Abstract

Background: Intracranial hypertension is found in patients with various neurological and neurosurgical conditions such as subarachnoid hemorrhage (more than 50% of the patients have intracranial pressure > 20 mmHg at some point during their hospital stay), traumatic brain injury, and stroke. Various modalities are used to control intracranial hypertension, therapeutic hypothermia is one of them. This systematic review aims to assess the efficacy of therapeutic hypothermia in controlling intracranial hypertension in an adult patient.

Methods: A systematic review of the literature published between one patient 1990 and 2020 was conducted. Four databases were searched including CINAHL, PubMed, the Cochrane Library, and EMBASE using keywords traumatic brain injury, intracranial pressure, randomized and controlled trials, and the effect of therapeutic hypothermia on intracranial hypertension.

Results: All of the studies included in this review were randomized controlled trials. Most of the studies provided their sample demographics. Sample sizes ranged from 14 to 501. Of the 12 studies, five of them were from the United Kingdom, three of them were from China, two from North America, one from India, and one from Japan.

Conclusion: Treating intracranial hypertension with therapeutic hypothermia may be beneficial according to a few studies but it is also associated with many adverse effects. Both the groups suffered from adverse events which were higher in the hypothermic group. However, these adverse events can be managed in any health-care setting. To treat the patients with therapeutic hypothermia, one (the managing team) should be competent enough to manage the adverse effects.

Keywords: Therapeutic hypothermia, Intracranial hypertension, Raised intracranial pressure

INTRODUCTION

Controlling intracranial hypertension (IHT) has gotten the attention of everyone working in neurosciences.[ 32 ] The normal intracranial pressure (ICP) is the pressure in the cranial vault which is created by three components; brain, cerebrospinal fluid, and blood. Normally, the pressure within the cranium is <20 mmHg. The Monro-Kellie Doctrine states that the contents of the cranium are in a state of constant volume, that is, the volume of brain tissue, cerebrospinal fluid, and blood are fixed, and to compensate for any increase in one component, the other components have to decrease its volume. An increase in these components will lead to decreased blood supply to the brain and herniation of the brain tissues in later stages.[ 22 ] IHT is found in patients with various neurological and neurosurgical conditions such as subarachnoid hemorrhage (more than 50% of the patients have ICP > 20 mmHg at some point during their hospital stay), Traumatic Brain Injury, stroke, etc.[ 18 ] The mechanism of IHT is different in various conditions, for example, in brain tumor, it is due to an increase in neoplastic tissue,[ 14 ] in subarachnoid hemorrhage, it is due to pooled blood inside the brain due to ruptured blood vessels,[ 1 , 11 , 19 ] in traumatic brain injury, it is because of brain tissue injury and inflammatory process,[ 12 , 13 ] and in ischemic stroke, it is due to cerebral edema after the inflammatory process. ICP within the normal range in neurosciences patients is considered a major factor toward better recovery and with the increase in the ICP more than 20 mmHg mortality rate increases.[ 24 ] Among various methods used for controlling IHT, the effectiveness of therapeutic hypothermia has been investigated by various researchers[ 15 , 16 ] and has been empirically used to treat IHT.[ 24 ]

Therapeutic hypothermia is defined as controlled induced hypothermia in which the potentially deleterious effects such as shivering are being controlled or suppressed.[ 32 ] A systematic review by Andrew et al. in 2018 on the effectiveness of hypothermia in reducing IHT or improving ICP in TBI patients found that low-quality studies reported a reduction in mortality rate.[ 4 ] Hence, there is a need for high-quality evidence in its favor. Yet, considering it reported previous benefits, it has been randomly used in neurological and neurosurgical patients. Although its beneficial effects are reported by various studies, many of them[ 25 - 29 , 31 , 34 ] have also reported a variety of adverse effects of therapeutic hypothermia, which are not given much emphasis. Researchers have also enlisted the side effects of rewarming such as abrupt elevation in the level of ICP and delayed estuation of the patient.[ 21 ] Hence, the purpose of this systematic review was to describe and synthesize the existing literature on adverse effects of the therapeutic hypothermia on patients with IHT.

MATERIALS AND METHODS

This systematic review is conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) declaration.

