide margin for selecting the level of support and complicates the interaction between mandatory and spontaneous breaths. For example, one common tactical error clinicians often make is to set the pressure support level high enough to deliver the same size tidal volume as the mandatory breaths. One result is that when the frequency of mandatory breaths is reduced, with the expectation of reducing support (i.e., weaning), the patient merely increases the spontaneous breath rate and the supported minute ventilation remains the same; weaning has not occurred and time has been wasted.

By the turn of this century, ventilators began to offer ATC (automatic tubing compensation). This mode (a form of servo control of airway pressure) allows more precise support of the resistive load of breathing through the artificial airway than pressure support. But with increased flexibility comes increased complexity, as ATC can be used with both mandatory and spontaneous breaths.

Current ventilators provide dual control (i.e., use of both pressure and volume signals to shape the breathing pattern). Practically, this means pressure control within breaths and automatic adjustment of the pressure limit between breaths to attain a preset tidal volume target. This achieves the gas exchange stability (despite changing lung mechanics) of volume control, along with the improved machine-patient synchrony of pressure control. Of course, such ventilators also provide all the older modes as well, adding to the complexity of mode selection. Thus, for example, the operator faces having to choose from 25 different modes on the Draeger Evita 4 ventilator.

Selecting the best mode

Any discussion of the “best” mode in any situation must be based on theoretical and empirical considerations. This is because there has never been conclusive scientific evidence that any mode is superior in any situation for any patient population. Even meta-analysis of such vastly different modes as high frequency oscillation and PC-IMV has failed to show irrefutable superiority of one over the other.

That said, we could reasonably argue that any form of dual control is better than either pressure or volume control for the reasons mentioned above (assuming that large airway leaks do not preclude its use). That narrows the options somewhat, but we are still faced with the choice of:

• DC-CMV (dual control continuous mandatory ventilation)
• DC-IMV (dual control intermittent mandatory ventilation, two types)
  1. Automatic adjustment of mandatory breath pressure limit only to maintain a preset tidal volume
  2. Automatic adjustment of mandatory breath pressure limit and frequency to maintain a preset minute ventilation
• DC-CSV (dual control continuous spontaneous ventilation)
• PC-CSV (pressure control continuous spontaneous ventilation)

On top of this, pressure support can be added to DC-IMV, and ATC can be added to any mode.

What I have observed is that experienced clinicians, because of the historically- based paradigm mentioned earlier, tend to “build” their own modes based on options that they have used as they became technologically available. For example, they have the distinct bias to use IMV rather than CMV. Then they will select DC-IMV for the theoretical advantages of more stable gas exchange along with better patient synchrony. Then they add pressure support (at various, seemingly arbitrary, levels) to support spontaneous breaths. Finally, they will add ATC to both spontaneous and mandatory breaths.

Because of the flexibility of options on the Draeger Evita 4, there are actually many possible mode combinations:

1. DC-CMV
2. DC-IMV
3. DC-IMV + Pressure Support
4. DC-IMV + ATC
5. DC-IMV + MMV (mandatory minute ventilation)
6. DC-IMV + Pressure Support + ATC
7. DC-IMV + Pressure Support + MMV
8. DC-IMV + MMV+ ATC

If there is a rational approach to selecting the “best” mode, it must be based on the principle of maximizing the benefit/cost ratio. Table 1 compares the above combinations in light of the previous discussion of benefits and costs.

We might dismiss DC-CSV in neonates because of the relatively high possibility of apnea or at least unstable breathing patterns. That leaves DC-CMV versus DC-IMV. A common clinical goal in small neonates is to minimize the work of breathing (WOB) and thus caloric expenditure. That gives CMV the advantage over IMV because the latter imposes the full WOB on the patient for spontaneous breaths. The table clearly shows that adding anything to IMV in an effort to decrease WOB simply complicates ventilator management without any obvious benefit over CMV. DC-IMV thus has a lower benefit/cost ratio than DC-CMV and seems to be the “best” mode choice. With DC-CMV at a low backup rate, the patient essentially increases and decreases (weans) ventilatory support on his own as lung function and spontaneous efforts change. After initial settings, the only adjustments required of the operator should be FiO 2 changes and perhaps tidal volume target changes for long-term ventilation as the patient grows.

