Hypothermia is associated with increased mortality in the preterm infant. There is currently no evidence that therapeutic hypothermia offers any benefits to infants younger than 35 weeks GA. Level of evidence: 4. In animal models, induced hypothermia causes significant physiological stress and is associated with prolonged elevation of circulating cortisol levels after asphyxia, which could increase neuronal loss [39][40].
Infusion of an analgesic, such as morphine, significantly reduces plasma cortisol and noradrenaline concentrations in ventilated newborns, compared with placebo treatment [41]. However, in human newborns the effects of sedative and analgesic therapy during hypothermia on short- and long-term outcomes are unclear; exercising caution is essential [3].
Hypothermia leads to longer serum clearance of morphine, fentanyl and midazolam [42]. Level of evidence: 3b. Similarly, antiepileptic drugs should be used with caution in newborns with HIE, due to their known neurotoxicity [44]. Despite this proviso, experts recommend to treat neonatal seizures, which are common in HIE and suspected to be an independent cause of brain injury [22][45][46]. Obtaining serum levels of antiepileptics, particularly in the first 72 hours if redosing is needed, should be strongly considered.
In fact, whole body hypothermia may even have beneficial effects on gastrointestinal morbidity and feeding tolerance [48]. However, more than minimal feeds is not as safe because gut perfusion may be decreased during cooling [49]. Minimizing fluctuations in blood carbon dioxide levels, avoiding hyperoxia, ensuring adequate tissue perfusion with appropriate use of vasopressors or inotropic agents, maintaining normal serum glucose, treating hyperbilirubinemia, and minimizing unnecessary stimulation or handling are additional management strategies to optimize outcome [50]—[53].
There has been considerable interest and ongoing research in evaluating the neuroprotective efficacy of different agents allopurinol, xenon, melatonin, erythropoietin, neural stem cells and magnesium sulphate in combination with hypothermia [54]—[60], but there is insufficient evidence to recommend their use at this time. MRI is the preferred technique for imaging the brains of infants with neonatal encephalopathy [61].
Research exploring the predictive role of ultrasound and near-infrared spectroscopy is ongoing. In the precooling era, days 3 to 5 of life provided the best time window for MRI with diffusion-weighted imaging, for prognostic purposes and the possibility of redirecting clinical care [62]. A few cohort studies examining the correlation between MRI findings at various ages and later outcome now suggest that, in infants who receive therapeutic hypothermia, an MRI performed between days 2 and 4 correctly identifies lesions on the DWI sequence that are seen after day 10 on T1 and T2 sequences [63][64].
Performing an MRI in an infant undergoing active cooling is a challenge, due to the needs to maintain a steady temperature and compatibility of thermoregulation equipment with MRI. In the absence of an MRI-compatible isolette and other specialized equipment, it is recommended to obtain an MRI once rewarming has taken place, on day of life 4 or 5.
Imaging can usually be done with the infant swaddled and after a feed, as opposed to under general anaesthesia. Centres should attempt to perform such MRIs on the same day of life for all patients, to increase local expertise in reading and interpreting findings.
Consider a repeat MRI between days 10 and 14 of life when the imaging and clinical features are discordant or when diagnostic ambiguity persists [65]. Level of evidence: 3. There is increasing recognition that cognitive deficits may be prominent, even in the absence of cerebral palsy [67]. Decreased visual acuity, visual fields or stereopsis are also described [68].
Behavioural difficulties, such as hyperactivity and emotional problems, should also be considered even in survivors who do not experience motor disability [71]. Follow-up at 18 to 24 months has been the standard of care in hypothermia trials. However, given the broad spectrum of neurodevelopmental impairments following hypoxic-ischemic brain encephalopathy and individual heterogeneity, following affected newborns closely through infancy and into later childhood is important.
Multidisciplinary follow-up could involve a neonatologist or paediatrician, nurse, physiotherapy, occupational therapy, psychology, an infant development program, neurology, developmental paediatrician, ophthalmology and audiology. In multivariate analyses, time to coldest temperature was the only variable significantly associated with neurologic outcome.
