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Overventilation and Lung Damage
Overventilation and Lung Damage
RESEARCH ARTICLE
Abstract
Airway management is important in trauma and critically ill patients. Prolonged mechanical ventilation results in overventilation-
induced lung barotrauma, but few studies have examined the consequence of acute (1 h or less) overventilation. We hypothe-
sized that acute hyperventilation, as might inadvertently be performed in prehospital settings, would elevate systemic inflamma-
tion and cause lung damage. Female Yorkshire pigs (40–50 kg, n = 10/group) were anesthetized, instrumented for hemodynamic
measurements and blood sampling, and underwent a 25% controlled hemorrhage followed by 1 h of 1) spontaneous breathing, 2)
“normal” bag ventilation (4.8 L·min volume, 400 mL tidal volume, 12 breaths/minute), 3) bag hyperventilation (9 L·min volume,
750 mL tidal volume, 12 breaths/minute), 4) maximum hyperventilation (15 L·min volume, 750 mL tidal volume, 20 breaths/mi-
nute), or 5) mechanical ventilation. Pigs then regained consciousness and recovered for 24 h, followed by euthanasia and collec-
tion of blood and tissue samples. No level of manual ventilation had any significant impact on hemodynamic variables. Blood
markers of tissue damage and plasma cytokines were not statistically different between groups with the exception of a transient
increase in IL-1b; all values returned to baseline by 24 h. On pathological review, severity and distribution of lung edema or other
gross pathologies were not significantly different between groups. These data indicate hyperventilation causes no adverse
effects, to include inflammation and tissue damage, and that acute overventilation, as could be seen in the prehospital phase of
trauma care, does not produce evidence of adverse effects on the lungs following moderate hemorrhage.
NEW & NOTEWORTHY Appropriate airway management is essential in trauma and critically ill patients. Prolonged mechanical
ventilation can result in overventilation-induced lung barotrauma, but few studies have examined the consequence of acute
overventilation. We investigated the outcome of hemorrhage followed by 1 h of overventilation in swine. We found that acute
overventilation, as could be seen in the prehospital phase of trauma care, does not produce evidence of adverse effects on oth-
erwise healthy lungs following moderate hemorrhage.
Bag-valve-mask ventilation with large tidal volumes and expiratory pressure was set to 5 cm H2O and duty cycle at
high ventilation rates can be associated with complications. 0.5. Anesthesia was provided with 1%–3% isoflurane. Urine
A standard adult-sized bag holds 1.5 L and the American output was collected via Foley catheter and body tempera-
Heart Association recommends 500–600 mL and 8–10 venti- ture was monitored via a rectal probe. The animal was placed
lations/min for a minute volume of 5 L (12, 13). Traditional on a warming blanket that was set to 37 C at the start of
approaches to mechanical ventilation use tidal volumes of instrumentation and was left unchanged during the experi-
10 to 15 mL/kg and may cause stretch-induced lung injury ment. A pulse oximeter (Nellcor) was attached to the tongue
(14). There are limited studies investigating tidal volume and or cheek for measuring peripheral oxygen saturation levels
respiration rate delivery in the prehospital setting, but data (SpO2 ), and ECG leads were attached for heart rate (HR). A
suggest that both tidal volume and ventilation rate are often small IV catheter was placed in the marginal ear vein for an-
elevated here, where situations tend to be chaotic, highly esthesia, the femoral artery and vein were percutaneously
stressful, and care is provided by those with less training. cannulated for hemorrhage and blood sampling, and the ca-
Tidal volumes are often above “lung protective levels” and rotid artery and external jugular vein cannulated for blood
ventilation rates well exceed the recommended 10 breaths pressure monitoring and Swan–Ganz catheter (Edwards
per minute (14–17). Lifesciences, Irvine, CA) for pulmonary artery pressure (PAP)
PPV via endotracheal intubation in severely hemorrhaged and continuous cardiac output (CO) measuring via thermo-
animals increases mortality (18). But, to date, no studies dilution, respectively. Once instrumented, isoflurane was
have assessed whether acute hyperventilation causes baro- replaced with continuous intravenous infusion of midazo-
trauma to otherwise healthy lungs that would predispose a lam (0.6–2.5 mg/kg/h) and ketamine (5–30 mg/kg/h), and ani-
hemorrhaged patient to later develop acute respiratory dis- mals were allowed to breathe room air spontaneously. Depth
tress or other lung morbidity. In addition, previous work of anesthesia was monitored based on breathing pattern, he-
shows cytokines are clinical markers of hemorrhage and modynamic variables, jaw tone, and lack of a withdrawal
trauma, as well as associated with varying ventilator strategies reflex in response to toe pinch.
