Johnson, Blair

Background In models of congestive heart failure, carotid body denervation decreases ventilatory oscillations, thereby increasing ventilatory stability. Low‐dose dopamine can acutely blunt carotid body chemosensitivity assessed by a reduction of the hypoxic ventilatory response (HVR), but whether it affects ventilatory stability was previously unknown. We hypothesized ventilatory oscillations [as assessed by coefficient of variation of tidal volume (%CV V t ) and breathing frequency (%CV F b )] would be reduced when the carotid chemoreceptors were desensitized by low‐dose dopamine. Methods Healthy adults (n=20, 6F/14M, 31±2 years) rested quietly for 5‐min and breath‐by‐breath ventilation was measured during normoxia under 2 IV infusion conditions: 1) saline, 2) an individualized dose of dopamine (1‐4 ug/kg/min) shown to result in a nadir HVR. Results Dopamine infusion increased breathing frequency (13±1 to 14±1 breaths/min, p=0.03) with no change in mean tidal volume (740±65 to 700±68 mL, p=0.18). Infusion of dopamine in young healthy adults increased ventilatory oscillations (%CV V t : saline = 21±2, dopamine = 30±4, p=0.01; %CV F b : saline = 17±1, dopamine = 21±2, p=0.07). There was no relationship between the decrease in HVR and the increase in ventilatory oscillations (V t : r=0.15, p=0.54; F b : r=0.33, p=0.16). Conclusion Contrary to our hypothesis, IV dopamine (at an individualized dose that attenuates HVR) significantly increases ventilatory oscillations in healthy subjects. These data suggest the effect of low‐dose dopamine on ventilatory oscillations in healthy adults is in contrast to that seen with carotid body denervation in disease. Funding : NIH DK090541

We tested the hypothesis that ventilation (VE) and the hypoxic ventilatory response (HVR) during hyperthermia would be attenuated when carotid body chemosensitivity is blunted by an IV infusion of dopamine (2 µg/kg/min) vs. IV saline. We studied 9 subjects (1 woman, 32 ± 2 years, 25.7 ± 0.7 kg/m2) over two randomized dopamine and saline study visits. We measured VE and HVR (3 minutes at: room air, 16% O2, and 10% O2) at baseline and during normothermia (NORMInf) and hyperthermia (HYPInf) (core temperature 1.2‐1.5°C above baseline) infusion conditions. VE increased during HYPInf vs. NORMInf during dopamine (8.2 ± 0.3 vs. 10.2 ± 1.1 L/min; P = 0.04) and saline (8.9 ± 0.3 vs. 9.7 ± 0.5 L/min; P = 0.04) with no difference between conditions (P = 0.95). HVR during saline increased from baseline (0.30 ± 0.1 L/min/%SaO2; P < 0.01) and NORMInf (0.42 ± 0.1 L/min/%SaO2; P = 0.02) to HYPInf (0.77 ± 0.2 L/min/%SaO2). HVR did not change throughout the dopmaine visit (baseline = 0.38 ± 0.1; NORMInf = 0.27 ± 0.1; HYPInf 0.42 ± 0.1 L/min/%SaO2; P > 0.46). Dopamine HVR was lower than saline during HYPInf (P < 0.01). These data indicate that carotid body chemosensitivity to hypoxia is augmented during hyperthermia and that low dose dopamine was unable to lower normoxic VE during hyperthermia. Grant Funding Source : Supported by NIH R01DK090541 and RO1HL61388

We tested the hypothesis that erythrocyte count (RBC), hemoglobin (Hgb), and hematocrit (Hct) would be similar during lower body negative pressure (LBNP) and graded blood loss (BL) in humans. Arterial blood pressure, central venous pressure and heart rate were measured in 12 healthy males (88 ± 3 kg) during LBNP and BL. The LBNP protocol consisted of 5 min stages at 0,‐15, ‐30, and ‐45 mmHg. The BL protocol consisted of removal of three 333 mL aliquots of blood (1 L total) which was stored for reinfusion. RBC, Hgb, and Hct were obtained via arterial catheter at baseline and at the end of the final stage for both LBNP and BL. There were no differences (P > 0.05) in baseline values between treatment groups for RBC, Hgb, or Hct. RBC (4.81 ± 0.10 to 4.97 ± 0.10 10 12 /L), Hgb (14.18 ± 0.39 to 14.68 ± 0.36 g/dL), and Hct (40.88 ± 0.82 to 42.36 ± 0.83 %) increased from baseline to final stage (p<0.001 for all) during LBNP, while all values decreased from baseline to final stage (p<0.015 for all) during BL (4.82 ± 0.11 to 4.72 ± 0.11 10 12 /L; 14.33 ± 0.37 to 13.95 ± 0.39 g/dL; 41.09 ± 0.82 to 40.25 ± 0.86 %; respectively). The final stage values were greater in LBNP than BL for RBC, Hgb, and Hct (p< 0.001 for all). LBNP results in relative hemoconcentration while BL results in relative hemodilution. The clinical significance of these findings remains to be elucidated. Grant Funding Source : Supported by U.S. Army MRMC Combat Casualty Care Research Program Grant # W81XWH‐11‐1‐0823.

