Oxygen: Friend or Foe?

Shout out to Chelsea Jorgenson, nurse at UW Medical Center, for the episode idea! 

Oxygen is a drug.

The FDA regulates medical gases like oxygen as a drug, with the approved indications of hypoxia and hypoxemia. Did you know these are different?

  • Hypoxemia: reduced partial pressure of O2 in the blood (low PaO2).

  • Hypoxia: reduced tissue levels of O2 so that cellular metabolism is impaired.

    • Hypoxemia generally precedes hypoxia. 

      • You have less oxygen to deliver, so there’s less O2 in the tissues over time. 

    • Hypoxemia does not always result in hypoxia

      • For instance, those who live at high altitude can by hypoxemic, but not hypoxic. 

Like other drugs, oxygen has benefits, but also has potential harms. And for a quick review of the benefits/harms of oxygen medically, check out the Journal of Hospital Medicine’s series, “Things We Do For No Reason.”

Many studies have shown, mostly on animal models, that hyperoxygenation leads to lung injury, inflammation through free radical generation, and changes in perfusion that may actually be harmful:

    • COPD: oxygen titrated to goal >88-92% is associated with 2x fold increased mortality risk.

      • Linked likely due to worsened ventilation-perfusion matching and poorer CO2 offloading as PaO2 rises (Haldane effect). 

    • MI: 1976 RCT of O2 in suspected MI patients at 6L/min. Patients receiving for 24 hours or more had more episodes of tachycardia with no improvement in mortality, analgesic use, or infarct size. 

      • Subsequent trials have found similar outcomes, and actually have also demonstrated increased rate of MI recurrence with O2 use.

      • European Society of Cardiology has now actually recommended no O2 use unless SpO2 < 90% for MI patients! 

    • Retinopathy of prematurity: hyper oxygenation of neonates increases risk of blindness.

    • Other illness: trials in settings ranging from ICUs, strokes, TBIs, and cardiac arrest have also linked liberal O2 use (ranging from 2L NC upwards) to increased mortality and other adverse events.

      • A meta analysis demonstrated a dose-dependent toxicity: for every 1% increase of SpO2 above 94-96%, there was 25% relative increase in in hospital mortality!!! 

So when is oxygen helpful?

Importantly, these studies have mostly looked at normoxemic patients who receive supplemental oxygen. Patients who are significantly hypoxemic or hypoxic will certainly benefit from O2. 

Additionally, patients with conditions such as CO poisoning, cluster headaches, sickle cell crisis, and pneumothorax may all benefit from O2. These are actual indications for the drug.

OK, so what about pregnancy and labor?

O2 is most commonly administered in labor, in an attempt to improve fetal status. The thought being that, if we see significant decelerations that reflect fetal hypoxia, administration of supplemental oxygen through the mother/placenta will help to correct it. 

  • Pro oxygen evidence:

    • Fetal pulse oximetry studies 2 small studies using a fetal pulse-oximeter in laboring women demonstrated increased fetal oxygenation of 5% with simple face masks, and 7-15% when using non-rebreathers, in non-hypoxic fetuses. In hypoxic fetuses, the observed benefit was greater, 20% with simple face mask and 26-37% with non-rebreather. 

      • Fetal pulse oximetry did not help to improve rates of cesarean delivery for fetal indications, and thus has not caught on as a routine technology in labor management. Thus critics would argue it’s hard to interpret these studies in context of whether O2 improves neonatal outcomes, or just makes the saturation numbers better.

  • Anti-oxygen evidence:

    •  Fetal scalp pH study:a small study examining the effect of administering 50-10% oxygen during first stage of labor actually had no effect on fetal scalp pH, and trended towards a worsening base deficit with supplemental O2. Another study of primates administered O2 with acidotic fetuses by scalp pH demonstrated worsening of acidosis with O2 administration. 

      • These studies though, like the others, were small and nonrandomized. There is also criticism in the timing and application of O2 in each of these trials. 