(19–21). With that, we hypothesized that overventilation com-
Experimental Design
bined with hemorrhage would significantly increase inflam-
matory markers and cause significant morbidity in the lungs A 20-min baseline of hemodynamic and respiratory pa-
as compared with spontaneous breathing. Lung morbidity rameters was recorded followed by hemorrhage and 1 h of
was assessed 24 h following combined hemorrhage and over- ventilation. A 25% hemorrhage, calculated based on body
ventilation using pathological approaches and measurement weight and the assumption of 70 mL blood/kg, was first per-
of systemic cytokine levels as an objective surrogate for sys- formed via computer-controlled roller pump set to 50 mL/
temic stress. min hooked to the femoral artery. Five minutes posthemor-
rhage, animals were randomly assigned to one of the follow-
ing ventilation groups (n = 10/group): 1) free breathing, 2)
METHODS
bag normal ventilation (4.8 L·min volume, 400 mL tidal
Research was conducted in compliance with the Animal volume, 12 breaths/minute), 3) bag hyperventilation (9 L·min
Welfare Act, implementing Animal Welfare Regulations volume, 750 mL tidal volume, 12 breaths/minute), 4) bag
and the principles of the Guide for the Care and Use of maximum hyperventilation (15 L·min volume, 750 mL tidal
Laboratory Animals, Nation Research Council. The facility’s volume, 20 breaths/minute), or 5) mechanical ventilation
Institutional Animal Care and Use Committee approved all (positive pressure 30% O2 at 8–10 mL/kg per breath and 8–12
research conducted in this study. The facility where this breaths per minute to maintain an end-tidal PCO2 of
research was conducted is fully accredited by AAALAC. 45 ± 5 mmHg). Bag ventilation was performed by attaching
an adult Ambu bag on the endotracheal tube, and efforts
Ventilation Validation were made to keep inflation/deflation time constants similar
Tidal volumes were validated using a RespiTrainer Advance (0.5 duty cycle). Blood samples were drawn from the femo-
(IngMar Medical, Pittsburgh, PA) with endotracheal tube sec- ral vein catheter at baseline, immediately posthemorrh-
urely in place before animal experiments began. “Normal” bag age, and at 30 and 60 min during ventilation challenge.
ventilation was performed with one-handed squeezes at the Following the 1-h period of assigned ventilation, sedation
designated rate. Hyperventilation and maximum hyperventila- was discontinued, catheters were withdrawn, hemostasis
tion were achieved by two-handed squeezes aimed to maxi- was created by direct pressure, and animals were allowed to
mally empty the bag. wake up before being returned to their cages for a 24-h moni-
toring interval. Additional blood samples were collected at
Instrumentation 4 h and 24 h after completion of ventilation via vena cava
puncture.
Female Yorkshire pigs (40–50 kg) were induced with an
intramuscular injection of tilatamine-zolazepam (Telazol, 4–
Blood Samples
6 mg/kg), intubated with endotracheal tubes (8 mm inter-
nal diameter), and secured on the table, set to 0 tilt, in the Blood samples were collected into K2 EDTA-containing
supine position. During instrumentation, animals were tubes and centrifuged at 5,000 g for 10 min, divided into ali-
mechanically ventilated with positive pressure 30% O2 at 8– quots, and stored at 80 C until analysis. Cytokines, to
10 mL/kg per breath and 8–12 breaths per minute to main- include GM-CSF, IFNg, IL-1a, IL-1ra, IL-1b, IL-2, IL-4, IL-6, IL-
tain an end-tidal PCO2 of 45 ± 5 mmHg. Positive end 8, IL-10, IL-12, IL-18, and TNFa, were analyzed using a
porcine-specific multiplex kit (EMD Millipore, Billerica, MA) ANOVA with repeated measures, as appropriate, from base-
according to the manufacturer’s instructions. line and control (spontaneously breathing) versus experi-
mental groups. Where significant effects were found, Tukey
Pathology post hoc tests were performed. A value of P < 0.05 identified
Following euthanasia, both lungs were excised to measure significant group or time effects.
