Autonomic activation links CNS oxygen toxicity to acute cardiogenic pulmonary injury

Abstract

Breathing hyperbaric oxygen (HBO₂), particularly at pressures above 3 atmospheres absolute, can cause acute pulmonary injury that is more severe if signs of central nervous system toxicity occur. This is consistent with the activation of an autonomic link between the brain and the lung, leading to acute pulmonary oxygen toxicity. This pulmonary damage is characterized by leakage of fluid, protein, and red blood cells into the alveoli, compatible with hydrostatic injury due to pulmonary hypertension, left atrial hypertension, or both. Until now, however, central hemodynamic parameters and autonomic activity have not been studied concurrently in HBO₂, so any hypothetical connections between the two have remained untested. Therefore, we performed experiments using rats in which cerebral blood flow, electroencephalographic activity, cardiopulmonary hemodynamics, and autonomic traffic were measured in HBO₂ at 5 and 6 atmospheres absolute. In some animals, autonomic pathways were disrupted pharmacologically or surgically. Our findings indicate that pulmonary damage in HBO₂ is caused by an abrupt and significant increase in pulmonary vascular pressure, sufficient to produce barotrauma in capillaries. Specifically, extreme HBO₂ exposures produce massive sympathetic outflow from the central nervous system that depresses left ventricular function, resulting in acute left atrial and pulmonary hypertension. We attribute these effects on the heart and on the pulmonary vasculature to HBO₂-mediated central sympathetic excitation and catecholamine release that disturbs the normal equilibrium between excitatory and inhibitory activity in the autonomic nervous system.

Fig. 1.

Central nervous system (CNS) O₂ toxicity and lung injury in intact and chronically vagotomized (Vt) awake rats in 5-atmospheres absolute (ATA) O₂. A: Kaplan-Meier plot of time to onset of motor convulsions in 12 intact and 12 Vt rats during 60-min exposure to 5 ATA O₂, beginning at time 0. Nine rats in each group exhibited convulsions. B: bronchoalveolar lavage fluid (BALF) total protein in intact (●) and Vt (○) rats was plotted against seizure latency. C: seizure latency in intact and Vt rats. D: BALF total protein in intact and Vt rats. Values are means ± SE. *P < 0.05 vs. 5 ATA.

Fig. 2.

Sympathetic activity in awake rats in 5 ATA O₂. A: heart rate (HR) in awake rats exhibiting seizures in hyperbaric oxygen (HBO₂). HR was measured before HBO₂ (control) and after the onset of electroencephalogram (EEG) spikes. B: plasma norepinephrine (NE) levels in rats exhibiting EEG spikes. Arterial blood samples from chronically catheterized rats were obtained immediately after 60-min HBO₂ exposures. Values are means ± SE. *P < 0.05 vs. air.

Fig. 3.

Central hemodynamic parameters in anesthetized rats in 6 ATA O₂. Changes in mean arterial (A) and venous blood pressures (B), cardiac output (CO; C), and HR (D) in individual rats were plotted for the control period in air at 1 ATA, followed by 6 ATA O₂ for 60 min. Compression to 6 ATA was achieved at time 0. Dashed lines are mean values. Arrows indicates the mean time for onset of EEG spikes.

Fig. 4.

Cardiopulmonary hemodynamic responses in anesthetized rats in 6 ATA O₂. A: right ventricular systolic pressure (RVSP). B: left ventricular end-diastolic pressure (LVEDP). C: calculated pulmonary blood volume (PBV). D: calculated pulmonary vascular resistance (PVR). RVSP and LVEDP are expressed as absolute values; PBV and PVR are shown as percentages of preexposure levels (in air at 1 ATA). Compression to 6 ATA was achieved at time 0. Values are means ± SE. *P < 0.05 vs. air.

Fig. 5.

Ventricular pressures and left ventricular function in anesthetized rats in 6 ATA O₂. Mean values of cardiac parameters are shown for 8 anesthetized animals that demonstrated EEG spikes during 60-min exposure. A: RVSP and LVEDP are shown for 10 min before and after the onset of EEG spikes (time 0). B: stroke work (stroke volume × mean arterial pressure), an index of left ventricular function, was calculated every 10 min. Left ventricular function (stroke work) diminished significantly in these rats, which exhibited EEG spikes. Values are means ± SE. *P < 0.05 vs. air.

Fig. 6.

BALF total protein and ventricular pressures in anesthetized rats in 6 ATA O₂. A: BALF total protein is shown for controls, as well as for rats exhibiting generalized EEG spikes (S) and those not exhibiting spikes (NS). Values are means ± SE. *P < 0.05 vs. air. #P < 0.05 vs. NS. B: peak values of LVEDP (●) or the RVSP (○) were plotted against BALF protein for individual rats.

Fig. 7.

Hemodynamic responses of anesthetized rats in 6 ATA HBO₂ after pretreatment with propranolol. Changes in mean arterial blood pressure (MABP; A), LVEDP (LVEDP; B), CO (C), and RVSP (RVSP; D) are shown as percentages of control values in air at 1 ATA. Compression to 6 ATA was achieved at time 0. *P < 0.05 vs. untreated rats exposed to 6 ATA O₂.

Fig. 8.

CNS-mediated sympathetic excitation and lung injury in anesthetized, intact, unilaterally Vt, and bilaterally Vt rats in 6 ATA O₂. Time courses are shown for changes in MABP (A) and mean HR (B) in bilaterally Vt rats (●), left-Vt rats (▴), and intact rats (■). C: seizure latencies in acutely left-Vt rats were not significantly different from those in intact rats, but bilaterally Vt rats had significantly shortened seizure latencies. D: lung damage, as indicated by BALF total protein, was significantly greater in bilaterally Vt rats than in intact animals. *P < 0.05 vs. intact rats.