    • Non-inferiority RCT: a 2018 RCT in JAMA used a non-inferiority approach to randomize 114 patients to supplemental O2 versus room air with category II EFM. They found no difference between groups in improving umbilical artery lactate, which was their primary marker for this trial.

      • There was also no difference in other cord gas components or rates of cesarean delivery for fetal indications. 

      • Umbilical artery lactate does have some ability to predict hypoxia-associated morbidity in neonates; however, it is not sensitive or specific for poor outcomes, a valid criticism. The trial was not powered for neonatal outcomes. 

    • A secondary analysis of this same RCT looked at umbilical venous O2 concentration and actually found lower O2 pressure in fetuses exposed to long periods of O2 than those exposed for short periods or on room air. 

The physiologic arguments for (or against) O2

Check out our fetal circulation episode for a quick review of how blood and oxygen travel in the fetus!

The maximum fetal PO2 (i.e., in the umbilical vein at the site of the placenta) cannot exceed maternal venous PO2. This is why fetal hemoglobin has to have a very high oxygen affinity, as it must extract O2 away from the venous side of maternal blood, which already is at a lower oxygen concentration. 

An oxygen dissociation curve. Fetal hemoglobin maintains relatively excellent saturations, even at usual venous O2 pressures in maternal circulation (HbA). Source: WIKIPEDIA.

  • A normal venous Po2 in adults is around 35-45 mmHg (arterial is around 100 mmHg). That would equate on a HbA dissociation curve to a saturation of around 65-75%. 

  • A normal Po2 in a venous cord gas, by comparison, is on average around 35mmHg, again representing maternal venous O2 tension. 

    • But the fetal hemoglobin affinity for O2 powers this to about an 80-90% saturation! And that is considered normal -- most O2 saturation values at the 5 minute Apgar are in the mid-80%s.

  • The question lies herein: by causing maternal hyperoxemia, will that result in fetal recovery if the fetus is hypoxic? 

    • By increasing the PaO2 in the mother with supplemental oxygen, theoretically there would be an increased oxygen gradient to diffuse downstream to the fetus. 

      • In effect, because there is more oxygen tension, the higher the maternal PvO2 and umbilical vein O2 pressure can become.

    • But as we discussed with ischemic events, sometimes oxygen may counterintuitively not improve outcomes, or mask worsening of the process! 

      • In this case, the fetus becomes hypoxic, or the “ischemic” tissue -- would the new O2 load in this case be detrimental? 

      • Or potentially, like in COPD, would the normoxemia actually mask worsening acidosis? 

      • Or finally, as demonstrated in the RCT we referenced, does the O2 even get to the fetus due to some placental transfer failure in the presence of hyperoxia?

What should the bottom line takeaway be?

That’s the other interesting thing about this -- in spite of the fact that there is little evidence supporting this practice, O2 is wildly popular as a resuscitative effort. It’s simple and quick to apply. 

Intrauterine resuscitation, defined as repositioning, oxytocin discontinuation, fluid administration, amnioinfusion, or oxygen administration in response to fetal heart rate tracing abnormalities, are all options. 

While we couldn’t identify any studies that shared the “natural history” of what’s done during a deceleration, anecdotally we know that reflexively, reaching for the facemask oftentimes will precede these other measures, despite the evidence on decelerations favoring these other options. In short, leave O2 for maternal hypoxia, or as a last-resort option for fetal resuscitation! 

Espresso: Umbilical Cord Gas Interpretation

Building somewhat on our fetal circulation episode from last week, today we’ll talk about umbilical cord gases. From an obstetrics perspective, these can be challenging to really interpret, but the simple interpretation is often worth some CREOG points if you can analyze these systematically.