levels of edema and perform histological analysis. The lung
wet-to-dry (W/D) weight ratio was used as an index of lung RESULTS
water accumulation due to edema resulting from overventi-
lation. To measure the total amount of lung water, a lung To determine appropriate minute volumes, bag ventila-
sample was measured immediately after its excision (wet tion studies were undertaken before animal experimenta-
weight). The lung tissue was then dried in an oven at 60 C tion. The currently recommended minute volume for
for 7 days and reweighed as dry weight. The W/D weight ratio ventilating prehospital patients is 4–5 L (12). Given this,
was calculated by dividing the wet by the dry weight. we sought to replicate those values in our normally venti-
Separate samples were placed in 10% neutral buffered for- lated group of animals. Adult Ambu bags hold 1.5 L. A
malin and sectioned in 4-mm-thick slices, which were stained complete one-handed squeeze elicited 389 ± 19 mL and a
with hematoxylin and eosin. Congestion severity was scored two-handed squeeze 744 ± 64 mL; therefore, a one-handed
on a 0–4 scale (0, none; 1, mild; 2, moderate; 3, marked; 4, squeeze was used for normoventilation and two-handed
severe), and thrombi presence was scored as either 0 (absent) squeeze for hyperventilation and maximum hyperventila-
or 1 (present) by a veterinary pathologist blinded to treat- tion. The following approximate minute volumes were
ment group. used for study: 4.7 L (normoventilation), 9 L (hyperventila-
tion), 15 L (maximum hyperventilation), and 4 L (mechani-
Data Analysis
cal ventilation).
Data were collected continuously on a custom-designed Effects of hemorrhage and ventilation on hemodynamic
data acquisition system based on Labview. All hemody- variables are shown in Fig. 1. As compared with baseline val-
namic, respiratory, and blood values are expressed as means ues, hemorrhage significantly decreased mean arterial pres-
± SE. Stroke volume (SV) was calculated as CO/HR. For he- sure (MAP; 99.5 ± 1.6 mmHg vs. 63.5 ± 2.3 mmHg), CO (7.0 ±
modynamic and respiratory variables, 30-s segments at each 0.2 L/min vs. 6.2 ± 0.2 L/min), SV (70.1 ± 1.8 mL vs. 57.1 ±
time point were compared with a 5-min baseline period mea- 2.2 mL), and PAP (15.8 ± 0.5 mmHg vs. 9.2 ± 0.4 mmHg), and
surement. Data were analyzed by t test, one-way, or two-way increased HR (101 ± 2.4 beats/min vs. 115 ± 3.3 beats/min), as
8 80 *
*#
(mL/beat)
40
(L/min)
(mmHg)
60
etCO2
6
CO
SV
20 *# 4 40
*# 2 * 20
0 0 0
150 160 25
*
140
20 *
100
(mmHg)
(mmHg)
15
(bpm)
PAP
MAP
HR
120
10
50
100
* 5
0 80 0
30 60 90 120 30 60 90 120 30 60 90 120
Time (min) Time (min) Time (min)
Figure 1. Summary data of the effects of hemorrhage and ventilation on ETCO2 , CO, SV, MAP, HR, and PAP (n = 10 animals/group). Values are means ±
SE, significant difference vs. baseline, #significant difference vs. spontaneous breathing. CO, cardiac output; HR, heart rate; MAP, mean arterial pres-
sure; PAP, pulmonary artery pressure; SV, stroke volume.
