Patients in hemorrhagic shock often require emergency airway management to provide adequate oxygenation and ventilation. Such airway management often involves preoxygenation, a rapid sequence induction, and subsequent tracheal intubation without intervening mask ventilation.1,2 Although adequate preoxygenation may raise PaO2 to >300 mm Hg in adults,3 prolonged apnea because of difficult airway management may expose patients to critical hypoxemia.4
Fluid resuscitation also is required frequently during hemorrhagic shock to restore adequate organ perfusion. Few studies, however, have examined the effect of fluid resuscitation of hemorrhagic shock on the apneic time to oxygen desaturation. In a porcine model of hemorrhagic shock, Pehböck et al.5 showed that increased cumulative blood loss shortened the time to pulse oximetry oxyhemoglobin saturation of ≤70% (SpO2 < 70%), with or without concurrent fluid resuscitation. These findings suggested that the amount of bleeding is a major factor in apneic time to desaturation and that fluid resuscitation to restore circulatory volume and/or hemodynamic stability did not affect the time to SpO2 <70%. However, Pehböck et al.5 did not compare effects before and after fluid resuscitation in each animal and did not investigate the accompanying changes in cerebral and/or peripheral tissue oxygenation. Changes in cerebral oxygenation and SpO2 are both important because circulatory blood shifts centrally during hemorrhagic shock6 and acute hemodilution causes a vasoconstrictive response, in which adequate cerebral perfusion is maintained.7–10 To clarify the effect of acute hemorrhage and/or fluid resuscitation on apneic time to desaturation, we studied the effect of repeated hemorrhage and resuscitation with hydroxyethyl starch on apneic time to desaturation in a pig model.
Our goal was to examine the effects of hypovolemia because of acute hemorrhage, subsequent fluid resuscitation, and cumulative blood loss on the apneic desaturation time and cerebral and peripheral tissue oxygenation. We examined changes in tissue oxygenation accompanied with apnea by using near-infrared spectroscopy.
This study was approved by the Institutional Ethics Committee (Committee on Animal Research, Hamamatsu University School of Medicine, Hamamatsu, Japan). Nine swine (body weight range: 24.6–26.5 kg, mean ± SD = 25.3 ± 0.6 kg) were used in the study. General anesthesia was achieved by isoflurane inhalation (5%) of oxygen at 6 L/min using a standard animal mask, and each pig was placed in a supine position. After tracheostomy with regional anesthesia, anesthesia was maintained with a 2.5% inhaled concentration of isoflurane (approximately 1.2 minimum alveolar anesthetic concentration for pigs11) and an oxygen−air mixture (oxygen/air = 1:1 L/min) via mechanical ventilation. A positive end-expiratory pressure of 5 cm H2O was applied throughout the study, except during apnea. Exhaled gases were analyzed using a Capnomac Ultima (ULT-V-31-04; Datex-Ohmeda, Helsinki, Finland). The ventilator was set to maintain end-tidal carbon dioxide levels between 35 and 45 mm Hg during the animal preparation period and throughout the study. Lead II of an electrocardiogram was monitored with 3 cutaneous electrodes. Pulse oximetry was monitored with a sensor (LNCS sensor; Masimo, Tokyo, Japan) positioned on the left shaved ear. A pulmonary artery catheter (5F, 4 lumen; Nihon Kohden, Tokyo, Japan) and a central venous catheter (16-gauge) were inserted via the right jugular vein, and a catheter (16-gauge) was placed in the right femoral artery. All catheters were placed with the use of local anesthetic. The blood temperature of the swine was maintained at 38.0 to 39.0°C with heating lamps throughout the study. After these preparation steps, near-infrared spectroscopy monitoring (NIRO-200; Hamamatsu Photonics, Hamamatsu, Japan) was applied by preparing the skin and positioning one electrode over the fronto-occipital region. The other electrode was positioned at the surface of the left femur to measure peripheral tissue oxygenation (mainly muscle tissue oxygenation). Tissue oxygenation indices (TOIs) were monitored at 1-second intervals by the use of spatially resolved spectroscopy, which is not influenced by the scalp or surface area.12
The experimental protocol is shown in Figure 1. After completion of animal preparation (baseline condition), the inspiratory oxygen−air mixture was changed to 2 L/min of 100% oxygen for 5 minutes. At 4 minutes after we changed the fraction of inspired oxygen (FIO2), 20 mg rocuronium bromide was administered to prevent spontaneous breathing. After 5 minutes of preoxygenation, apnea was induced by disconnecting the pigs from the ventilator. The time until SpO2 reached <70% was then measured (apnea experiment). After reaching this criterion, mechanical ventilation with 100% oxygen was restarted for 5 minutes, and then the inspiratory gas mixture was returned to baseline 1 L/min of oxygen and 1 L/min of air.
