Johnson, Blair D.

Due to the relationship between stroke volume (SV) and pulse pressure (PP) during lower body negative pressure (LBNP), we hypothesized that PP reflects SV during hemorrhage (HEM). After a 5‐minute baseline, 6 men were exposed to LBNP at ‐15, ‐30, and ‐45 mmHg for 5 minutes at each pressure. After 45 minutes of recovery, three progressive 333‐ml stages of HEM (1 L total) were performed. SV was assessed using a CC Nexfin and PP was calculated using an arterial catheter. SV (111 ± 2.1 vs. 77 ± 6.7 mL; p = 0.04) and PP (58±2.7 vs. 41 ± 4.3 mm Hg; p = 0.03) decreased from baseline to ‐45 mmHg LBNP. SV (118 ± 4.4 to 99 ± 6.8 mL; p = 0.06) and PP decreased (58 ± 2.9 to 48 ± 4.9 mmHg; p = 0.06) from baseline to ‐1 L of HEM. PP correlated with SV during HEM (amalgamated r 2 = 0.98) and LBNP (amalgamated r 2 = 0.99). There was limited inter‐subject variability in PP vs. SV during LBNP ( r 2 range 0.57 to 0.99, 5/6 had an r 2 >; 0.90), but substantial inter‐subject variability during HEM ( r 2 range 0.21 to 0.99, 2/6 had an r 2 >; 0.90). Reductions in PP induced by LBNP or HEM are strongly correlated with SV. However large inter‐individual differences in this correlation during HEM, which may indicate a significantly variable compensatory response in human arterial distensibility, may limit the use of PP as a surrogate for SV during clinical blood loss. Funded by U.S. Army MRMC Combat Casualty Care Research Program Grant # W81XWH‐11–1‐0823.

Background Lower body negative pressure (LBNP) increases carotid body chemosensitivity. Whether the increase in chemosensitivity is functionally significant in the hemodynamic response to LBNP was previously unknown. We tested the hypothesis that desensitization of the carotid body chemoreceptors would improve the hemodynamic response to LBNP. Methods Ten healthy, non‐obese male subjects (35 ± 3 years, BMI: 25 ± 1 kg/m 2 ) completed 2 study visits (Saline, Dopamine), separated by a minimum of 4 weeks. Intravenous dopamine was infused at an individualized dose (1–2 mg/kg/min) shown to maximally blunt the hypoxic ventilatory response (a measure of carotid body chemosensitivity). Arterial blood pressure (brachial catheter) and heart rate (ECG) were continuously recorded. On each study day subjects underwent step‐wise exposures of LBNP (−15, −30, and −45 mmHg) to simulate hemorrhage. Cumulative stress index (CSI) was calculated by summating the product of negative pressure (mmHg) by the time (min) during each LBNP level (−15, −30, and −45 mmHg). Results Dopamine tended to reduce CSI (Saline: 503 ± 52; Dopamine: 408 ± 45 mmHg*min; p=0.07). Changes in heart rate from baseline during graded LBNP were not statistically distinguishable between Saline and Dopamine conditions (− 15 mmHg: +4 ± 1 vs +3 ± 2 BPM, p=0.99; − 30 mmHg: +12 ± 1 vs +12 ± 3 BPM, p=0.99; − 45 mmHg: HR +21 ± 2 vs +19 ± 5 BPM, p=0.99). Similarly, change in systolic blood pressure from baseline during graded LBNP was not different between Saline and Dopamine conditions (− 15 mmHg: +1 ± 1 vs −1 ± 2 mmHg p=0.99; − 30 mmHg: −7 ± 3 vs −6 ± 4 mmHg, p=0.99; − 45 mmHg: −12 ± 4 vs −22 ± 6 mmHg, p=0.19). However, change in diastolic blood pressure from baseline during graded LBNP was higher at −45 mmHg between Saline and Dopamine conditions (− 15 mmHg: +2 ± 1 vs −0 ± 1 mmHg p=0.47; − 30 mmHg: −1 ± 2 vs −2 ± 2 mmHg p=0.26; − 45 mmHg: −2 ± 2 vs −12 ±3 mmHg, p=0.0004). Conclusions Desensitization of the carotid body chemoreceptors reduced diastolic blood pressure responses to LBNP at −45 mmHg only, with minimal effect at lower levels. These data suggest chemoreflex activity during LBNP may be functionally significant in the blood pressure responses only during higher levels of simulated hemorrhage. Support or Funding Information Funding: W81XWH‐13‐2‐0038 (DOD)

