Reply to the “Letter to the Editor: Bezold–Jarisch reflex in the near-term fetus during labor: a matter of time”

REPLY: We thank Dr. Frasch (1) for his always thought-provoking comments. Dr. Frasch suggests that the Bezold–Jarisch reflex becomes activated late during a prolonged series of repeated umbilical cord occlusions (UCOs), in association with the development of hypotension. It is important to appreciate that this is not the original hypothesis, which links impaired preload/Bezold–Jarisch reflex activation with fetal heart rate (FHR) decelerations (2, 3), nor is it the hypothesis tested in our study. We stand by our conclusion that there is no impairment of ventricular preload, nor a subsequent Bezold–Jarisch reflex, during a brief labor-like UCO (4).

In principle, of course, this does not mean that the Bezold–Jarisch reflex might not be involved in other settings. Nevertheless, it is difficult to see a physiological rationale for Dr. Frasch’s alternative hypothesis. Dr. Frasch refers to hypotension, but we assume this is meant to refer to a hypotension-induced fall in venous return and ventricular filling, as arterial hypotension per se cannot plausibly activate the ventricular receptors. Neither the abstract nor manuscript cited in Dr. Frasch’s letter provides any objective evidence that the Bezold–Jarisch reflex was stimulated in his team’s studies. His suggestion that the heart rate variability measure, the root mean square of successive differences (RMSSD) of R-R intervals, can serve as a measure of Bezold–Jarisch reflex activation is unsubstantiated, and it is somewhat unlikely since there is no evidence that this reflex triggers high-frequency, beat-to-beat changes in FHR.

We believe Dr. Frasch’s alternative hypothesis is flawed for the following reasons.

First, the key efferent response of the Bezold–Jarisch reflex that would distinguish it from the peripheral chemoreflex is peripheral vasodilation due to sympathetic nervous activity withdrawal (5, 6). We have shown using chemical sympathectomy with 6-hydroxy-dopamine that sympathetic nervous system-mediated peripheral vasoconstriction is maintained throughout a prolonged series of repeated UCOs despite the onset of arterial hypotension (6, 7). In a preliminary analysis of a series of 1-min repeated UCOs that resulted in severe hypotension (<20 mmHg on the final 2 UCOs), we have found that profound decreases in femoral blood flow and vascular conductance (FBF and FVC, respectively) continue to occur during the UCOs to values well-below baseline levels, despite the presence of severe hypotension. Collectively these findings directly demonstrate that the efferent vasomotor responses during a prolonged series of UCOs resulting in hypotension are consistent with activation of the peripheral chemoreflex and inconsistent with Bezold–Jarisch reflex activation (5, 6). Although we have shown that prolonged, complete UCO does result in inhibition of sympathetic nervous activity, this occurs well before the onset of hypotension (8). This is therefore inconsistent with Bezold–Jarisch activation and most likely secondary to profound hypoxia of the brainstem and/or efferent neurons (8).

Second, Nuyt et al. (9) reported physiological responses consistent with the Bezold–Jarisch reflex during hypotension induced by infusions of nitroprusside. Critically, these experiments were confounded by the use of sedatives and paralytics. We have recorded renal sympathetic nervous activity during almost identical experiments without these confounding agents and did not replicate Nuyt’s findings nor find any evidence of Bezold–Jarisch activation (10). The collective evidence of multiple studies strongly suggests that the Bezold–Jarisch reflex is immature or inconsistent during the perinatal period (11–14). Interestingly, even Nuyt et al. (9) found it was more active in newborn (3–7 days after birth) than in fetal (131–137 days of gestation) sheep. It is also important to appreciate that nitroprusside-induced hypotension is not reflective of either labor or repeated UCOs.

Third, for the sake of the argument, if we accept that the Bezold–Jarisch reflex is, at least partially, functional in fetal life, the relevance of the findings of Nuyt et al. (9) relies on two further assumptions, which do not appear to be true:

1. There is a long-standing belief that impaired ventricular filling (not hypotension per se) actives the Bezold–Jarisch reflex, as was suggested by Thorén et al. (15). However, more recent studies strongly suggest that the Bezold–Jarisch reflex does not function in this manner (16–18). This highlights that Nuyt et al. (9) failed to exclude other potential explanations for their findings. Woods et al. (19, 20) found that the fetal bradycardic response to hypotension was attenuated by sino-aortic denervation, implicating a role for nonventricular afferents.