Remember, the umbilical vein is carrying oxygenated blood, and the umbilical arteries are carrying deoxygenated blood. This can help you remember the normal values, as they’ll be opposite those for an ABG versus VBG on an adult. Additionally, the umbilical vein is originating at the site of the placental interface with the mother -- so venous pHs will give a sense of maternal acid-base status, or the acid-base status at this interface. For this reason, the arterial pH is more helpful to truly measure fetal acid-base status.

The components of the blood gas are:

  • pH: represents the inverse log of the concentration of hydrogen ions in the circulating blood, or how acidic the blood is. In essence, more acid represents a lower pH, which represents more compromise. 

    • Normal value for a venous pH is around 7.35 (as it is in adult blood).

    • Normal value for an arterial pH is around 7.28.

  • pO2: the pressure of oxygen (in essence its concentration) in fetal blood.

  • pCO2: similarly, the pressure/concentration of CO2 in fetal blood.

    • The pO2 and pCO2 can given additional clues to help with non-straightforward (i.e., mixed) acidosis.

  • Base Excess/Deficit: in blood, acid is buffered by bicarbonate ions. The base excess or deficit represents how much difference there is between those bicarbonate ions and hydrogen ions in order to return to a normal pH value of 7.35 in the umbilical vein. An excess is more bicarb; a deficit is less bicarb. However, these tend to get used interchangeably, and in these acid-base status questions, you’ll see the “excess” written as a negative number — implying what is actually a deficit.

    • Normal values for base excess are around 4 mmol/L in both the umbilical artery and vein.

    • A more significant base deficit signifies a metabolic acidosis -- i.e., the process causing insult has been longstanding, and there has been time to utilize bicarbonate to buffer the acid. 

    • A lower base deficit signifies a respiratory acidosis -- i.e., the process has been acute, so there has been no buffering of the hydrogen ions. 

      • A base deficit of 12 mmol/L has been suggested as severe, and more suggestive of metabolic acidosis. 

(c) MDEdge

(c) MDEdge

What about administering more O2 to the mother? Won’t that help things and reduce the fetal risk of acidosis?

If only it were that simple! Sadly, the answer is no. In most cases, maternal hemoglobin is fully saturated on room air. Fetal hemoglobin has a greater O2 avidity, and will pull O2 across the placental circulation. But when maternal blood is already saturated, the fetus won’t get any more O2 even if you pump it up to 4000L a minute by mega face mask! Some studies have suggested the additional free O2 in maternal serum may actually lead to vasospasm and cause harm! 

The exception to this certainly is a change in maternal oxygenation or an indication for maternal O2 use -- but these indications suggest that maternal Hb is less than 100% saturated. 

When should I get a cord gas?

It’s a good idea to practice the technique for cord gas collection, which requires collecting a 10-20cm doubly-clamped (i.e., proximally and distally) cord segment. Even on routine, vigorous deliveries, getting into this habit as part of your deliveries will help you be prepared. 

Cord gases are not recommended to be sent with delayed cord clamping, so don’t send these if DCC is part of your practice! However, collecting the cord segment can be good practice for those learning proper technique.

There are no consensus rules about when to send a cord gas sample. At our institution, the general thought is “if you think you need one, send one.” However, common scenarios where cord gas sampling can be helpful to at least set aside on a “just in case basis”  include:

  • Nonvigorous infant at delivery (i.e., Apgars at 5 mins less than 7)

  • Category III or “bad category II” tracings

  • Operative deliveries performed for NRFHT

  • Multiple gestation

  • Premature infants

  • Meconium stained fluid

  • Growth restriction

  • Breech deliveries

  • Shoulder dystocia

  • Intrapartum fevers or chorioamnionitis

Obviously this list is non-exhaustive, but goes to show there are a lot of indications! Some literature has suggested even universal arterial blood sampling at delivery may be cost-effective. 

The best way to learn this is to do some practice cases. Check out the below resources for some practice questions and further explanations.






Fetal Circulation

One of the neonatology/pediatric points the CREOG exam will test on is flow of blood through the fetal circulation. It can be quite confusing, but it’s worth remembering. We’ll take you on the journey of a red blood cell in today’s episode.