When time to coldest temperature was excluded from the multivariate model, time to target temperature independently predicted neurologic outcome. For each hour delay in achieving the target temperature, the odds of a good outcome were reduced odds ratio for a good outcome per hour: 0. In such cases the treatment is a Class IIb recommendation indicating that "usefulness is less well established by evidence or opinion".
Because animal studies have shown that temperatures below Generally the treatment is also contraindicated in patients with a code status of "comfort measures only. Therapeutic hypothermia following cardiac arrest proceeds in three stages: induction, maintenance, and rewarming.
Induction refers to the rapid cooling of the patient by means of either invasive or noninvasive techniques. The chilled fluid pumped into the central catheter remains in the catheter and does not come in direct contact with the blood. Advantages to central intravascular cooling include speed cooling occurs at an average rate of 3.
Disadvantages include the potential risks associated with central catheter insertion-specifically, pneumothorax, infection, and venous embolism-as well as cost. Noninvasive methods include lowering the room temperature or applying surface coolants, such as cooling blankets, pads, or ice packs. The method of cooling does not appear to alter neurologic outcome.
A review of subjects cooled with either surface or intravascular cooling methods found no significant difference in survival with good neurologic function defined as a cerebral performance category score of 1 to 2 either to hospital discharge or at six-tomonth follow-up.
Maintenance refers to the period during which the patient is kept at the target temperature of At the University of Pittsburgh Medical Center UPMC , we use a fixed period of 24 hours of maintenance unless the patient develops life-threatening complications such as coagulopathy. Rewarming may be passive accomplished solely through the withdrawal of cooling devices or actively managed through external or invasive warming methods.
Target rewarming rates are often set at 0. Nurses caring for patients undergoing therapeutic hypothermia administer the cooling protocol and assess all body systems, with the goal of preventing complications resulting either from hypothermia or from common sequelae of critical illness, such as immobility, sedation, and mechanical ventilation.
A multiple-lumen, pulmonary artery catheter Swan-Ganz is generally used to monitor core temperature, volume status, cardiac function, central venous pressure, and cardiac output. The cellular metabolic shifts from aerobic to anaerobic metabolism that occur during cardiac arrest elevate serum lactate, so nurses need to monitor levels during all three phases of treatment.
Initial serum lactate levels suggest the duration of ischemia the longer the patient is without circulation, the higher the lactate level , and persistently elevated levels may represent ongoing ischemia. During all three phases of therapeutic hypothermia, patients should be assessed for treatment complications, as well as for signs of adverse events associated with cardiac arrest see Table 1 Shivering, pneumonia, bleeding, hypoglycemia, sepsis, pulmonary edema, and bacterial translocation are some of the more common complications of therapeutic hypothermia, whereas seizures and cardiac arrhythmias may occur in any patient following cardiac arrest, regardless of whether hypothermia is induced.
Shivering, which occurs in almost all cases, can increase the patient's metabolic rate, oxygen consumption, and carbon dioxide production.
Neuromuscular blocking agents, benzodiazepines, or opiates may be used to reduce shivering and other physiologic stress responses during all phases of therapeutic hypothermia and to facilitate mechanical ventilation. Because these drugs interfere with neurologic assessment, at UPMC we reduce sedation for up to an hour daily depending on patient tolerance to assess motor and brain stem function. Aspiration pneumonia is a frequent complication of therapeutic hypothermia because airway reflexes are lost during cardiac arrest, and the majority of patients are not intubated prior to arrest.
Watch for rising oxygen requirements as well as signs and symptoms of infection, such as elevated white blood cell count and rapid heart rate. Bear in mind that fever may be suppressed if the patient is in the cooling phase. Notify the primary care provider of any suspected infection so that antibiotic treatment can begin as soon as possible.
In some centers, nurses are trained to recognize malignant EEG patterns and contact the neurologist when such patterns occur.
All nurses, however, should remain vigilant for sudden changes in neurologic or hemodynamic status, which may be secondary to seizures. Cardiac arrhythmias may develop during induction particularly tachycardia , maintenance particularly bradycardia , and rewarming as a result of electrolyte imbalances.