With DC-IMV + anything, the complexity of the mode escalates unnecessarily. Increasing and decreasing support becomes a matter of balancing the interaction of mandatory breaths (frequency and pressure limit) and spontaneous breaths (pressure limit). And since there are no data to support rational guidelines for doing this, the inevitable result is wasted time. Furthermore, mixing dual controlled mandatory breaths with pressure supported spontaneous breaths actually defeats the advantage of dual control. Keep in mind that the main goal of mechanical ventilation is to maintain adequate, stable minute ventilation and hence gas exchange. With dual controlled breaths, adequacy is determined by the operator-selected tidal volume target. Stability is maintained by the ventilator's automatic adjustment of the mandatory breath pressure limit. Allowing spontaneous breaths (i.e., IMV) destabilizes the minute ventilation. Adding arbitrary and varying values of pressure support to spontaneous breaths further destabilizes minute ventilation.

Summary

Selection of the most appropriate mode of ventilation must be based on a comparative benefit/cost ratio analysis. Neonatal ventilation can now be accomplished with the same fifth generation modes available for adults. Newer modes allow dual control of the breathing pattern, thus gaining the advantages of both volume control (stable minute ventilation) and pressure control (better machine-patient synchrony). Ventilators like the Draeger Evita 4 offer so many options that the operator may effectively select from ten different dual control modes. When viewed from the perspective of a theoretical benefit/cost analysis, DC-CMV seems to make the most sense for most neonates who do not have excessive leaks around the endotracheal tube and who are not at significant risk for apnea.

Table 1. Comparison of dual control modes.

[Top]

Since its introduction into clinical practice 15 years ago, exogenous surfactant therapy has been associated with striking improvements in outcomes for preterm infants with respiratory distress syndrome. In his review of natural vs. synthetic surfactants in 1996, Henry Halliday (1) described the history of surfactant, “Following a few false starts in the 1960s and 1970s, it was shown in the 1980s that a synthetic surfactant, (artificial lung expanding compound, ALEC or Pumectant) containing diamitoylphosphatidylcholine (DPPC) and phosphatidylglycerol (PG), blown or instilled in the lungs, and one prepared from bovine lungs, (Surfactant TA) appeared to have beneficial effects on the course and outcome of infants with respiratory distress syndrome.”

Both natural surfactants derived from animal lung and synthetic, protein-free preparations have been scientifically proven to reduce neonatal mortality compared with no treatment. (1) Exosurf ® Neonatal TM was made available for clinical use under the FDA's treatment IND program in July of 1989 and became officially approved for clinical use on August 6, 1990. Exosurf Neonatal and Tursurf are both synthetic protein-free surfactants. (1,2) Beractant (Survanta ® ), a natural surfactant, became approved soon after in 1991. This was followed by several other natural surfactants; bovactant (Alveofact ® SF R11) and calf lung surfactant (CLSE, Infasurf ® ) were FDA approved on July 1, 1998, and a porcine-derived lung surfactant (PLS Curosurf ® ) was approved November 18, 1999. (1)

Synthetic and natural surfactants have both been evaluated using randomized, controlled clinical trials using both prophylactic and rescue strategies for administration. Prophylactic administration is defined as immediately after birth or within the first 15-30 minutes of life. Rescue administration is defined as 1-2 hours after birth, or after the infant begins to show signs of respiratory distress syndrome. (3) The Cochrane Library Database of Systemic Reviews completed a meta-analysis of 11 randomized, controlled trials that met their inclusion criteria. The 11 trials compared administration of synthetic surfactants to administration of natural surfactant extracts in premature infants at risk for or afflicted with respiratory distress syndrome. Based on the results of the meta-analysis, the reviewers, Soll RF and Blanco F, (3) concluded, “Comparative trials demonstrate greater early improvement in the requirement for ventilator support, fewer pneumothoraces, and fewer deaths associated with natural surfactant extract treatment. Natural surfactant may be associated with an increase in intraventricular hemorrhage; though the more serious hemorrhages (Grade 3 and 4) are not increased. Despite these concerns, natural surfactant extracts would seem to be the more desirable choice when compared to currently available synthetic surfactants.” Researchers theorize that the improved outcomes with natural surfactants are due to surfactant associated proteins, SP-B and SP-C. (1)