expected across all groups. And as expected, at the end of only spontaneously breathing and mechanically ventilated
hemorrhage, there were slight decreases in pH and increases animals, whereas creatine kinase was significantly elevated
in lactate. There was no difference in these responses to in normoventilation, maximum hyperventilation, and mec-
hemorrhage across groups. hanically ventilated animals at 24 h compared with
Normoventilation, hyperventilation, and maximum hyp- baseline.
erventilation significantly decreased ETCO2 . A significant Proinflammatory and anti-inflammatory cytokine levels
increase in heart rate compared with baseline was exhibited in plasma were quantified across time (Fig. 3) and compared
in those that underwent maximum hyperventilation and with levels in spontaneously breathing control animals.
mechanical ventilation, but there were no significant hemo- Expression levels of IL-1b and IL-2 were significantly ele-
dynamic differences observed between ventilation groups vated above spontaneous breathing controls at 4 h posthe-
(Fig. 1). There were significant changes in blood gases during morrhage in the maximally hyperventilated group; there
the course of ventilation, but all returned to baseline by 24 h were no other significant changes and values returned to
with the exception of pH (Fig. 2). PCO2 was significantly baseline by 24 h. Although IL-4 expression trended upward
impacted by ventilation, decreasing from baseline in hyper- in the maximum hyperventilation group at 4 h, it was not
ventilation and maximum hyperventilation groups and statistically elevated as compared with controls and returned
increasing in spontaneously breathing and mechanically to baseline levels by 24 h. IFNg, IL-1a, IL-1ra, IL-6, IL-8, IL-10,
ventilated animals. Likewise, hyperventilation and maxi- IL-12, IL-18, and TNF-a had no significant changes. GM-CSF
mum hyperventilation decreased bicarbonate levels. Blood was below detectable levels.
pH was significantly changed from baseline during the 1 h of Lung W/D weight ratio was comparable across all groups
ventilation; pH was decreased in spontaneously breathing at 24 h. Likewise, there was no significant difference in con-
and mechanically ventilated swine but was increased by gestion severity or the presence of thrombi (Fig. 4).
maximum hyperventilation. Maximum hyperventilation sig-
nificantly increased pH compared with spontaneous breath- DISCUSSION
ing. pH remained statistically elevated in all groups at 24 h,
except for the normoventilation group. Lactate was also sig- In this study, we sought to mimic a prehospital trauma
nificantly elevated in all groups but returned to baseline lev- scenario to test whether acute overventilation increases mor-
els by 24 h. Alanine aminotransferase was elevated at 24 h in bidity following hemorrhage. We found no negative side
80 35 7.6
40
* * *# *
30
7.5
*#
(mmol/L)
(mmHg)
HCO3
pCO2
pH
60 7.4
25
20 *# *# 7.3
#*
20 * #* 7.2
* *
0
Alanine Aminotransferase
15 150 25000
*
*
Creatine Kinase
20000
10 100
(mmol/L)
Lactate
(U/L)
15000
(U/L)
10000
5 50
5000
0 0 0
Baseline
Hemorrhage
30” Ventilation
60” Ventilation
4h
24 h
Baseline
Hemorrhage
30” Ventilation
60” Ventilation
4h
24 h
Baseline
Hemorrhage
30” Ventilation
60” Ventilation
4h
24 h
Figure 2. Summary data of the effects of hemorrhage and ventilation on PCO2,HCO3 , pH, lactate, alanine aminotransferase, and creatine kinase (n = 10
animals/group). Values are means ± SE, significant difference vs. baseline, #significant difference vs. spontaneous breathing.
ng/mL
ng/mL
'lL-6
'lL-2
0.00
-0.1 0.05
-0.05
0.02 0.02
0.1
0.01
'TNF-D
ng/mL
ng/mL
0.01
ng/mL
'lL-8
'lL-4
0.0 0.00
0.00
-0.01
-0.1
-0.01 -0.02
effects associated with 1 h of overventilation following hem- no mandate for use of pediatric bags in the prehospital
orrhage, to include hemodynamic changes, systemic inflam- space, we felt that use of an adult bag was most pertinent.
