Neonatal Research

Noori S, Wu T-W, Seri I. pH Effects on Cardiac Function and Systemic Vascular Resistance in Preterm Infants. The Journal of pediatrics. 2013;162(5):958-63.e1. This study examined the effects of pH on ventricular outputs and calculated vascular resistance. There was little effect detectable on ‘contractility’ or outputs or SVR in the first few days, but a reduction in SVR with lower pH after the first 3 days, which is accompanied by an increase in systemic flow.
Animal models show different effects of respiratory acidosis and metabolic acidosis, probably largely because of differential effects on intracellular pH, the authors here find no effect of CO2 in the first 3 days, but increasing flow with decreased SVR as CO2 increases thereafter.

I find the study reasssuring, but I am not sure how good we are at measuring true contractility with ultrasound, the indices that are measured are highly derived, nevertheless Noori and colleagues find no effect of pH on contractility.

This may not be very surprising, they quote a review article  Orchard CH, Kentish JC. Effects of changes of pH on the contractile function of cardiac muscle. American Journal of Physiology – Cell Physiology. 1990;258(6):C967-C81. (open access) which examines the mechanisms, if you read it you will notice, on the few occasions that actual pH values are discussed, they show that the major effects of changes in intracellular acidosis are when the pH is less than 7, sometimes as low as 6.6 or even 6.0! There is not much effect in these animal models in general of pH over 7.0.

Nevertheless I think these studies can help us to feel less worried about acidosis in our babies, it is so common for small preterm babies to develop metabolic, mixed and respiratory acidosis. There is probably little effect on cardiac function, certainly my practice, with permissive hypercapnia, is not to worry about high CO2 down to a pH of 7.20, maybe even lower would be OK too.

Where are we now with permissive hypercapnia? When I was a boy… we aimed to keep PCO2 relatively normal in ventilated infants, in the 40’s (mmHg, obviously). Then there was a paper that I was struggling to find until a few minutes ago, I thought the internal RAM in my head had failed me, but I had correctly remembered some details of the study but not the fact that they called it  ‘Mechanical controlled hypoventilation in status asthmaticus.’ It was by Darioli R and Perret C. Am Rev Respir Dis 1984, 129:385-387. This was a case series from an adult ICU with enormously reduced pulmonary trauma when the CO2 was ignored. They only intubated the asthmatic patients if they couldn’t maintain oxygenation; and when they were ventilated the only goal was to maintain an adequate oxygenation, but if the CO2 was very high, they said, ‘so what’. They reported a series of 159 adults with respiratory failure due to asthma with a 100% survival rate, with little barotrauma (pneumothoraces etc). After that, the term permissive hypercapnia was invented and the approach was extended to ARDS with reductions in barotrauma in that condition also.

Case series of patients surviving after very high CO2s showed no apparent long term ill effects and a small series of children who survived after PCO2 greater than 150 showed no ill effects (they called it supercarbia, Goldstein B, Shannon D, Tedres I. Supercarbia in children: Clinical course and outcome. Crit Care Med. 1990 1990;18:166). Permissive hypercapnia became widely accepted in the adult and pediatric ICU.

It must be stated though that not increasing ventilation in order to normalize a CO2 is a reasonable approach, but it still matters how you ventilate a baby. You can damage lungs by ventilating them slowly with very high volumes and still ‘achieve’ a high CO2! Over-distension of the lungs, which usually occurs at end-inspiration, (or atelectasis at end expiration) damages the lungs.

At the same time there was some reluctance to introduce this approach in the newborn, with observational studies associating high CO2 with intracranial hemorrhage in preterm infants.

Wally Carlo has been studying permissive hypercapnia in infants, the trials that he tried to do were difficult to perform, and the separation between permissive and standard groups was not great. But he has now put all of the data together in a review article, Ryu J, Haddad G, Carlo WA. Clinical effectiveness and safety of permissive hypercapnia. Clin Perinatol. 2012;39(3):603-12. They note that there is some evidence of beneficial effects of hypercapnia in acute illness, and the clinical neonatal studies have been reassuring regarding safety. I don’t know if we will ever get the large RCT of permissive hypercapnia, it will have to be designed to use appropriate ventilation with attempts to avoid overdistension in both groups, and allow the permissive group to have higher CO2, but protocolize how the ventilation is increased in the low (normal) CO2 group in order to bring the CO2 below a certain limit. It would be tough to do. 

In the meantime not pushing ventilation to achieve arbitrary CO2 goals, as long as acidosis is not too severe, seems reasonable, and is probably safe.