Rewarming shifts potassium from the cellular to the extracellular space, potentially producing hyperkalemia. For these reasons, potassium levels should be monitored every four to six hours, and magnesium and phosphate levels as clinically indicated. To reduce rapid shifts in electrolyte levels, patients should be rewarmed at a slow, controlled pace. Bleeding time may increase when the patient's core temperature drops below 95[degrees]F 35[degrees]C because hypothermia inhibits both coagulation protease activity and platelet function.
Stool guaiac and bleeding times must be closely monitored. If bleeding occurs during therapeutic hypothermia, it is standard clinical practice to rewarm the patient to 35[degrees]C as quickly as possible; in the hemorrhagic patient, stopping the bleeding takes precedence over preventing potential ischemic brain injury.
Glycemic abnormalities. Glucose levels should be closely monitored during rewarming. Hypothermia can result in a relative insulin resistance. During rewarming, however, sensitivity to insulin normalizes and the patient may become hypoglycemic. A multicenter trial that included patients who were resuscitated in an ED after out-of-hospital cardiac arrest found that patients whose care plan included therapeutic hypothermia had a higher rate of sepsis and other infections than those who remained normothermic during treatment, even though the differences were not statistically significant and hypothermia's benefit was deemed greater than its potential for adverse effects.
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More related articles. Download other formats More. Bioavailability in the critically ill may not be reliable. Meperidine is an opioid analgesic. Meperidine is probably the single most useful antishivering drug, but has significant adverse events. Meperidine acts on both mu and kappa receptors, is considered the most effective antishivering agent among the opioids. It is thought that activation of [kappa]-opioid receptors, anticholinergic action, and N-methyl-d-aspartate antagonism all play a role.
In studies, plasma concentrations near 1. Meperidine is effective for postoperative shivering and, it inhibits shivering twice as much as vasoconstriction. Meperidine has major side effects; the more significant of them is lowering of seizure threshold. Other reported adverse events include arrhythmias, hyperreflexia, and myoclonus.
The metabolite Normeperidine accumulates in patients with renal failure and could potentiate these adverse events. Fentanyl, morphine are pure mu opioid receptor agonists, and have had mixed results in studies. High doses may be needed to achieve this effect, and this may potentiate side effects The alpha 2 -receptor agonists are another important class of drugs used as pharmacologic measures to control shivering.
Bradycardia and hypotension are the main adverse events with this class of drugs. Important to remember, they may also exacerbate the bradycardia induced by hypothermia. Clonidine decreases the vasoconstriction and shivering thresholds. Prophylactic use of clonidine lowered the threshold of vasoconstriction in healthy volunteers.
At least from these data, clonidine appears to be as effective as meperidine for postanesthetic shivering Dexmedetomidine is another agent that has been shown to decrease postanesthetic shivering when compared to both placebo and Meperidine. In studies with dexmedetomidine in healthy volunteers, it showed a decrease in the vasoconstriction and shivering thresholds by similar amounts.
A small study looked at healthy volunteers and found that Meperidine and Dexmedetomidine were synergistic as well. Magnesium is another anti shivering agent. It is thought to act as an antagonist of the NMDA receptors. In addition, hypothermia causes hypomagnesaemia commonly, and magnesium replacement is often required.
Results on magnesium as a neuroprotectant have been variable. In a study of healthy volunteers, despite reducing the shivering threshold, the authors concluded that it was not clinically significant in counteracting the shivering effect of therapeutic hypothermia.
In this small study, 22 volunteers were randomly assigned to one of four therapies: meperidine monotherapy; meperidine plus buspirone; meperidine plus ondansetron; or meperidine, ondansetron, and magnesium sulfate. In this study, Magnesium was shown to decrease time to target temperature and increase patient comfort. Although the presence of shivering was recorded in this investigation, these data were not reported.
Dantrolene is another agent that has been used for malignant hyperthermia. It acts on the skeletal muscle and interferes with the release of calcium from the sarcoplasmic reticulum, and inhibits the excitation-contraction coupling of skeletal muscles.