Search strategy

We searched PubMed, CINAHL, the Cochrane Library, and EMBASE using the following keywords: traumatic brain injury, ICP, randomized and controlled trials, and the effect of therapeutic hypothermia on IHT. We included articles published from January 1990 to July 2020. The search terms were derived from a preliminary review. The search was modified and tailored for searches conducted across the databases to account for differences in syntax. We tracked the search process with PRISMA flow diagram [ Figure 1 ]. In [ Table 1 ], we have provided summaries of the articles meeting our inclusion criteria.

Figure 1:

PRISMA flow diagram for study selection.

Table 1:

Review matrix.

Inclusion and exclusion criteria for selection of randomized and controlled trial

Studies had to meet the following inclusion criteria to be included in the review: (1) randomized and controlled trials on patients with increased ICP, (2) use of therapeutic hypothermia as an intervention to control or reduce increased ICP versus the standardized patient care. Therapeutic hypothermia is defined as any intervention to reduce core body temperature to below 36°C.[ 3 ] (3) Three studies that enrolled adult patients as participants, (4) participants must have sustained increased ICP >20 mmHg, and (5) articles written in and accessible in English. We excluded from our review dissertations, books, abstracts, ongoing unpublished studies, systematic and integrative reviews, and conference proceedings.

Bias

The risk of bias was assessed through the Cochrane Collaboration’s tool during the data extraction process. The areas assessed include selection, performance, detection, attrition, reporting, other biases such as small sample size, ethical considerations, funding included, or not [ Table 2 ]. The academic bias was also present because we had included RCTs done by the same author. The selected RCTs were arranged into the domain-based assessment of the risk of bias [ Figure 2 ].

Table 2:

Risk of bias assessment

Figure 2:

(a and b) Risk of bias assessment.

Data management and extraction

For each study, two team members (H.K. and K.T.) completed the data screening and data extraction (H.K., K.T., and M.D.) using a predeveloped form and were exported into Microsoft Word, and the consensus was taken by M.D. and T.X. [ Table 1 ] summarizes the information extracted from each study. The assessment of the risk of bias and quality was done by M.D. and L.G., and the consensus was taken by S.G. The review was done based on PRISMA guidelines in all three stages. First, the duplicates were removed from the databases; then, the abstract and titles were screened against the predetermined inclusion and exclusion criteria. Second, the abstracts were read against the set criteria. Third, all the articles were thoroughly studied and the final decision based on inclusion and exclusion criteria was taken. Other team members verified all extracted data, and disagreements were resolved through discussion with other team members when consensus could not be reached.

RESULTS

All of the studies included in this review were randomized controlled trials. The most of the studies provided their sample demographics. Sample sizes ranged from 14 to 501. Of the 12 studies, five of them were from the United Kingdom, three of them were from China, two from North America, one from India, and one from Japan.

Interventions

Hypothermia was applied immediately after injury in TBI patients; right after decompressive craniotomy in a few and just before applying the first clip in patients with an aneurysm. The treatment with hypothermia was given for 48 h in maximum in the experimental group and for 72 h in one of the groups. The methods used for cooling were water circulating cooling blankets,[ 15 ] infusion of I.V refrigerated NaCl 20–30 ml/kg of body weight,[ 16 ] cooling catheter inserted in the femoral vein to the inferior vena cava.[ 16 ] In the studies which used hypothermia intraoperatively: OT temperature was reduced to 18–20°C; polar air machine was set at 10°C, and cold NS and RL were infused.[ 21 , 33 ] In one of the studies, internal and external techniques were used for cooling, but it is not mentioned which techniques were used.[ 23 ] In the majority of the studies, the temperature was brought down to 32–35°C except in one study[ 33 ] in which the body temperature was kept at 33°C. Then, the rewarming was introduced after 48 h with 0.25°C/h (until ICP was 20 mmHg or less). In the control group, the standard care or usual care was given to the patients but without therapeutic hypothermia. In one of the studies, 45 patients were randomized into Group A, Group B, and Group C. Group A patients received ICP and cerebral perfusion pressure (CPP)-guided management only. Group B patients received mild hypothermia along with ICP and CPP-guided management. Group C patients received mild hypothermia and PO2 management ICP and CPP-guided management.[ 20 ]

Comparators

We included comparator interventions which are defined as the usual or the standard care. Routine care is the standard medical care received in the hospitals or ICU by patients to reduce the ICP and maintain the CPP with other supportive measures such as monitoring the vital signs and ICP/ CPP, maintaining normal body temperature by either ice bags if the temperature was <38.5°C, and administering the antipyretics if temperature >38.5°C, administering prophylactic antibiotics, sedatives, etc. Studies in patients with TBI, the routine care consisted of “guidelines for the management of severe TBI” given by the American Brain Injury Association which included measures to manage ICP and CPP.