2. There is an implicit assumption that a precipitous drop in ventricular filling occurs during labor-like hypoxia. Complete UCOs must represent the most potent potential trigger, as UCOs cause severe systemic hypoxemia, with complete cessation of umbilical venous return. This was the hypothesis that our present study tested. In three 1-min UCOs, we did not find evidence of impaired ventricular filling, illustrating preservation of preload in fetuses, presumptively due to redirection of blood flow (4). Our preliminary data from a prolonged series of repeated UCOs in near-term fetal sheep show that inferior vena cava pressure (IVCP) remains above baseline levels at all times and progressively increases during UCOs despite the onset of severe hypotension. This increase is likely due to venous congestion, secondary to a combination of intense peripheral vasoconstriction reducing the volume of the arterial compartment and impaired combined ventricular output. This is highly consistent with the concept that ventricular filling is preserved even during fetal compromise and hypotension. No evidence, by Dr. Frasch and colleagues or others, has ever been provided to the contrary.

Fourth, alternatively, Dr. Frasch may hypothesize that acidosis is a trigger of the Bezold–Jarisch reflex. The citations provided, however, do not support this concept– Ref. 21 in Dr Frasch’s letter does not mention acidemia, and Ref. 7 in Dr Frasch’s letter refers to atrial receptors and the Bainbridge reflex. It is important to appreciate that the work by Thorén et al. (22, 23) that could be used to support this theory actually suggested that acidosis (induced via “asphyxia”) triggered the Bezold–Jarisch reflex indirectly via ventricular dilation “rather than being an effect of chemical influence consequent to the disturbed metabolism” (22). This finding, therefore, still relies on the now dubious belief that ventricular receptors are mechanoreceptive (16–18). More importantly, the pattern of acidemia during repeated UCOs tells us that acidosis simply cannot be involved. Acidemia progressively worsens during a prolonged series of UCOs (24). If severe acidemia triggered the Bezold–Jarisch reflex, we would expect a prolonged and unremitting bradycardia to occur during a prolonged series of UCOs once a threshold level of acidemia was reached. However, hypotension and bradycardia occur only during each UCO and rapidly recover between UCOs, despite persisting severe acidemia (6). Prolonged bradycardia during labor-like UCOs is seen only as a sentinel finding in a minority of fetuses (21, 24) and is highly likely to represent complete exhaustion of myocardial glycogen stores and evolving myocardial injury (6, 21) rather than an active reflex response.

In summary, there is no available evidence that the stimuli necessary to evoke the Bezold–Jarisch reflex occur during labor-like hypoxia, either in fetuses maintaining arterial pressure or those with evolving hypotension, as we have found in our preliminary studies above. Furthermore, the efferent vasomotor responses observed during a labor-like series of UCOs are inconsistent with Bezold–Jarisch reflex activation. Thus, although the present study did not examine all potential scenarios, the evidence does not support a potential role of the Bezold–Jarisch reflex in labor.

GRANTS

This work was supported by the Health Research Council of New Zealand Grant 17/601 (to L.B., A.J.G., C.A.L.).

DISCLOSURES

The funding sources had no role in the design or undertaking of the study, the interpretation of results, writing of the article nor the decision to submit this article for publication. No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

C.A.L., L.B., J.A.W., and A.J.G. conceived and designed research; C.A.L. and B.A.L. performed experiments; C.A.L., B.A.L., and A.J.G. analyzed data; C.A.L., J.A.W., and A.J.G. interpreted results of experiments; C.A.L. prepared figures; C.A.L. drafted manuscript; C.A.L., L.B., B.A.L., J.A.W., and A.J.G. edited and revised manuscript; C.A.L., L.B., B.A.L., J.A.W., and A.J.G. approved final version of manuscript.