Another meta-analysis performed by the Cochrane group compared prophylactic surfactant to rescue administration. Eight studies were identified that met inclusion criteria for the meta-analysis. The reviewers, Soll RF and Morley CJ (4), concluded the following, “Prophylactic surfactant administration to infants judged to be at risk of developing respiratory distress syndrome (infants less than 30-32 weeks gestation), compared to selective use of surfactant in infants with established RDS, has been demonstrated to improve clinical outcome. Infants who receive prophylactic surfactant have a decreased risk of pneumothorax, a decreased risk of pulmonary interstitial emphysema and a decreased risk of mortality. However, it remains unclear exactly which criteria should be used to judge 'at risk' infants who would require prophylactic surfactant administration.”

Four additional randomized, controlled trials that looked at early versus delayed surfactant therapy were reviewed. These studies all enrolled infants requiring intubation for respiratory distress within the first two hours of life secondary to established RDS. Two of the trials utilized a synthetic surfactant (Exosurf Neonatal), and two utilized a natural surfactant. This meta-analysis was reviewed by Yost CC and Soll RF (3), who concluded the following based on the results of these four studies: “Early selective surfactant administration given to infants with RDS requiring assisted ventilation leads to a decreased risk of acute pulmonary injury (decreased risk of pneumothorax and pulmonary interstitial emphysema) and a decreased risk of neonatal mortality and chronic lung disease compared to delaying treatment of such infants until they develop established RDS.”

Many nurseries are currently initiating early and more aggressive use of NCPAP in the delivery room in an attempt to increase FRC while limiting the lung injury and barotrauma associated with invasive mechanical ventilation. (5) More randomized trials are needed, and are underway, to evaluate early surfactant administration with brief mechanical ventilation (less than 1 hour) followed by extubation, versus later, selective surfactant administration, continued mechanical ventilation, and extubation from low respiratory support. (6) Only one randomized, controlled trial met the criteria for a Cochrane review in 2002, Verder (7) (1994). Stevens TP, Blennow M, and Soll RF (6) performed the review and reported the following results: “In this study of infants with signs of RDS, intubation and early surfactant therapy followed by rapid extubation to nasal CPAP (NCPAP) compared with later, selective surfactant administration was associated with a lower incidence of mechanical ventilation (ventilation continuing for one hour or more after surfactant administration in the early surfactant group or initiated for respiratory insufficiency or apnea in either group [RR 0.51, 95% CI 0.32, 0.76]). A larger proportion of infants in the early surfactant group received surfactant than in the selective surfactant group [RR 1.74, 95% CI 1.30, 2.33]. The number of surfactant doses per patient was significantly greater among patients randomized to the early surfactant group [MD 0.51, 95% CI 0.32, 0.70]. Trends towards a decreased incidence of mortality, and a higher rate of patient ductus arteriosus requiring treatment were seen in the early surfactant group. There was no evidence of effect on median time in oxygen, duration of mechanical ventilation, or incidence of BPD (oxygen at 28 days).”

