Inhaled Carbon Dioxide Causes Dose-Dependent Paradoxical

Respiratory Physiology & Neurobiology 217 (2015) 1–7

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Respiratory Physiology & Neurobiology

jou rnal homepage: www.elsevier.com/locate/resphysiol

Inhaled carbon dioxide causes dose-dependent paradoxical

bradypnea in animals anesthetized with pentobarbital, but not with isoﬂurane or ketamine

a,∗ b,c a a

Yehuda Ginosar , Nathalie Corchia Nachmanson , Joel Shapiro , Charles Weissman , b,c

Rinat Abramovitch

Department of Anesthesiology and Critical Care Medicine, Jerusalem, Israel

The Goldyne Savad Institute of Gene Therapy, Jerusalem, Israel

MRI Laboratory, Human Biology Research Center, Hadassah Hebrew University Medical Center, Ein Karem, Jerusalem, Israel

a r t i c l e i n f o a b s t r a c t

Article history: Introduction: In spontaneously breathing mice anesthetized with pentobarbital, we observed unexpected

Received 19 January 2015

paradoxical bradypnea following 5% inhaled CO2.

Received in revised form 12 June 2015

Methods: Observational study 7–8 week CB6F1/OlaHsd mice (n = 99), anesthetized with 30 mg/kg

Accepted 13 June 2015

intraperitoneal pentobarbital. Interventional study: Adult male Wistar rats (n = 18), anesthetized either

Available online 19 June 2015

with 30 mg/kg intraperitoneal pentobarbital, 100 mg/kg intraperitoneal ketamine or 1.5% isoﬂurane.

Rats had femoral artery cannulas inserted for hemodynamic monitoring and serial arterial blood gas Keywords:

measurements.

Control of respiration

Results: Observational study: There was a marked reduction in respiratory rate following 4 min of

Carbon dioxide ventilatory response

normoxic hypercapnia; average reduction of 9 breaths/min (p < 0.001) (17% reduction from base-

Respiratory rate

Anesthesia line). Interventional study: increasing CO2 caused dose-dependent increase in respiratory rate for

Animals ketamine–xylazine (p = 0.007) and isoﬂurane (p = 0.016) but dose-dependent decrease in respiratory rate

for pentobarbital (p = 0.046). Increasing inspired CO2 caused dose-dependent acidosis following pen-

tobarbital and isoﬂurane (p = 0.013 and p = 0.017, respectively); but not following ketamine–xylazine

(p = 0.58).

Conclusions: Inhaled CO2 caused paradoxical dose-dependent bradypnea in animals anesthetized with

pentobarbital, an observation not hitherto reported as a part of anesthesia-related respiratory depression.

1. Introduction 1977; Siafakas et al., 1983), they are more limited for volatile

anesthetics, where there is a more pronounced effect on the ven-

The ventilatory response to hypercarbia, hypoxemia and tilatory response to hypoxia than to hypercarbia (Gautier et al.,

acidemia is inhibited in a dose-dependent manner by many 1987; Pandit, 2005, 2007, 2014; Pandit et al., 1999; Pandit and

anesthetic drugs (in particular opioids and barbiturates) (Lumb, Moreau, 2005). Other anesthetic drugs, most notably ketamine,

2010). In response to these anesthetic drugs, the PaCO2 venti- do not signiﬁcantly depress spontaneous ventilation (Gautier and

lation response curve is both ﬂatter and is shifted to the left Gaudy, 1978).

(with both an increased apneic PaCO2 threshold and an increased This concept is supported by many years of animal and human

hyperpnic PaCO2 threshold) (Lumb, 2010). While these anesthetic- research, underlies the core of respiratory physiology and high-

mediated effects are predominantly marked for opioids (Dahan, lights the need to restore normal chemoreﬂex control of breathing

2007; Dahan et al., 2008; Eckenhoff and Helrich, 1958) and bar- for successful recovery from anesthesia, as depressed breathing

biturates (Eckenhoff and Helrich, 1958; Goldberg and Milic-Emili, or depressed responses to hypoxia and hypercapnia can increase

risk. Consequently, in ongoing studies of mice anesthetized with

pentobarbital for blood oxygen level dependent functional mag-

∗

Corresponding author at: Mother and Child Anesthesia Unit, Department of

Anesthesiology and Critical Care Medicine, Hadassah Hebrew University Medical

Center, POB 12000, Ein Kerem, Jerusalem 91120, Israel. Fax: +972 2 6434434.

E-mail address: [email protected] (Y. Ginosar). Lumb, 2010.

http://dx.doi.org/10.1016/j.resp.2015.06.003

2 Y. Ginosar et al. / Respiratory Physiology & Neurobiology 217 (2015) 1–7

netic resonance imaging (BOLD-fMRI) (Barash et al., 2008; Edrei thetized with 30 mg/kg intraperitoneal pentobarbital (CTS group,

et al., 2011), we were surprised to observe paradoxical bradypnea Hod-Hasharon, Israel) and were all spontaneously breathing inside

immediately following the administration of small doses of inhaled a MRI spectrometer. Throughout the procedure, animals were not

carbon dioxide. In this brief report, we present the observed effect intubated, but attached by a loose-ﬁtting facemask to a breathing

of both normoxic hypercapnia and hyperoxic hypercapnia on the system with 4 L/min fresh gas ﬂow. For three consecutive 4 min