Hypovolemia‐induced sympathoexcitation might initiate an immune response through an increase in circulating epinephrine and splenic demargination. We tested the hypothesis that lower body negative pressure (LBNP) and blood loss (BL) result in comparable increases in white blood cell counts (WBCs). We determined WBCs and epinephrine levels in 12 men who performed a LBNP and BL protocol in a randomized order. LBNP consisted of 5‐minute stages at 0, ‐15, ‐30, and ‐45 mmHg of suction. BL included 5 minutes at baseline and following three stages of 333 mL of blood removal (up to 1000 mL total). Blood draws were performed at baseline and after the last stage of each protocol. LBNP to −45mmHg was a greater central hypovolemic stimulus vs. BL, therefore WBCs and epinephrine concentrations were plotted against central venous pressure (CVP) to obtain stimulus‐response relationships using the linear regression line slopes for both protocols. Paired tests were used to determine if the slopes of these regression lines fell on similar trajectories for each protocol. Mean regression line slopes fell on similar trajectories for total WBC (LBNP 183±46 vs. BL 155±109 mcL −1 *mmHg −1 , p=0.15), neutrophils (LBNP 110±29 vs. BL 96±72 mcL −1 *mmHg −1 , p=0.15) and lymphocytes (LBNP 65±21 vs. BL 59±38 mcL −1 *mmHg −1 , p=0.90). Mean regression line slopes for epinephrine were similar as well (LBNP 15±5 vs. BL 16±4 pg *mL −1 *mmHg −1 , p=0.84). Our results indicate that LBNP models the stimulus‐response relationship between CVP and WBCs observed during BL. Central hypovolemia, induced by LBNP or BL, elicits a relative leukocytosis with a predominantly neutrophil‐based response. Support or Funding Information US Army MRMC Combat Casualty Care Research Program Grant # W81XWH‐11‐1‐0823

We examined the role of sympathetic activation in restraining vasodilatory responses to hyperinsulinemia and sustaining blood pressure in healthy adults. Data are reported from two separate experimental protocols in humans and one experimental protocol in isolated arteries from mice. Contrary to our hypothesis, the present findings support the idea that during hyperinsulinemia, a sympathetically mediated increase in cardiac output, rather than restraint of peripheral vasodilation, is the principal contributor to the maintenance of systemic blood pressure.