To begin the next stage (hypovolemia 1), 600 mL (approximately 33% of the estimated total blood volume) blood was removed at a rate of approximately 0.5 mL/s via the arterial catheter. After stabilization of hemodynamic parameters, preoxygenation was restarted and the apnea experiment was performed as previously described.
To begin the third stage (resuscitation 1), 600 mL hydroxyethyl starch (6% hydroxyethyl starch, with a mean molecular weight of 70,000 and a degree of substitution of 0.5–0.55) was infused at a rate of approximately 0.5 mL/s via the central venous catheter. After stabilization of hemodynamic parameters, 5 minutes of preoxygenation was initiated and the apnea experiment was performed again as described previously. A fourth stage (repeating the 600 mL hemorrhage, “hypovolemia 2”) and a fifth stage (repeating the 600 mL hydroxyethyl starch infusion, “resuscitation 2”) were then performed.
Heart rate (HR), mean arterial pressure, mean pulmonary arterial pressure (MPA), central venous pressure (CVP), and cerebral and peripheral TOIs were recorded, and arterial blood gases were measured before preoxygenation, after 5 minutes of preoxygenation, every 1 minute after the start of apnea before reaching SpO2 <70%, and at SpO2 <70%. Cardiac output (CO), hematocrit, lactate, and mixed venous blood gases were measured before preoxygenation. CO was determined via thermodilution (Cardiac Output Computer, MTC6210; Nihon Kohden) using 5 mL cold 5% glucose injected into the right atrium. CO measurements were performed 4 times at each time point, and the mean of the last 3 values was recorded. Arterial oxygen content, mixed venous oxygen content, oxygen delivery, and oxygen consumption before apnea were calculated. After completion of each experiment, the pigs were killed with 500 mg propofol.
Data were expressed as mean values ± SD. Statistical analysis was performed with StatView 5.0 for Windows (Abacus Concepts, Berkeley, CA). Hemodynamic, arterial blood, metabolic variables, and TOI for each time point during each apnea experiment and for each condition at the same time point were analyzed by repeated-measures 1-way analysis of variance (ANOVA). The apneic desaturation time for each condition was also analyzed by repeated-measures 1-way ANOVA. If the ANOVA was found to be significant, a Scheffe F test was performed for multiple comparisons. SpO2 and cerebral TOIs during hypovolemia 1 (or hypovolemia 2) at the time to SpO2 <70% in resuscitation 1 (or resuscitation 2) were compared with those in resuscitation 1 (or resuscitation 2) via paired t test. P values and/or 99% confidence intervals (CIs) were reported, and P values <0.01 were considered to be statistically significant. We did not perform a power analysis before the study because a reference study was not available, and several major findings of Pehböck et al.5 were inconsistent with those in our pilot study. On the basis of data for the first 5 animals, a power analysis was performed using G*Power for Windows (version 220.127.116.11; The G*Power Team, Universität Düsseldorf, Germany) to determine the correct sample size. On the basis of our calculation, 9 animals would be required to detect significant changes in the apneic desaturation time between each condition with a power of 80% and a type I error rate of 0.01, using a 2-sided t test.
All animals survived all phases of the study. Mean values for hemodynamic and metabolic variables before apnea in each stage are shown in Table 1. Both hemorrhage stages increased HR and decreased CVP and CO relative to the previous resuscitated stage, and both resuscitation (hydroxyethyl starch infusion) stages decreased HR and hematocrit and increased MPA, CVP, and CO. Overall, HR and CO after each fluid resuscitation stage were greater than their respective baseline values. PaO2 levels before apnea in both resuscitation 1 and resuscitation 2 stages also were greater than that at baseline but did not differ after 5 minutes of preoxygenation with 100% oxygen. Both fluid resuscitation stages decreased arterial oxygen content. Mixed venous oxygen content gradually decreased with progression of the experiment. Both hemorrhage stages decreased oxygen delivery.
Hemodynamic changes during apnea in each stage are shown in Figure 2. Mean arterial pressure and MPA increased during apnea in all stages. HR increased during apnea at baseline and in both resuscitation stages, and CVP decreased in both hypovolemic stages and remained low. HR in each hypovolemia stage was clearly greater, and MPA and CVP were lower than those at baseline and after resuscitation.
Changes in arterial blood gas variables during apnea in each stage are shown in Figure 3. PaO2 increased after preoxygenation. Apneic periods decreased pH, PaO2, and SaO2 and increased PaCO2. pH at the end of apnea in each hypovolemia stage was lower and PaCO2 was greater than in other stages. PaO2 at SpO2 <70% did not change among stages.