Within their individual package inserts, manufacturers of exogenous surfactant currently allow for retreatment at a minimum of six hours after the initial dose. (8) Two randomized, controlled trials have compared the administration of multiple doses of natural surfactant to single doses of natural surfactant in infants with respiratory distress syndrome and were analyzed according to the Neonatal Cochrane group. Soll RF (9) reviewed the studies and concluded, “A policy of multiple doses of natural surfactant extract results in greater improvements regarding oxygenation and ventilatory requirements, a decreased risk of pneumothorax and a trend toward improved survival. The ability to give multiple doses of surfactant to infants with ongoing respiratory insufficiency leads to improved clinical outcome and appears to be the most effective treatment policy.” Kattwinkel (8) et al. (2000) conducted a large, randomized, multi-center, controlled trial enrolling 2,484 infants that compared a low threshold retreatment strategy (FiO2>30%) of Infasurf ® to a high threshold retreatment strategy (FiO2 >40%; mean airway pressure >7 cm H 2 O). The infants were retreated at minimum six-hour intervals each time they reached their assigned threshold. Subjects were separated into groups according to whether they received the surfactant as Rescue or Prophylaxis, and whether their RDS was considered complicated (evidence of perinatal compromise or sepsis) or uncomplicated. Based on the results, Kattwinkel concluded, “Substantially less surfactant use and thus presumably a significant cost-savings can be realized by delaying surfactant retreatment of patients with uncomplicated RDS until they have reached a higher level of respiratory support than is currently recommended by the manufacturers of the commercially available surfactants.” (8)

A second method of potential cost savings can be achieved from the ability to reenter a surfactant vial to administer a second dose of surfactant to a patient. Surfactant is available in single-use, preservative-free vials, but with VLBW infants, the vials contain enough volume to provide multiple doses . (10) Reiter et al. (2003), from the department of pharmacy at the University of Colorado Hospital and School of Pharmacy, conducted a short-term sterility study with Calfactant at 12 and 24 hours following initial entry into the vial. The data suggest that 1-2 re-entries into a vial of calfactant, within 24 hours after the initial breach, can be a safe and economical method of providing more than a single dose of s urfactant to infants weighing <1 kg. The surfactant should be properly labeled and refrigerated between doses according to the manufacturers' recommendations. (10)

In addition to treatment for RDS, a large focus of current research is on the use of exogenous surfactant to treat surfactant depletion and inactivation in other diseases and patient populations. Examples of these populations include full term infants with meconium aspiration, congenital diaphragmatic hernia, and both pediatric and adult ARDS. (11) A few randomized, controlled trials have studied the effect of surfactant administration in the treatment of full term infants with meconium aspiration. Findlay (1996) reports a decrease in the risk of pneumothorax (relative risk 0.09, 95% CI 0.01, 1.54, risk difference -0.25, 95% CI -0.45, -0.05). Both Findlay (12) (1996) and Lotze (13) (1998) report a decrease in the number of infants receiving extracorporeal membrane oxygenation. Surfactant therapy in patients with meconium aspiration has yet to be compared to, or tested in conjunction with, other approaches to treatment, such as inhaled nitric oxide and high frequency ventilation. (14) In 1996, Anzueto (15) et al., conducted a randomized clinical assay with 725 adult patients with sepsis-induced ARDS to assess the efficacy of aerosolized surfactant . There was no statistically significant difference in survival rate 30 days after treatment, length of stay in the ICU, length of mechanical ventilation, or physiological outcome (oxygenation). More recent studies with ARDS have evaluated surfactant administration via direct tracheal instillation/pulmonary lavage. Both natural and newer synthetic surfactants are being evaluated. (11)

Third generation synthetic surfactants containing surfactant proteins and peptides are now being developed, and research is currently underway to determine their efficacy and safety. Examples of these surfactants include: r-h CuZnSOD (rSP-C) and KL-4 ( Surfaxin ® ) . (1,11) Surfaxin (lucinactant), marketed by Discovery Laboratories Inc., which has recently completed two phase III clinical trials for infants with RDS. The drug is also currently in phase III clinical trials for meconium aspiration and phase II clinical trials for ARDS. Discovery Labs (16) markets Surfaxin ® as “an engineered version of natural human lung surfactant containing a peptide, sinapultide, which is designed to precisely mimic the essential human lung surfactant protein B (SP-B).” The company is presently developing aerosolized formulations to treat patients with asthma, COPD, ALI, OSA, and otitis media.

The amount of research and effort that have gone into understanding RDS and surfactant replacement therapy has had a phenomenal impact on the outcomes of infants who are born prematurely. This research remains ongoing, as more studies continue to determine best practice, and scientists continue to work diligently to perfect synthetic surfactants. Based on results seen in animal studies of some of the new, third generation surfactants, there is a strong possibility that they may become the surfactants of choice in the future, with even more improved outcomes.