Background Maintaining baroreflex sensitivity is integral to ensuring blood pressure maintenance and end‐organ perfusion during hemorrhage. This is especially true under conditions of hypoxemia, where decreased tolerance to central hypovolemia is commonly observed. Hypoxia activates peripheral chemoreceptors and reduces baroreceptor‐vascular resistance reflex sensitivity. However, a direct role for the peripheral chemoreceptors in the hemodynamic response to hemorrhage in hypoxia remains unclear. Objective We tested the hypothesis that attenuation of peripheral chemoreceptor activity (low‐dose dopamine; 1–2 μg/kg/min) during acute hypoxia would promote maintenance of mean arterial pressure, pulse pressure, and other hemodynamic markers [heart rate (HR), stroke volume (SV), cardiac output (CO), total peripheral resistance (TPR)] during simulated hemorrhage. Methods Ten healthy men (35±3 years, BMI 25±1 kg/m 2 ) participated in a randomized, double‐blind, placebo controlled study. Participants completed two experimental visits (saline and low‐dose dopamine) at which lower body negative pressure (LBNP) was conducted during hypoxia (SpO 2 ~85%; PaO2 ~52 mmHg) delivered via a non‐rebreather mask. Ventilation [V̇ (turbine transducer)], arterial blood pressure (brachial artery catheter), HR (ECG), and central venous pressure (peripherally inserted central catheter) were measured continuously and SV, CO, and TPR were calculated. Following a 5‐min rest, participants underwent LBNP for 5‐min at 3 intervals (−15, −30, and −45 mmHg). Outcome values were analyzed and compared using a mixed linear model (SAS PROC MIXED) with a direct product AR(1) covariance structure using indicator variables for saline vs. dopamine. Data from the mixed linear model are reported as an estimated change per 15 mmHg of LBNP. Results Dopamine had no effect on hypoxia P a O 2 , P a CO 2 , V̇ or respiratory rate (all P >0.05) and this relationship persisted throughout all LBNP stages. The mixed linear model showed no effect of dopamine vs. saline on changes in: central venous pressure (−1.1±0.4 vs −1.3±0.3 mmHg, P =0.15), mean arterial pressure (−4.7±2.3 vs −5.3±1.4 mmHg, P =0.25), pulse pressure (−6.7±1.5 vs −8.3±1.4 mmHg, P =0.50), HR (7.8±1.5 vs 6.1±1.5 bpm, P =0.41), SV (−10.9±1.9 vs −11.6±3.3 mL, P =0.41), CO (−0.3±0.2 vs −0.4±0.4 L · min −1 , P =0.31) or TPR (0.2±0.4 vs 0.7±0.6 mmHg · L · min −1 P =0.27). Discussion Intravenous infusion of low‐dose dopamine designed to attenuate peripheral chemoreflex activity during acute hypoxia did not alter the integrated hemodynamic response to simulated hemorrhage. Our data suggests that peripheral chemoreceptors have a limited role during hypoxic central hypovolemia. More research is needed to understand the sensitivity and cross‐talk between chemoreceptors and baroreceptors during hemorrhage. Support or Funding Information Funding: W81XWH‐13‐2‐0038 (DOD), DK90541 (NIH), UL1 TR000135 (NIH).

We examined the contribution of the carotid chemoreceptors to insulin-mediated increases in muscle sympathetic nerve activity (MSNA) in healthy humans. We hypothesized that reductions in carotid chemoreceptor activity would attenuate the sympathoexcitatory response to hyperinsulinemia. Young, healthy adults (9 male/9 female, 28 ± 1 yr, 24 ± 1 kg/m2) completed a 30-min euglycemic baseline followed by a 90-min hyperinsulinemic (1 mU·kg fat-free mass−1·min−1), euglycemic infusion. MSNA (microneurography of the peroneal nerve) was continuously measured. The role of the carotid chemoreceptors was assessed at baseline and during hyperinsulinemia via 1) acute hyperoxia, 2) low-dose dopamine (1–4 µg·kg−1·min−1), and 3) acute hyperoxia + low-dose dopamine. MSNA burst frequency increased from baseline during hyperinsulinemia ( P < 0.01). Acute hyperoxia had no effect on MSNA burst frequency at rest ( P = 0.74) or during hyperinsulinemia ( P = 0.83). The insulin-mediated increase in MSNA burst frequency ( P = 0.02) was unaffected by low-dose dopamine ( P = 0.60). When combined with low-dose dopamine, acute hyperoxia had no effect on MSNA burst frequency at rest ( P = 0.17) or during hyperinsulinemia ( P = 0.85). Carotid chemoreceptor desensitization in young, healthy men and women does not attenuate the sympathoexcitatory response to hyperinsulinemia. Our data suggest that the carotid chemoreceptors do not contribute to acute insulin-mediated increases in MSNA in young, healthy adults.