The apneic times to desaturation in each stage were 136 ± 41 (baseline), 147 ± 41 (hypovolemia 1), 131 ± 38 (resuscitation 1), 147 ± 38 (hypovolemia 2), and 134 ± 36 seconds (resuscitation 2), respectively (Fig. 4). The difference in apneic time to desaturation between each adjacent stage was significant, but the time to desaturation after both hypovolemia stages did not differ. Hemorrhagic hypovolemia prolonged the apneic desaturation time, and hydroxyethyl starch resuscitation reversed the effect. This phenomenon was observed in all animals, although the desaturation time at baseline varied widely among animals. Hemorrhagic hypovolemia had similar effects on the times to mild desaturation (SpO2 <90%): 109 ± 39 (baseline), 119 ± 41 (hypovolemia 1), 108 ± 37 (resuscitation 1), 121 ± 38 (hypovolemia 2), and 111 ± 34 seconds (resuscitation 2), respectively, with differences between each adjacent stage (mean differences with 99% CI: 10.2 [4.9 to 15.6], P = 0.0065; −11.0 [−18.4 to −3.6], P = 0.009; 12.9 [8.7 to 17.1], P = 0.0019; and −10.1 [−14.8 to −5.5], P = 0.0073, respectively).
Cerebral TOI was greater than peripheral TOI throughout the study in all animals. Both TOIs decreased with progression of apnea, and both TOIs at SpO2 <70% were clearly lower than those before apnea in each stage (Fig. 5, A–C). The decreases in cerebral and peripheral TOIs until SpO2 <70% (TOI before apnea—TOI at SpO2 <70%) in each stage are shown in Figure 5D. Each hemorrhage reduced the changes in peripheral TOI with apneic desaturation, and the second hemorrhage reduced the change in cerebral TOI. Conversely, fluid resuscitation produced a greater decrease in cerebral TOI with apneic desaturation.
We found, in a pig model, that hemorrhagic hypovolemia prolonged the time to apneic desaturation and that subsequent fluid resuscitation reversed the effect. The time to SpO2 <70% was the same in both hypovolemia stages, indicating that changes in hemoglobin concentration did not affect the apneic desaturation time. Compared with the corresponding hypovolemic stage, each fluid resuscitation event shortened the time to SpO2 <70% by 16 ± 7.5 and 13 ± 8.0 seconds (11 ± 9.1 and 10 ± 5.8 seconds for time to mild desaturation [SpO2 < 90%]). This difference, approximately 10% of the total time to desaturation, is potentially important in rapid sequence induction, where intubation must occur during the apneic phase. In our study, SpO2 had only decreased to 84% ± 6% in the first hypovolemic stage in the same elapsed time that the SpO2 had decreased to <70% in the first resuscitation stage (P < 0.0001), and the cerebral TOIs were 58% ± 3% (hypovolemia 1) and 53% ± 3% (resuscitation 1), respectively (P = 0.0036). Similarly, SpO2 was still 81% ± 7% in hypovolemia 2 after the same elapsed time that SpO2 had fallen to <70% in resuscitation 2 (P = 0.0008), and the cerebral TOIs were 55% ± 2% in hypovolemia 2 and 51% ± 5% in resuscitation 2, respectively (P = 0.0176).
Our findings suggest that in patients with acute hemorrhagic shock and hypovolemia, the apneic time to desaturation will be longer if apnea is induced before fluid resuscitation. In patients with difficult airways, this increased time may facilitate successful first-pass intubation.
The mechanism underlying the effect of hypovolemia on apneic oxygen desaturation time is unclear. In our study, the apneic period both changed hemodynamic parameters (Fig. 2) and systemic blood distribution induced by secretion of endogenous catecholamines.13 In addition, hemorrhagic shock causes circulatory blood volume to shift centrally to maintain cerebral blood flow,6 possibly causing the decreased CVP values we observed (Fig. 2). We speculate that the physiologic responses to hypovolemia and apnea decreased peripheral oxygen consumption (as seen in the reduced changes in peripheral TOI during apnea; Fig. 5D) and decreased whole-body oxygen consumption, leading to a longer apneic time to desaturation with hypovolemia. Correspondingly, we hypothesized that subsequent fluid resuscitation in our animals may have increased systemic oxygen consumption because of improvement in systemic blood flow, resulting in reversal of the prolonged time to SpO2 <70%.