We tested the hypothesis that the catecholamine response would be similar during lower body negative pressure (LBNP) vs. blood loss (BL). Twelve men underwent randomized LBNP and BL protocols on the same day. LBNP consisted of 5‐minute stages at 0, ‐15, ‐30, and ‐45 mmHg of pressure. The BL protocol included 5 minutes at baseline and then after three stages of 333 ml of whole blood draws (1000 ml total) which were stored for reinfusion. Central venous pressure (CVP) was recorded during each protocol. Blood samples were collected at baseline and at the end of the last stage of each protocol. CVP was greater in LBNP vs. BL at baseline (7.3 ± 0.6 vs. 6.1 ± 0.6 mmHg; P < 0.01) and was lower during LBNP vs. BL (‐0.2 ± 0.6 vs. 1.8 ± 0.8 mmHg; P < 0.01). The increase in epinephrine (EPI) during LBNP (53 ± 7 vs.144 ± 30 pg/ml) and BL (49 ± 7 vs. 103 ± 19 pg/ml; P < 0.01) was similar (P = 0.16). An increase in norepinephrine (NE) during LBNP (148 ± 20 vs. 354 ± 44 pg/ml; P < 0.01) was greater (P < 0.01) than the trend to increase during BL (155 ± 22 vs. 211 ± 29 pg/ml; P = 0.09). Individual slopes of catecholamines vs. CVP were calculated to determine if the responses had similar trajectories between the two protocols. The EPI vs. CVP slope was steeper in LBNP vs. BL (‐13.5 ± 4.6 vs. ‐0.6 ± 0.1 pg/ml/mmHg; P < 0.01). The NE vs. CVP slope was steeper in LBNP vs. BL (‐27.8 ± 5.6 vs. ‐8.7 ± 5.9 pg/ml/mmHg; P = 0.01). LBNP to ‐45 mmHg appears to be a greater sympathetic stressor than 1000 ml of BL. Grant Funding Source : Supported by US Army MRMC Combat Casualty Care Research Program Grant # W81XWH‐11‐1‐0823

We tested the hypothesis that the carotid body chemoreceptors (CB) contribute to ventilatory control during steady‐state exercise. Six men completed two randomized bouts of cycling exercise at 65% VO 2 max for up to 2 hours during an IV infusion of dopamine (D; 2 µg/kg/min) to acutely inactivate the CB, or a saline infusion (S). Expired gases were analyzed at baseline, resting‐infusion, and during exercise (25%, 50%, 75% and 100% of total exercise time). A hypoxic ventilatory response (HVR) test was performed after exercise during the infusion condition. Subjects were classified as responders (RS; n=3) if their HVR was lower during D vs. S (1.03 ± 0.6 vs. 2.14 ± 0.4 L/min/%SaO 2 ). In RS, partial pressure of end‐tidal CO 2 had a greater delta from baseline at 75% (2.9 ± 2.1 vs. 1.1 ± 1.9 mmHg) and 100% (0.9 ± 3.4 vs. ‐0.3 ±3.3 mmHg) during D than S, and the increase in oxygen uptake at 100% was greater during D vs. S (34.7 ± 2.6 vs. 33.0 ± 2.6 mL/min/kg). In RS, there were no differences in the changes from baseline for ventilation (VE), VE/VCO 2 , respiratory rate, tidal volume, and respiratory exchange ratio between conditions. In the non‐responders group, there were no differences between D and S in any variables. When the data was pooled, HVR accounted for 37% of the variance in VE at 100%. Despite evidence that CB chemosensitivity was blunted, the CB appear to play a minor role in controlling ventilation during steady state exercise. Grant Funding Source : NIH R01DK090541

We tested the hypothesis that administering low‐dose dopamine (2 mcg/kg/min) to desensitize the carotid body chemoreceptors would alter metrics of heart rate variability (HRV). Electrocardiogram (ECG) recordings were obtained from 18 healthy adults (age = 31 ± 2 years; BMI = 24.6 ± 0.6 kg/m 2 ) during two randomized study days where they received an IV infusion of saline (S) or dopamine (DA). HRV was analyzed during five minute segments at baseline and during infusions of S and DA. Time‐domain analysis of the root mean square of the successive differences (RMSSD) along with spectral domain analysis of low (LF) and high frequency (HF) were obtained. There were no differences (P > 0.05) in respiration rate or blood pressure at any time point. Heart rate increased from baseline during DA (60 ± 2 vs. 63 ± 2 bpm; P < 0.01) and during infusion it was greater in DA vs. S (63 ± 2 vs. 58 ± 2 bpm; P < 0.01). RMSSD decreased from baseline to infusion during DA (68.2 ± 7.6 vs. 51.6 ± 6.0 ms; P < 0.01) and during infusion it was lower in DA vs. S (78.3 ± 10.3 vs. 51.6 ± 6.0 ms; P < 0.01). HF was reduced during DA vs. baseline (1733± 301 vs. 870 ± 171 ms 2 ; P < 0.01), and during infusion DA was also lower than S (1936 ± 471 vs. 870 ± 171 ms 2 ; P = 0.02). There were no changes (P > 0.05) in LF, LF/HF or normalized HF and LF values. These data indicate that during resting conditions the carotid body chemoreceptors likely modulate parasympathetic components of HRV in healthy adults. Grant Funding Source : Supported by NIH R01DK090541 and RO1HL61388