Abstract The carotid bodies (CBs) are multi‐modal sensory organs located bilaterally at the bifurcation of the carotid artery and innervated by the carotid sinus nerve (Hering's nerve), a branch of the IX cranial nerve. While the CBs (or embryologically analogous structures) are well known as the dominant oxygen‐sensing organ in vertebrates, in mammals there is evidence that the CBs may also sense glucose and temperature, and respond to circulating hormones and other factors. Additionally, the CBs likely participate in regulating baseline levels of sympathetic tone. In this brief review, we focus on the evolution of our efforts to understand ‘what else’ beyond oxygen sensing the CBs do in humans. image

The carotid body chemoreceptors are activated during hypoglycemia and contribute to glucoregulation during prolonged exercise in dogs. Low-dose intravenous infusions of dopamine have been shown to blunt the activation of the carotid body chemoreceptors during hypoxia. Therefore, we tested the hypotheses that dopamine would blunt glucoregulatory responses and attenuate plasma glucose during prolonged aerobic exercise in healthy participants. Twelve healthy participants completed two randomized exercise sessions at 65% peak oxygen consumption for up to 120 min. Saline was infused during one exercise session, and dopamine (2 μg·kg−1·min−1) was infused during the other session. Arterial plasma glucose, growth hormone, glucagon, cortisol, norepinephrine, and epinephrine were measured every 10 min. Exercise duration during dopamine infusion was 107 ± 6 and 119 ± 0.8 min during saline infusion. Glucose area under the curve during exercise was lower during dopamine (9,821 ± 686 vs. 11,194 ± 395 arbitrary units; P = 0.016). The ratio of circulating growth hormone to glucose and the ratio of glucagon to glucose were greater during dopamine ( P = 0.045 and 0.037, respectively). These results indicate that the infusion of dopamine during aerobic exercise impairs glucoregulation. This suggests that the carotid body chemoreceptors contribute to glucoregulation during prolonged exercise in healthy exercise-trained humans.

New Findings What is the central question of this study? Is lower body negative pressure a useful surrogate to study white blood cell responses to haemorrhage in humans? What is the main finding and its importance? We found that lower body negative pressure appears to be a useful surrogate to study the early white blood cell mobilization response during blood loss. Hypovolaemia has been associated with an immune response that might be secondary to sympathoexcitation. We tested the hypothesis that simulated hypovolaemia using lower body negative pressure (LBNP) and real hypovolaemia induced via experimental blood loss (BL) cause similar increases in the white blood cell concentration ([WBC]). We measured [WBC] and catecholamine concentrations in 12 men who underwent an LBNP and a BL protocol in a randomized order. We compared 45 mmHg of LBNP with 1000 ml of BL; therefore, [WBC] and catecholamine concentrations were plotted against central venous pressure to obtain stimulus–response relationships using the linear regression line slopes for both protocols. Mean regression line slopes were similar for total [WBC] (LBNP 183 ± 4 μl−1 mmHg−1 versus BL 155 ± 109 μl−1 mmHg−1, P = 0.15), neutrophils (LBNP 110 ± 2 μl−1 mmHg−1 versus BL 96 ± 72 μl−1 mmHg−1, P = 0.15) and lymphocytes (LBNP 65 ± 21 μl−1 mmHg−1 versus BL 59 ± 38 μl−1 mmHg−1, P = 0.90). Mean regression line slopes for adrenaline were similar (LBNP 15 ± 5 pg ml−1 mmHg−1 versus BL 16 ± 4 pg ml−1 mmHg−1, P = 0.84) and were steeper during LBNP for noradrenaline (LBNP 28 ± 6 pg ml−1 mmHg−1 versus BL 9 ± 6 pg ml−1 mmHg−1, P = 0.01). These data indicate that central hypovolaemia elicits a relative leucocytosis with a predominantly neutrophil‐based response. Additionally, our results indicate that LBNP models the stimulus–response relationship between central venous pressure and [WBC] observed during BL.