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POINT-COUNTERPOINT
1Divisions of Pediatric Cardiology and 2Neonatalogy
Department of Pediatrics
and 3The Vanderbilt Kennedy Center
Vanderbilt University Medical Center
Nashville, Tennessee
e-mail: judy.aschner{at}vanderbilt.edu
Single ventricle physiology, as exemplified by hypoplastic left heart syndrome (HLHS), is characterized by complete intracardiac mixing of pulmonary and systemic venous return and a functional single great artery. As pulmonary vascular resistance (PVR) falls in the early postnatal period, blood flow is diverted to the lungs (Qp), often at the expense of the systemic (Qs) and coronary circulations (14). This Qp:Qs mismatch imposes three physiological perturbations: 1) excessive Qp leads to pulmonary edema and tachypnea and hence augments the global metabolic rate, 2) excessive Qp results in an added volume load to the single ventricle, with that chamber often seeing three to four times its intended volume, resulting in ventricular dysfunction and valvar regurgitation, and 3) Qs may fall, leading to diminished oxygen delivery (DO2), acidosis, necrotizing enterocolitis, renal and hepatic dysfunction, and other complications (14, 18). We contend that therapeutic hypoxia by administration of inhaled nitrogen (N2) can address some of these concerns, but is inadequate in severe cases where augmented oxygen delivery is needed most. Additionally, we assert there are therapies that are ultimately superior to hypoxia for some clinical scenarios.
In single ventricle preoperative physiology, flow to the systemic vs. pulmonary vascular beds is determined primarily by their relative resistances. Generally, systemic vascular resistance (SVR) is less amenable to independent pharmacologic manipulation than is PVR, and so PVR has become the target for balancing blood distribution in these cases. PVR has multiple determinants, both mechanical and humoral (1, 8, 11, 16). The alveolar partial pressure of oxygen (PaO2) and carbon dioxide (PCO2) are critically important mediators of ventilation-perfusion matching (23). Both hypoxia (30) and hypercarbia (10) diminish pulmonary blood flow, but in large part due to its ease of administration, therapeutic hypoxia by the addition of inhaled N2 has gained greater use. In some centers, neonates with HLHS awaiting heart transplantation have been kept on inhaled N2 for prolonged periods of time, up to a month or more, with good reported results (6, 7).
Why then should a practitioner consider alternative therapies to control pulmonary blood flow when hypoxia has been shown to be beneficial? To address that question one must explore the potential detriments of hypoxic therapy and review the literature comparing it with alternate therapies.
The Fick equation can be manipulated in the single ventricle heart (15) to estimate Qp:Qs by: Qp:Qs = (SaO2 – SvO2)/(SpvO2 – SaO2), where SaO2 is the systemic oxygen saturation, SvO2 the mixed systemic venous saturation, and SpvO2 its pulmonary venous counterpart. Barnea et al. (3) demonstrated that the practitioner can be easily misled if SpvO2 is not considered when estimating Qp:Qs from the measured SaO2 and SvO2. If a single ventricle patient were given 14% oxygen, the alveolar gas formula (24) and modifications of the Hill equation (19, 25) predict that the SpvO2 would be 94% in a neonate with 80% fetal hemoglobin in the absence of pulmonary pathology. If SaO2 were measured at 80% and SvO2 at 55%, the calculated Qp:Qs would be a tolerable 1.8:1. However, if this same patient had lung pathology (pneumonia, atelectasis, pulmonary edema, etc.) resulting in a SpvO2 of 85% and the practitioner did not account for this drop, then the actual Qp:Qs would be an astounding 5:1 using the same SaO2 and SvO2 values! As we cannot practically measure SpvO2 on a routine basis, we do not really know how we are affecting Qp:Qs as we titrate nitrogen.
There is an additional concern regarding hypoxic gas therapy. As the PaO2 falls, the patient's gas mechanics operate on the nearly vertical portion of the oxygen-hemoglobin dissociation curve, where a very small change in PaO2 results in a profound fall in SaO2. Clinical hypoxia may be difficult to recognize in the neonate, and there are concerns regarding the sensitivity of pulse oximetry equipment in the lower range of clinically relevant hypoxia, particularly with older models (2, 5, 9, 17, 20). Unrecognized excessive hypoxia could contribute to subtle or profound developmental delays.