References

1. Halliday HL. Natural vs. Synthetic Surfactants in Neonatal Respiratory Distress Syndrome. Drugs 1996 Feb: 51(2); 226-37.
2. Kemper E. Surfactant for Preemies. http://www.fda.gov/bbs/topics/NEWS/NEW00044.html Retrieved 2004, February.
3. Yost CC, Soll RF. Early versus delayed selective surfactant treatment for neonatal respiratory distress syndrome (Cochrane Review). In: The Cochrane Library, Issue 1, 2004. Chichester, UK: John Wiley & Sons, Ltd.
4. Soll RF, Morley CJ. Prophylactic versus selective use of surfactant in preventing morbidity and mortality in preterm infants (Cochrane Review). In: The Cochrane Library, Issue 1, 2004. Chichester, UK: John Wiley & Sons, Ltd.
5. Merrill JD, Ballard RA. Pulmonary Surfactant for Neonatal Respiratory Disorders. Current Opinion in Pediatrics. 15(2): 149-54, 2003 Apr.
6. Stevens TP, Blennow M, Soll RF. Early surfactant administration with brief ventilation vs. selective surfactant and continued mechanical ventilation for preterm infants with or at Risk for RDS (Cochrane Review). In: The Cochrane Library, Issue 1, 2004. Chichester, UK: John Wiley & Sons, Ltd.
7. Verder H, Robertson B, Greisen G, Ebbesen F, Albertsen P, Lundstrom K, Jacobsen T. Surfactant therapy and nasal continuous positive airway pressure for newborns with respiratory distress syndrome. Danish-Swedish Multicenter Study.
8. Kattwinkel, J. High vs. Low-Threshold Surfactant Retreatment for Neonatal Respiratory Distress Syndrome. Pediatrics, Volume 106(2) Part 1of 3. August 2000.282-288.
9. Soll RF. Multiple versus single dose natural surfactant extract for severe neonatal respiratory distress syndrome (Cochrane Review). In: The Cochrane Library, Issue 1, 2004. Chichester, UK: John Wiley & Sons, Ltd .
10. Reiter PD, Sims C, Harmes L, Paisley J, Rosenberg AA, Valuck RF. Calfactant sterility in multiple doses from single-use vials. Ann Pharmacotherapy. 2003 Sep; 37(9):1219-23.
11. Rebello, CM, Proenca, RS, Troster EJ, Jobe, AH. Exogenous Surfactant Therapy-What is established and what still needs to be determined? J Pediatr (Rio J) 2002; 78(Suppl.2):s215-s26.
12. Findlay RD, Taeusch HW, Walther FJ. Surfactant Replacement Therapy for Meconium Aspiration Syndrome. Pediatrics, Volume 97(1).  January 1996. 48-52.
13. Lotze A, Mitchell BR, Bulas DI, Zola EM, Shalwitz RA, Gunkel JH. Multicenter study of surfactant (beractant) use in the treatment of term infants with severe respiratory failure. Survanta in Term Infants Study Group. J Pediatr. 1998 Jan;132(1):40-7
14. Soll RF, Dargaville P. Surfactant for meconium aspiration syndrome in full term infants (Cochrane Review). In: The Cochrane Library, Issue 1, 2004. Chichester, UK: John Wiley & Sons, Ltd.
15. Anzueto A et al. Aerosolized Surfactant in adults with Sepsis Induced Adult Respiratory Distress Syndrome. New England Journal of Medicine, Volume 334:22. May 30, 1996. 1417-1422.
16. Discovery Labs, Inc. Commercializing Surfaxin. http://www.discoverylabs.com/abt-disc-commercializing.htm. Retrieved 2004, February.

[Top]

Specialty Practitioner of the Year: Submit your 2004 nominations now.

Bulletin Deadlines: Winter Issue: December 10; Spring Issue: March 10; Summer Issue: June 10; Fall Issue: September 10.

[Top]