matory markers, or lung tissue damage. This indicates that Up to 60,000 people die from hemorrhage per year in the
hyperventilation, as could be seen in the prehospital phase United States (26), and it is the leading cause of potentially
of care, does not adversely affect hemorrhaged casualties survivable death on the battlefield (27). It was, therefore, im-
with otherwise healthy lungs. portant to include hemorrhage as part of the insult in combi-
Approximately 5% of trauma casualties receive prehospi- nation with positive pressure ventilation to simulate a
tal airway management (22). We replicated the currently rec- prehospital trauma scenario. Previous studies show that
ommended minute volume of 4–5 L with a one-handed hemorrhage and positive pressure ventilation independently
squeeze of an adult Ambu bag, which holds 1.5 L. To produce affect hemodynamic variables but did not assess damage to
hyperventilation, we expelled as much air from the Ambu the lungs (28, 29). Given this, we anticipated an additive neg-
bag as possible with a two-handed squeeze, which resulted ative effect on hemodynamics in the hyperventilation and
in minute volumes of 9.4 L and 15.6 L, for hyperventilation maximum hyperventilation groups. In contrast, although
and maximum hyperventilation, respectively. These vol- hemorrhage slightly decreased CO, there was no significant
umes are similar to those achieved in previous studies exam- further decrease during positive pressure ventilation in any
ining proper grip during bag-valve-mask ventilation (23) and of the groups. This is inconsistent with previous evidence
represent plausible volumes during rigorous ventilation. We that positive pressure ventilation in combination with severe
opted to include groups with varying volumes and rates to hemorrhagic shock increased mortality compared with
capture any differences that may have arisen as a result of spontaneous breathing (11). One difference between these
the changing rate, given that a higher rate did not allow time studies is the level of hemorrhagic shock, as the previous
for the lungs to fully deflate. The maximum respiration rate investigators allowed animals to exsanguinate (11). Our study
used, 20 breaths/min, was similar to previous reports on pre- simulated casualties in level II hemorrhagic shock based on
hospital bag valve mask ventilation (17). In this study, we percent blood loss (26), a moderate hemorrhage that allowed
used room air for 1 h of ventilation, but to understand the animals to survive so that the extent of barotrauma could be
full scope of prehospital positive pressure ventilation, a assessed at a later time, to maximize the possibility that any
future study will need to examine the effects of using 100% pathology produced by the ventilation strategy would be evi-
O2 as hyperoxia may have deleterious effects, as shown in dent. It is unknown what impact greater blood loss would
patients with traumatic brain injury (24). We opted for room have on our model. In addition, female swine were used for
air, as far-forward providers do not often have access to sig- this study and sex hormones play a significant role in physi-
nificant amounts of 100% oxygen. In addition, there is ological responses including respiratory and cardiovascular
debate about the use of adult versus pediatric Ambu bags systems (30). Although females have a lower tolerance to
(16, 25) to help offset overventilation, but given that there is blood loss (31), it is unknown how sex differences impact
1.5
proinflammatory effects of hyperventilation, we are unable
to foresee a net benefit of hyperventilation in pursuit of a
1.0
very modest increase in IL-4.
0.5 One limitation of this study is that the animals were intu-
0.0
bated throughout the experimental phase and intrathoracic
pressure was not measured. Therefore, the influx of air into
-0.5
the stomach that might normally occur during bag-valve-
-1.0 mask ventilation was prevented. It is possible that this
impacted our outcome variables but given the swine anat-
1.5 omy, achieving a proper seal around the mouth would not
have been possible. In addition, animals were recovered for
1.0 only 24 h. Given that all outcomes measured, with the excep-
Thrombi Presence
the later development of acute respiratory distress following 9. Eckstein M, Chan L, Schneir A, Palmer R. Effect of prehospital
moderate hemorrhage. advanced life support on outcomes of major trauma patients. J
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00010.
ACKNOWLEDGMENTS 10. Aufderheide TP, Lurie KG. Death by hyperventilation: a common and
life-threatening problem during cardiopulmonary resuscitation. Crit
We acknowledge Gary Muniz for technical assistance and the Care Med 32: S345–S351, 2004. doi:10.1097/01.ccm.0000134335.