It is a good adjunctive antishivering agent. In a study with healthy volunteers, dantrolene decreased the gain of shivering. Dantrolene had no effect on the vasoconstriction threshold. Hepatitis is a complication of dantrolene, especially in people older than 35 years. The reaction can be dose dependent or idiosyncratic.
Propofol has been widely studied in Shivering control. It has been compared to Thiopental and isoflurane. Patients on propofol experienced less shivering compared to thiopental alone or thiopental plus isoflurane. Clinicians should also be aware of propofol infusion syndrome.
Additional proposed risk factors include a young age, critical illness, high fat and low carbohydrate intake, inborn errors of mitochondrial fatty acid oxidation. Patients present with cardiac dysrhythmias, metabolic acidosis, rhabdomyolysis, and renal failure.
It can be associated with a high mortality. There is limited data on the use of other agents such as Ketamine, methylphenidate and doxapram as anti shivering agents in hypothermia.
By redistributing blood flow away from muscle, skin, and fat, hypothermia alters drug pharmacokinetics. Drugs with a large volume of distribution, in the setting of hypothermia distribute to reduced volume and thereby produce higher plasma concentrations. Due to reduced blood flow, these drugs may initially be sequestered in tissue, but subsequently with rewarming and vasodilation, these drugs now redistribute from tissues, leading to high plasma concentrations, thereby increasing the risk of toxicity.
Common electrocardiographic findings during hypothermia include prolonged P-R and Q-T intervals and widening of the QRS complex as well as altered T waves and appearance of the J wave. These usually do not require interventions.
Arrhythmias: Initially, hypothermia causes tachycardia, and then bradycardia ensues. The bradycardia may be severe enough to warrant discontinuing hypothermia.
This is compounded by the fact that the anti arrhythmics become less effective, and so does electrical defibrillation. Attempts at electrical defibrillation can initiate malignant arrhythmias. In the setting of a cardiac arrest, the myocardium in a deeply hypothermic patient is easily susceptible to manipulations such as CPR, defibrillation, and can predispose to arrhythmias. While mild hypothermia can be protective by stabilizing membranes, severe hypothermia increases risk of malignant arrhythmias.
Limited data exist on the efficacy of various antiarrhythmics. Bretylium, the most commonly studied agent, has been recommended as the drug of choice during moderate-to-severe hypothermia. Observational data from humans and experimental animal models have looked at Bretylium. Bretylium is a parenteral Class III antiarrhythmic agent. However, Bretylium is no longer available in the US secondary to lack of availability of raw materials needed to produce the drug, as well as declining usage in clinical practice.
Amiodarone has been studied in an animal model. Stoner et al looked at thirty anesthetized dogs and induced hypothermic VF. They compared defibrillation rates after drug therapy with amiodarone, bretylium, and placebo. In this study, neither amiodarone nor bretylium was significantly better than placebo in improving the resuscitation rate.
The benefits of amiodarone during hypothermia have not been clearly established in humans. In the Bernard study looking at hypothermia after cardiac arrest, Lidocaine was administered for 24 hrs.
Clinically significant cardiac arrhythmias occurred with less frequency in the Australian study compared to the European study, where no lidocaine was employed. Coronary blood flow has been shown to decrease during mild hypothermia in patients with coronary artery disease.
Dixon et al looked at a randomized study of 42 patients with acute myocardial infarction and where cooling was maintained for 3 hours after reperfusion core temperature target 33 degrees C. There were no significant adverse hemodynamic events with cooling; however, the median infarct size was not significantly smaller in those that were cooled compared with the control group Other clinical studies of therapeutic hypothermia in patients with acute myocardial infarction who are undergoing primary PCI have not shown any beneficial effects.
Despite these data, hypothermia can potentially cause hypotension and myocardial dysfunction. It induces a cold diuresis and induces hypovolemia. This is through increased venous return, stimulation of atrial natriuretic peptide, decreased anti diuretic hormone levels, and renal tubular dysfunction.
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