In recent years, hypothermia, the lowering of body temperature for therapeutic purposes, has been adopted in neonatal intensive care facilities across the country for the treatment of hypoxic encephalopathy in newborns. In simpler words, it’s used to treat brain damage from asphyxia, or suffocation, often brought about by the umbilical cord wrapping around the neck. The babies are chilled down for three days, giving their brains a chance to heal. While use of hypothermia for this particular condition is likely outside the scope of practice of naturopathic physicians, hypothermia itself is among the most fundamental and traditional naturopathic therapies to treat illness. We might argue that hypothermia is indeed within our scope, but the required equipment is definitely outside our budgets. There is value to our being cognizant of this treatment’s application in the neonatal realm. For those of us who, in the course of practice, may deal with hypoxic newborns, this article should be a timely reminder of the importance of having emergency referral systems in place and up to date. While hypothermia can be near miraculous in helping newborns recover from brain injury, it only helps if started within the six-hour window after birth. For the rest of us, knowing more about this specialized use of hypothermia may allow us to better understand the underlying mechanisms of action so we may translate this application into other situations where hypoxia and reperfusion injuries occur.

We were exposed to the basic ideas of hypothermia when we studied hydrotherapy as naturopathic students. Water transfers heat to and from the body well so is often employed to raise or lower body temperature. However, in hydrotherapy we typically use cold water to trigger reactive responses in the body in order to direct blood flow to a cooled area to warm it. Hydrotherapy is of course far more complex and that was an oversimplification. In an excellent 2014 article published in NDNR, Sussanna Czerenko reviewed the distinctions between the goals of four forms of hydrotherapy—fluxion, reaction, retrostasis, and revulsion: “… fluxion speeds up the flow of blood, reaction initiates the body’s healing responses, retrostasis moves blood from the surface of the skin to the organs, and revulsion moves blood from one part to another distally.”¹

In this article, hypothermia, even if achieved through cold water, describes the actual reduction of body temperature and maintaining it lower than normal, overriding compensatory attempts the body makes to rewarm.

Hypothermia treatments are directed to cool either one specific area of the body or systemically to cool the entire body. Those of us who work with cancer patients are aware of the cooling caps now in fashion used during chemotherapy to prevent or reduce hair loss. In their case, the effect is directed only toward the scalp to prevent damage to the hair follicles. Hypothermia treatment of neonates can be either whole body or directed to the head, and while recent reviews suggest possible greater benefis to limiting cooling just to the head,² my impression is that whole body cooling is currently the more common method used. Using what is essentially a crib-sized waterbed with tightly regulated water temperatures, the infant is cooled to a core temperature (measured as an esophageal temperature) of 33.5°C for 72 hours (92.3 degrees F).

While we might consider hydrotherapy a naturopathic discipline dating back to Priessnitz,³ this modern usage to cool the brain and treat hypoxic encephalopathy dates back only to the early 1980s when case reports were published of children who survived cold water drowning with negligible neurologic damage.^4,5 Such reports led to animal experiments that then led to human trials.⁶ The first clinical trials on babies were published in the late 1990s⁷ and early 2000s.^{8 9 10 11} We should note that, “….hypothermia is one of the few therapeutic modalities in neonatology that was studied extensively in animal models before clinical application in humans.“¹² (A Russian article suggests that hypothermia was being used for this purpose as early as 1977.¹³)

In the years since, hypothermia has been studied repeatedly to the degree that we now look to meta-analyses and Cochrane Reviews to confirm benefit. An early Cochrane review published in 2007 included eight randomized controlled trials and concluded that “…therapeutic hypothermia treatment for term infants with moderate to severe HIE [hypoxia induced encephalopathy] significantly reduced death as well as long-term neurodevelopmental disabilities to 18 months of age. Most importantly, therapeutic hypothermia improved mortality and neurodevelopmental outcomes among survivors.”¹⁴ A 2013 Cochrane review updated these findings. Analyzing 11 randomized controlled trials (n=1505 term and late preterm infants with moderate/severe encephalopathy), “Therapeutic hypothermia resulted in a statistically significant and clinically important reduction in the combined outcome of mortality or major neurodevelopmental disability to 18 months of age (typical RR 0.75 (95% CI 0.68 to 0.83); typical RD -0.15, 95% CI -0.20 to -0.10);…. Cooling also resulted in statistically significant reductions in mortality (typical RR 0.75 (95% CI 0.64 to 0.88), ….”¹⁵

In China, where hypothermia is not fully accepted, over half of the hospitals surveyed recently provided this treatment.¹⁶ A statistic summarizing the percentage of US hospitals possessing the necessary equipment to offer hypothermia remains elusive, but it seems that the number might be lower: “Because the majority of infants who have neonatal encephalopathy are born at community hospitals, centers that perform cooling should work with their referring hospitals to implement education programs focused on increasing the awareness and identification of infants at risk for encephalopathy, and the initial clinical management of affected infants.”¹⁷ In the US infants are transported to tertiary hospitals with neonatal intensive care units for treatment. The American Academy of Pediatrics maintains an online search tool to locate the nearest neonatal intensive care unit (NICU) to a specified location.¹⁸

The most recent studies have expanded the list of possible uses. A February 2021 metanalysis evaluated data on kidney function, as acute kidney injury is a frequent complication of perinatal asphyxia. The authors report a 19% reduction in acute kidney injury in infants treated with hypothermia (RR: 0.81; 95% CI 0.67-0.98; p = 0.03). Additionally, four out of five identified studies, reported significant reductions in cardiac biomarkers and less myocardial dysfunction on ECG and cardiac ultrasound.¹⁹

Use has expanded beyond newborns and children: “Hypothermia is widely accepted as the gold-standard method by which the body can protect the brain. Therapeutic cooling—or targeted temperature management (TTM)—is increasingly being used to prevent secondary brain injury in patients admitted to the emergency department and intensive care unit. Rapid cooling to 33 °C for 24 h is considered the standard of care for minimizing neurological injury after cardiac arrest….”²⁰

In recent years neonatal specialists have begun prescribing hypothermia treatment more liberally and treating children outside of the initial criteria that signal severe brain injury. Now studies are assessing more subtle indications of injury and applying hypothermia to milder cases. At this point questions remain whether this is justified.