US Army Institute of Surgical Research Veterinary Support 46859.09.
Branch, to include Antoinette Davidson, BJ Malone, Belinda 11. Taghavi S, Jayarajan SN, Ferrer LM, Vora H, McKee C, Milner RE,
Meyers, and Breanna Estrada. Gaughan JP, Dujon J, Sjoholm LO, Pathak A, Rappold JF, Santora
TA, Houser SR, Goldberg AJ. Permissive hypoventilation” in a swine
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GRANTS 2014. doi:10.1097/TA.0000000000000278.
12. Kleinman ME, Goldberger ZD, Rea T, Swor RA, Bobrow BJ,
This work was supported by funding from the Medical Brennan EE, Terry M, Hemphill R, Gazmuri RJ, Hazinski MF,
Research and Materiel Command, Tactical Combat Casualty Care Travers AH. 2017 American Heart Association focused update on
Research Program and the U.S. Army Medical Research and adult basic life support and cardiopulmonary resuscitation quality:
Development Command (MRDC) Grant D_003_2017_USAISR (to an update to the American Heart Association Guidelines for cardio-
M.B.B.) pulmonary resuscitation and emergency cardiovascular care.
Circulation 137: e7–e13, 2018 [Erratum in Circulation 137: e14, 2018].
doi:10.1161/CIR.0000000000000539.
DISCLAIMERS 13. Siegler J, Kroll M, Wojcik S, Moy HP. Can EMS providers provide
The views expressed in this article are those of the authors appropriate tidal volumes in a simulated adult-sized patient with a
and do not reflect the official policy or position of the U.S. Army pediatric-sized bag-valve-mask? Prehosp Emerg Care 21: 74–78,
Medical Department, Department of the Army, DoD, or the U.S. 2017. doi:10.1080/10903127.2016.1227003.
Government. 14. Stoltze AJ, Wong TS, Harland KK, Ahmed A, Fuller BM, Mohr NM.
Prehospital tidal volume influences hospital tidal volume: a cohort
study. J Crit Care 30: 495–501, 2015. doi:10.1016/j.jcrc.2015.02.013.
DISCLOSURES 15. Culbreth RE, Gardenhire DS. Manual bag valve mask ventilation
performance among respiratory therapists. Heart Lung S0147-9563
No conflicts of interest, financial or otherwise, are declared by (20)30404-0: 2020. doi:10.1016/j.hrtlng.2020.10.012.
the authors. 16. Dafilou B, Schwester D, Ruhl N, Marques-Baptista A. It's in the bag:
tidal volumes in adult and pediatric bag valve masks. West J Emerg
Med 21: 722–726, 2020. doi:10.5811/westjem.2020.3.45788.
AUTHOR CONTRIBUTIONS 17. O'Neill JF, Deakin CD. Do we hyperventilate cardiac arrest patients?
M.B.B. conceived and designed research; M.B.B., I.L.H., and Resuscitation 73: 82–85, 2007. doi:10.1016/j.resuscitation.2006.09.
C.R. performed experiments; M.B.B., C.R., and N.W. analyzed 012.
data; M.B.B. and I.L.H. interpreted results of experiments; M.B.B. 18. Pepe PE, Raedler C, Lurie KG, Wigginton JG. Emergency ventila-
tory management in hemorrhagic states: elemental or detrimental? J
prepared figures; M.B.B. drafted manuscript; M.B.B., I.L.H., C.R.,
Trauma 54: 1048–1055; discussion 1055-1047, 2003. doi:10.1097/01.
N.W., and K.L.R. edited and revised manuscript; M.B.B., I.L.H., C.R., TA.0000064280.05372.7C.
N.W., and K.L.R. approved final version of manuscript. 19. Abdul-Malak O, Vodovotz Y, Zaaqoq A, Guardado J, Almahmoud
K, Yin J, Zuckerbraun B, Peitzman AB, Sperry J, Billiar TR, Namas
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