Pehböck et al.5 investigated the influence of FIO2 for preoxygenation, fluid resuscitation, and severity of hemorrhagic shock on the apneic desaturation time in a porcine hemorrhagic shock model and found that FIO2 and the severity of hemorrhagic shock influenced the apneic desaturation time but that fluid resuscitation did not do so. Several findings were inconsistent with those in the current study. Animals underwent stepwise hemorrhage, with or without fluid resuscitation, and the apneic desaturation time gradually decreased with increasing hemorrhage volume in both resuscitated and nonresuscitated pigs. However, the desaturation time did not differ between groups at each bleeding step. Pehböck et al.5 did not compare the effect of fluid resuscitation before and after fluid infusion in each animal, making it difficult to identify modest differences between groups. They also found that PaO2 after 100% oxygen ventilation was greater with fluid resuscitation, whereas we found that PaO2 did not improve after fluid resuscitation. One important finding in the previous study was that the apneic desaturation time gradually shortened with progression of hypovolemia because of hemorrhage. Pehböck et al.5 anesthetized animals with propofol and piritramide, and anesthetic depth may have deepened with progressing hemorrhage because of pharmacokinetic and pharmacodynamic alterations of IV anesthetics during hemorrhagic shock.14–16 Data suggest that propofol concentrations increase during apnea because of accumulation in the central compartment and a reduction in clearance.13,17 Anesthetic-induced suppression of catecholamines in response to stress may also have played a role. In contrast, anesthetic depth was relatively stable in our animals because anesthesia was maintained with a 2.5% inhalational concentration of isoflurane throughout the study, and the pharmacokinetic and pharmacodynamic changes were minimal18 compared with those with IV anesthetics. Collectively, these results indicate that further investigations on the relationship between anesthetic methods or anesthetic depth and apneic desaturation time are required.
Several limitations of the study should be addressed. We measured the apneic desaturation time using a pulse oximeter, which may have been influenced by hemodynamic changes and/or peripheral circulation during hypovolemia and/or after fluid resuscitation. However, the pulse oximeter was positioned on the pig’s ear, which is rich in vasculature, and arterial blood is fed from a thick branch of the external carotid artery near the heart. On the basis of the consistency of PaO2 at SpO2 <70% in each condition, SpO2 measurements by pulse oximetry were likely accurate. We used the apneic desaturation time at baseline as a reference for the results in the stepwise hemorrhage and fluid resuscitation model, whereas interpretation of the data may have been more reliable if a time control group without hemorrhage and/or fluid resuscitation had been included. However, in a pilot study using 3 pigs, we continuously measured the apneic desaturation time 3 times per hour without hemorrhage and/or fluid infusion and found no significant changes (120 ± 44, 123 ± 46, and 122 ± 42 seconds, respectively; mean differences between each adjacent condition with 99% CI: 2.3 [−4.4 to 9.0], P = 0.6582 and −0.3 [−6.3 to 5.7], P = 0.9906). Thus, the apneic desaturation time is unlikely to change without hemorrhage and/or fluid infusion. We also note that the time to SpO2 <70% in our animals was only 130 to 150 seconds, despite 100% oxygen ventilation for 5 minutes, which is somewhat shorter than the expected time in adult humans.19 The oxygen consumption of pigs aged about 2 months in the current study was approximately 170 mL/min/m2 at baseline before apnea (the body surface area is 0.77 m2, calculated by body weight20), which is equivalent to the oxygen consumption of an infant. Although the size of the oxygen reservoir in the lung and/or the functional residual capacity might be small in pigs, high oxygen consumption is likely to be the main reason for the early decrease in SpO2. Therefore, our findings should not be directly extrapolated to adult human patients. In addition, modern trauma management is tolerant of moderate hypotension (permissive hypotension), and thus, a 1:1 fluid resuscitation protocol replacing blood loss with the same volume of hydroxyethyl starch may not reflect current clinical practice. The use of hydroxyethyl starch itself is also less likely in humans because of the risk of acute kidney injury.21,22 Finally, as mentioned previously, the anesthetic method and/or anesthetic depth might affect the results because of an influence on secretion of endogenous catecholamines during apnea or a direct effect of hypovolemia on minimum alveolar concentration.11
In summary, we found that hemorrhagic hypovolemia in a pig model prolonged the apneic desaturation time compared with a nonhemorrhagic baseline or the nonhypovolemic state. In emergency tracheal intubation using rapid sequence induction for patients with acute hemorrhagic shock, a hypovolemic state thus might allow more time for intubation. In patients judged difficult to intubate, caregivers should consider performing airway management before fluid resuscitation to extend the time to critical desaturation and preserve cerebral oxygenation.
Name: Tadayoshi Kurita, MD.
Contribution: This author helped design the study, collect the data, analyze the data, and write the first draft of the paper.
Attestation: Tadayoshi Kurita approved the final manuscript, attests to the integrity of the original data and the analysis reported in this manuscript, and is the archival author.
Name: Koji Morita, PhD.
Contribution: This author helped to collect the data and analyze the data.
Attestation: Koji Morita approved the final manuscript and attests to the integrity of the original data and the analysis reported in this manuscript.
Name: Shigehito Sato, MD.
Contribution: This author helped design the study.
Attestation: Shigehito Sato approved the final manuscript and attests to the integrity of the original data and the analysis reported in this manuscript.
This manuscript was handled by: Avery Tung, MD.
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© 2015 International Anesthesia Research Society
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