If hypoxic gas therapy is not the panacea for this clinical situation, what other options are available? Two animal studies have compared inhaled CO2 and N2 (21, 22). Unfortunately, both studies have methodological drawbacks that limit their clinical application. Tabutt et al. (28) performed the only human comparison trial of inhaled N2 vs. CO2 and found that both strategies clearly induced the desired fall of Qp:Qs, however, hypoxic gas did not improve DO2, while CO2 therapy increased DO2 by 44%. Furthermore, there is evidence that hypercapnic acidosis is a lung protective strategy that preserves pulmonary mechanics, attenuates lung protein leakage, reduces pulmonary edema, and improves DO2 in an animal model of lung injury (12, 13). Interestingly, hypercapnic acidosis affords greater protection than metabolic acidosis, and buffering hypercapnic acidosis with NaHCO3 attenuates its protective effects in acute lung injury, suggesting that elevated CO2 per se rather than low pH confers protection (12). The protective effect of hypercapnic acidosis is not confined to the lung. Mild hypercapnia protects the perinatal brain from hypoxic-ischemic damage (29), prevents myocardial stunning in ischemia reperfusion (26), and shifts the oxygen-hemoglobin dissociation curve to the right, improving tolerance to hypoxia at the tissue level.
It is important to note the inherent limitations of CO2 therapy. Infants will invariably hyperventilate to normalize pH and pCO2 when given exogenous CO2. To achieve the desired hypercapnic acidosis, mechanical ventilation and muscle paralysis may be necessary. Additionally, over time, a compensatory metabolic alkalosis will develop. Nonetheless, the study by Tabutt et al. (28) provides a compelling rationale for the use of short-term inhaled CO2 over hypoxic therapy for patients in shock with inadequate DO2 requiring mechanical ventilation; that is, those patients needing therapy most.
We are not advocating that inhaled CO2 be used in every case of HLHS prior to operative repair. In fact, it rarely is necessary. In most, the diagnosis is made prior to a shock presentation, and a high a Qp:Qs can be tolerated for short periods of time until the Norwood operation is performed, a procedure that ultimately resolves this dilemma through the use of a restrictive shunt to the pulmonary vasculature (4). The practitioner also must be aware that a high Qp:Qs may represent a Qs that is too low rather than a Qp that is too high, and so must ensure that the ductus arteriosus is widely patent, that there is not significant valvar regurgitation, and that ventricular function is adequate. Some have proposed vasodilator therapy with the aim of diminishing SVR in an attempt to augment Qs and subsequently improve DO2 (27). Finally, we must admit to you, the reader (and unfortunately also to our antagonist, Dr. Ebenroth), that we do in fact use hypoxic gas therapy in situations where the patient is excessively tachypneic and at risk of hemodynamic decompensation awaiting surgical repair. Nonetheless, we can emphatically state that surgery, not hypoxia, is the optimal means of reducing pulmonary blood flow in the single ventricle heart. In those situations where the patient is critically ill with shock, inhaled CO2 has been shown in the best prospective comparison study to outperform hypoxia because it not only reduces pulmonary flow but also improves oxygen delivery.
ACKNOWLEDGMENTS
We express our gratitude to Dr. Angela J. Liske for editorial assistance.
REFERENCES
This article has been cited by other articles:
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  M. Yildiz Hypoxia is/is not the optimal means of reducing pulmonary blood flow in the preoperative single ventricle heart J Appl Physiol, June 1, 2008; 104(6): 1840 - 1840. [Full Text] [PDF]
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D. R. Jobes, E. S. Prakash, and R. W. Day Drawbacks in using hypercapnic acidosis in preoperative children with single ventricle physiology. J Appl Physiol, June 1, 2008; 104(6): 1841 - 1841. [Full Text] [PDF]
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