Our patients are not average people. Often, they come to see us in part because they have unusual health responses. Their health conditions may make their lives more challenging or hold world views on the fringes of normal. We need to be prepared for the unexpected. If your practice includes neonates, you need to know which hospitals in your area offer hypothermia and have their phone number handy. Many NICUs dispatch specially equipped ambulances so that cooling can be started while the infant is being transported to the hospital.

This discussion is about neonates and not preterm babies. Infants who emerge from the womb too early often suffer from hypothermia, that is being too cold. This is a life-threatening situation and preterm infants need to be kept warm.²¹ Being able to distinguish between infants who need to be warmed and those that should be cooled is a skill set that we won’t attempt to teach here. What you need to learn is the phone number of a neonatal intensive care unit to reach out to when help is needed.

Three Phases of Brain Injury

Understanding the mechanisms by which hypothermia helps these injured neonates may be useful for us as it may add a dimension of understanding to how some naturopathic therapies work. Let’s focus first on brain injuries in hypoxic infants. A cascade of brain injuries is triggered by lack of oxygen. For ease of explanation this cascade is often divided into three phases.²² In the acute phase of injury, “… the culmination of energy failure, acidosis, glutamate release, lipid peroxidation, and the toxic effect of nitric oxide leads to cell death via necrosis and activates apoptotic cascades.”²³

The acute phase is followed by partial recovery and a latent phase that lasts up to six hours, but then secondary deterioration occurs. This secondary phase begins 6 to 15 hours after the initial injury and may last hours to days. Hypoxia activates a switchover from oxidative to anaerobic metabolism that progresses to energy failure, mitochondrial dysfunction, intracellular calcium overload, free radical production leading to an inflammatory response and apoptosis of injured cells; all of which contribute further to brain injury.²⁴

The third phase involves processes that can occur months after initial injury and include late cell death, remodeling of the brain, and “… astrogliosis due to persistent inflammation and epigenetic changes.”²⁵ “It is the time period following resuscitation, before the secondary phase of injury, that provides a potential window for neuroprotection or diminution of injury.”²⁶ In other words, hypothermia comes into play during this second stage where damage continues to accumulate even though oxygen has been restored.

Astrogliosis

is a defense mechanism to minimize and repair the initial damage after CNS injuries and is characterized by remarkable molecular, cellular, and functional alterations in glial cells, especially in reactive astrocytes.²⁷

Hypothermia is currently so well accepted as the primary treatment for hypoxic encephalopathy that much of the current research is focused instead on adjunctive therapies that might make hypothermia more effective²⁸ such as xenon or hydrogen inhalation,^29,30 melatonin,³¹ CBD,³² erythropoietin,³³ and carnosine. ³⁴ A number of natural products are being considered as prophylactic agents to administer during pregnancy that might offer the fetus and neonate protection. These include polyphenols, omega-3 fatty acids, vitamins, plant-derived compounds (tanshinones, sulforaphane, and capsaicin), and endogenous compounds (melatonin, carnitine, creatine, and lactate).³⁵ These agents all seem to share, anti-inflammatory, anti-oxidative, anti-apoptotic, and neurofunctional regulatory properties.³⁶

Additionally, animal data theoretically suggest additional plant extracts that might be protective in human newborns including pomegranate,³⁷ grape seed extract,³⁸ quercetin,³⁹ saffron,⁴⁰ and Salvia miltiorrhizae.⁴¹

It is conceivable that an expectant mother might be encouraged to drink pomegranate juice days or weeks prior to delivery. Yet it is difficult to imagine women even those at high risk for birth complications, making the effort to take nutritional supplements just in case.

Some combination of these herbal extracts could be helpful for the percentage who are proactive, yet mothers should be understandably hesitant until strong human evidence supports use.

Hypothermia, Heart Disease, and Cancer

Knowing how hypothermia reduces hypoxic brain injury may help us translate its use to other conditions. The idea that hypothermia is useful for injuries that result from switching over to anaerobic metabolism and prevention of resultant mitochondrial failure may inspire us to list other conditions where anaerobic metabolism leads to injury. We already use cold in the form of ice for post-exercise muscle pain and injury.

What about with cancer? Many of us talk about how cancer cells switch to anaerobic respiration so could cold be employed against cancer? We think first of hyperthermia as a cancer treatment, but could hypothermia also have use? There are recent indications that this indeed may be the case. A March 2021 report described how hypothermia restores function to mutated p53 enzymes, a major promoter of cancer cell death. Then in May 2021 another study reported on in vitro experiments with glioblastoma cells and tells us that cooling these tumors enhanced standard treatments significantly.⁴²

We may eventually fall back on our old therapy. alternating heat and cold. For the moment, hypothermia is an avenue of therapy that we should be keep our eyes on.