The important foundational bit of knowledge for this is the nomenclature of arteries and veins. Arteries carry blood away from the heart (Arteries Away), whereas veins carry blood towards the heart. Arteries and veins do not denote oxygenation status, particularly in the fetal circulation!

(C) Children’s Hospital of Philadelphia

Let’s start at the umbilical vein, which is carrying oxygenated blood from the placenta towards the fetal heart. Remember there is a single large umbilical vein with normal umbilical cords.

  • The umbilical vein enters at the umbilicus, and moves superiorly towards the liver, where it ultimately needs to meet the inferior vena cava. However, the umbilical vein naturally empties into the portal hepatic vein

    • This is where we encounter our first fetal shunt, the ductus venosus.

      • This allows oxygenated blood from the umbilical vein to connect to the inferior vena cava, bypassing the portal vein and the liver. 

      • The ductus venosus closes functionally in term infants within minutes of birth, and full closure naturally occurs within one week of birth. In preterm infants this may take longer. The remnant structure is known as the ligamentum venosum.

  • From the IVC, we can get blood into the right atrium of the heart. Now blood will move to the right ventricle naturally in adult circulation. In fetal circulation, though, the lungs have yet to open. The pulmonary circulation is of very high resistance. Rather than take the long, high resistance trip around the lungs, we encounter our second shunt, the foramen ovale between the right and left atria. 

    • The relatively high pressure in the right atrium allows for blood to move across this shunt into the left atrium. 

    • With the first neonatal breaths, the lungs open and the resistance to the pulmonary circulation drastically drops. This allows for the foramen ovale to close, as the septum secundum (some tissue in the right atrium where the foramen ovale is located), is effectively a one way valve from right to left; when flow starts to go left-to-right, this valve closes.

      • In up to 25% of adults, this one-way valve closure is not completely effective, leading to the patent foramen ovale.

  • Now blood is in the left heart, where it can move from left atria, to left ventricle, to aorta, and now supply the fetal brain and other tissues.

  • However, some blood may still move to the right ventricle in spite of the pressure gradient, and try to move through the pulmonary circulation. 

    • To exit the pulmonary circulation more quickly and supply oxygenated blood to the lower extremities, we encounter our third shunt, the ductus arteriosus. This connects the pulmonary artery to the descending aorta. After birth, this closes and becomes the ligamentum arteriosum

    • In some individuals, the ductus arteriosus remains open, leading to a patent ductus arteriosus. Because of the change in pressure after birth, now oxygenated blood is leaving the aorta and overloading the pulmonary artery. This can lead to pulmonary hypertension and right heart failure. 

      • In PDA and rarely PFO, but more commonly with ventricular septums, the pulmonary hypertension becomes so great as to change the pressure differential again (i.e., pulmonary or right heart circulation pressure is greater than left heart or systemic circulation). This changes the shunt to send deoxygenated blood from the right heart into the systemic circulation, and is known as Eisenmeger syndrome

  • Now that we’ve gotten all the blood to the left heart, it moves through the arteries to supply organs and tissues, and will end up in the veins. 

    • Coming from superiorly, blood will end up in the superior vena cava, and end up back in the right atrium. From here, it’s the same cycle all over again -- some will go through the foramen ovale, some will go to the right ventricle and pass through the ductus arteriosus. 

    • If blood went inferiorly (i.e., went through the descending aorta/ductus arteriosus), the umbilical arteries will carry blood back towards the placenta for re-oxygenation and deposition of CO2 and waste products. 

      • The umbilical arteries originate off the internal iliac arteries bilaterally. After birth, they become obliterated and are known as the medial umbilical ligaments. These can be seen during laparoscopic surgery and are good markers for the position of the superior vesical arteries. More on that in a future episode on pelvic anatomy!

Though we have the anatomic picture above, some folks may find a schematic helpful. Run through this a few times before your exam and you’ll be golden!