respiratory rate of a large sample of mice. Based on this observation, periods, animals breathed the following gases in sequence: medi-

we prospectively tested anesthetized rats in whom we had inserted cal air (21% O2, 79% N2), air-carbon dioxide (5% CO2, 21% O2, 74%

femoral arterial catheters to test the hypothesis that inspired car- N2) and carbogen (5% CO2, 95% O2); all gases supplied by Oxygen

bon dioxide causes a dose-dependent paradoxical bradypnea (with & Argon Works Ltd., Israel. Respiratory monitoring inside the MRI

exacerbation of respiratory acidosis) in rats anesthetized with pen- spectrometer was performed using an MRI-compatible chest wall

tobarbital. We conducted a dose–response study for the effects pneumotachometer (SA instruments, Inc., Stony Brook, NY).

of different inspired concentrations of inhaled carbon dioxide on

respiratory rate and arterial blood gases in rats anesthetized with 2.2. Interventional study

pentobarbital; we compared pentobarbital anesthesia with stan-

dard doses of ketamine and xylazine or isoﬂurane. Animals in the interventional data set were adult male Wis-

tar rats (270 ± 20 g; n = 18), anesthetized either with 30 mg/kg

2. Methods intraperitoneal pentobarbital injection (PB; n = 6), 100 mg/kg

intraperitoneal ketamine injection (with 5 mg/kg xylazine) (KET;

All experiments were performed in accordance with the guide- n = 6) or 1.5% inhaled isoﬂurane (ISO; n = 6). All rats had femoral

lines and approval of the Animal Care and Use Committee (IACUC) artery cannulas inserted for hemodynamic monitoring (heart rate,

of the Hebrew University which holds NIH approval (OPRR-A01- systolic and diastolic arterial pressure) and serial arterial blood gas

5011). measurements. All experiments were performed during the morn-

ing, at the same cycle of the circadian rhythm.

2.1. Observational study Animals were not intubated, and were attached by a loose-

ﬁtting facemask to a breathing system, as above. Gas cylinders

Animals in the observational data set were 7–8 week old were medical air (21% O2, 79% N2), air–carbon dioxide (5% CO2,

CB6F1/Ola Hsd mice (n = 99) who were all undergoing BOLD-fMRI 21% O2, 74% N2) and carbogen (5% CO2, 95% O2) as above. The

with a hypercapnic challenge test, as reported in previous studies choice of inspired gas mixtures was designed to provide a dose-

(Barash et al., 2008; Edrei et al., 2011). These animals were all anes- response for inspired CO2 yet to stay within the framework of the

3 data points in the observational study. In six sequential 4 min

periods the animals received the following inspired gas combina-

tions: baseline (BL) = 4 L/min medical air; normoxic hypercapnia 1

(NH-1) = 1 L/min air-carbon dioxide + 3 L/min medical air (expected

ﬁnal concentration of 1.25% CO2; 21% O2; 77.75% N2); normoxic

hypercapnia 2 (NH-2) = 2 L/min air–carbon dioxide + 2 L/min medi-

cal air (expected ﬁnal concentration of 2. 5% CO2; 21% O2; 76.5%

N2); normoxic hypercapnia 3 (NH-3) = 3 L/min air–carbon diox-

ide + 1 L/min medical air (expected ﬁnal concentration of 3.75%

CO2; 21% O2; 75.25% N2); normoxic hypercapnia 4 (NH-4) = 4 L/min

air-carbon dioxide (expected ﬁnal concentration 5% CO2; 21% O2;

74% N2); hyperoxic hypercapnia (HH) = 4 L/min carbogen (expected

ﬁnal concentration 5% CO2; 95% O2).

All inspired gas contents were conﬁrmed by inspired oxygen,

nitrogen and carbon dioxide measurement from the inspiratory

limb of the breathing system, measured continuously throughout

the study. At the end of each time period, the following assessments

were made: respiratory rate, heart rate, arterial pressure (systolic,

diastolic and mean) and arterial blood gas analysis (pH, PaCO2 and

PaO2). Arterial blood (0.2 mL) was sampled into a 1 mL heparinized

syringe; after the aspiration of 2 mL dead space, which was re-

injected). Arterial blood samples were gently agitated, air bubbles

thoroughly expunged, and immediately stored on ice. Arterial blood

gas analysis was performed within 1 h (Cobas B221Omni-S, Roche

Diagnostics, Indianapolis, IN, USA).

2.3. Statistics

Data are presented as actual numbers and either absolute

change from baseline or percentage change from baseline where

appropriate. In the observational study, paired t-tests were used

to test differences between (a) baseline vs normoxic hypercapnia

and (b) normoxic hypercapnia vs hyperoxic hypercapnia; effects

are presented as mean difference (95% CI; p value). In the interven-

Fig. 1. The effect of normoxic hypercapnia and hyperoxic hypercapnia on spon-

tional study, repeated assessments of within-group effect measures

taneous respiratory rate: observational study in CB6F1 mice anesthetized with

as a function of dose of inhaled CO were assessed by repeated mea-

pentobarbital (n = 99). Four minutes each at baseline, 5%CO2 & 21% O2 and 5%CO2 & 2

95% O2. Error bars represent standard deviation. sures analysis of variance (RM-ANOVA) using simple contrast to Download English Version: https://daneshyari.com/en/article/2846808

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