TY - JOUR
T1 - Low-dose morphine reduces tolerance to central hypovolemia in healthy adults without affecting muscle sympathetic outflow
AU - Watso, Joseph C
AU - Belval, Luke N
AU - Cimino, Frank A
AU - Orth, Bonnie D
AU - Hendrix, Joseph M
AU - Huang, Mu
AU - Johnson, Elias
AU - Foster, Josh
AU - Hinojosa-Laborde, Carmen
AU - Crandall, Craig G
PY - 2022/7/1
Y1 - 2022/7/1
N2 - Hemorrhage is a leading cause of preventable battlefield and civilian trauma deaths. Low-dose (i.e., an analgesic dose) morphine is recommended for use in the prehospital (i.e., field) setting. Morphine administration reduces hemorrhagic tolerance in rodents. However, it is unknown whether morphine impairs autonomic cardiovascular regulation and consequently reduces hemorrhagic tolerance in humans. Thus, the purpose of this study was to test the hypothesis that low-dose morphine reduces hemorrhagic tolerance in conscious humans. Thirty adults (15 women/15 men; 29 ± 6 yr; 26 ± 4 kg·m-2, means ± SD) completed this randomized, crossover, double-blinded, placebo-controlled trial. One minute after intravenous administration of morphine (5 mg) or placebo (saline), we used a presyncopal limited progressive lower-body negative pressure (LBNP) protocol to determine hemorrhagic tolerance. Hemorrhagic tolerance was quantified as a cumulative stress index (mmHg·min), which was compared between trials using a Wilcoxon matched-pairs signed-rank test. We also compared muscle sympathetic nerve activity (MSNA; microneurography) and beat-to-beat blood pressure (photoplethysmography) during the LBNP test using mixed-effects analyses [time (LBNP stage) × trial]. Median LBNP tolerance was lower during morphine trials (placebo: 692 [473-997] vs. morphine: 385 [251-728] mmHg·min, P < 0.001, CI: -394 to -128). Systolic blood pressure was 8 mmHg lower during moderate central hypovolemia during morphine trials (post hoc P = 0.02; time: P < 0.001, trial: P = 0.13, interaction: P = 0.006). MSNA burst frequency responses were not different between trials (time: P < 0.001, trial: P = 0.80, interaction: P = 0.51). These data demonstrate that low-dose morphine reduces hemorrhagic tolerance in conscious humans. Thus, morphine is not an ideal analgesic for a hemorrhaging individual in the prehospital setting.NEW & NOTEWORTHY In this randomized, crossover, placebo-controlled trial, we found that tolerance to simulated hemorrhage was lower after low-dose morphine administration. Such reductions in hemorrhagic tolerance were observed without differences in MSNA burst frequency responses between morphine and placebo trials. These data, the first to be obtained in conscious humans, demonstrate that low-dose morphine reduces hemorrhagic tolerance. Thus, morphine is not an ideal analgesic for a hemorrhaging individual in the prehospital setting.
AB - Hemorrhage is a leading cause of preventable battlefield and civilian trauma deaths. Low-dose (i.e., an analgesic dose) morphine is recommended for use in the prehospital (i.e., field) setting. Morphine administration reduces hemorrhagic tolerance in rodents. However, it is unknown whether morphine impairs autonomic cardiovascular regulation and consequently reduces hemorrhagic tolerance in humans. Thus, the purpose of this study was to test the hypothesis that low-dose morphine reduces hemorrhagic tolerance in conscious humans. Thirty adults (15 women/15 men; 29 ± 6 yr; 26 ± 4 kg·m-2, means ± SD) completed this randomized, crossover, double-blinded, placebo-controlled trial. One minute after intravenous administration of morphine (5 mg) or placebo (saline), we used a presyncopal limited progressive lower-body negative pressure (LBNP) protocol to determine hemorrhagic tolerance. Hemorrhagic tolerance was quantified as a cumulative stress index (mmHg·min), which was compared between trials using a Wilcoxon matched-pairs signed-rank test. We also compared muscle sympathetic nerve activity (MSNA; microneurography) and beat-to-beat blood pressure (photoplethysmography) during the LBNP test using mixed-effects analyses [time (LBNP stage) × trial]. Median LBNP tolerance was lower during morphine trials (placebo: 692 [473-997] vs. morphine: 385 [251-728] mmHg·min, P < 0.001, CI: -394 to -128). Systolic blood pressure was 8 mmHg lower during moderate central hypovolemia during morphine trials (post hoc P = 0.02; time: P < 0.001, trial: P = 0.13, interaction: P = 0.006). MSNA burst frequency responses were not different between trials (time: P < 0.001, trial: P = 0.80, interaction: P = 0.51). These data demonstrate that low-dose morphine reduces hemorrhagic tolerance in conscious humans. Thus, morphine is not an ideal analgesic for a hemorrhaging individual in the prehospital setting.NEW & NOTEWORTHY In this randomized, crossover, placebo-controlled trial, we found that tolerance to simulated hemorrhage was lower after low-dose morphine administration. Such reductions in hemorrhagic tolerance were observed without differences in MSNA burst frequency responses between morphine and placebo trials. These data, the first to be obtained in conscious humans, demonstrate that low-dose morphine reduces hemorrhagic tolerance. Thus, morphine is not an ideal analgesic for a hemorrhaging individual in the prehospital setting.
KW - Blood Pressure
KW - Female
KW - Heart Rate
KW - Hemorrhage/chemically induced
KW - Humans
KW - Hypovolemia
KW - Lower Body Negative Pressure
KW - Morphine/pharmacology
KW - Muscle, Skeletal/innervation
KW - Muscles
KW - Sympathetic Nervous System
U2 - 10.1152/ajpheart.00091.2022
DO - 10.1152/ajpheart.00091.2022
M3 - Article
C2 - 35452317
SN - 0363-6135
VL - 323
SP - H89-H99
JO - American journal of physiology. Heart and circulatory physiology
JF - American journal of physiology. Heart and circulatory physiology
IS - 1
ER -