Outcome

We have included 12 studies in our review, out of which six studies concluded positive outcomes for patients with raised ICP;[ 20 , 21 , 26 , 27 , 29 , 31 ] two reported negative outcomes for patients,[ 3 , 5 , 23 ] and four were showing no difference.[ 2 , 6 , 33 ] Between both groups, one of which showed more complications in the experimental group.[ 23 ] In one study, there was a decrease in ICP and raised CPP assessed[ 31 ] 1–7 days after randomization, there was no significant difference between both the groups in neurological outcomes in 6–48 months assessment. One study showed improvement in the neurological outcomes in 6 months assessment; on the other hand, one study reported no difference in the outcomes and one concluded serious complication in the experimental group. In five studies, the time of follow-up is not mentioned. In one of the RCTs, the mortality and the rate of complications were higher in the experimental group.

Along with the beneficial effects, there are side effects of hypothermia mentioned in the nine studies in the present review. The most common adverse event was an infection, particularly pneumonia reported in three and bacteremia and other infection in two studies. Other reported adverse effects were delayed extubation, shivering, nausea/vomiting, electrolyte disorders such as hyperkalemia and hypernatremia, GI complications such as bleeding, gastric retention, and stress hyperglycemia in one study (once in different studies). Cardiovascular events such as bradycardia and arrhythmias were documented in three studies. Neurological complications, unfavorable outcomes, and higher mortality were reported in one study. In one three-armed study; the group with hypothermia showed high creatinine phosphokinase (CpK). The steps of rewarming after treatment with hypothermia were mentioned in three studies, and in four studies, rewarming was mentioned without its side effects or its effects. The most common effect of rewarming was an abrupt increase in ICP three studies and late extubation in two studies, hypovolemic shock (also named as a rewarming shock) in one study, and pulmonary infections, peptic ulcer, and leukocytopenia in one study in the hypothermic group.

DISCUSSION

Overall; this systematic review concluded that therapeutic hypothermia is beneficial for patients with IHT but it can lead to delay in recovery in many patients. Hence, there is a need for high-quality evidence on this aspect to bring it into practice or to excise it from practice. Some studies reported benefits to the patients with hypothermia;[ 20 , 21 , 26 , 27 , 29 , 31 ] the temperature of the control group was maintained between 36°C and 37°C and analgesics were used to lower down the temperature if it was > 38.5°C. In all of the studies, the temperature was kept to the lower side for 48 h except for the patients with aneurysms. The beneficial effect of hypothermia for patients is considered due to low metabolic demands in lower temperature and does not lead to increases cerebral blood flow and ultimately high ICP as is the care of high CMR (cerebral metabolic rate).[ 30 ]

Talking about the adverse effects of therapeutic hypothermia: Infections; including pulmonary infections, pneumonia, bacteremia, electrolyte imbalances; hyperkalemia and hypernatremia, cardiovascular events; bradycardia and arrhythmias, gastric complications; peptic ulcers, gastric retention, GI bleeding, stress hyperglycemia, longer incubation period, high CPK, shivering, neurological complications at 6-month follow-up, an abrupt surge in the ICP and hypovolemic (rewarming shock), and leukocytopenia as effects of rewarming, were reported in the majority of the studies included in this review.

Although the reported adverse effects were not severe and were manageable, they were seen in the hypothermic group; furthermore, some complications were present in both groups and the incidence was higher in the hypothermic group. The patients in the hypothermic group suffered from more pulmonary infections such as pneumonia and bacteremia. In a study by Broessner et al., infection is shown as a complication of hypothermia secondary to impairment in the secretion of pro-inflammatory cytokines and suppresses leukocyte migration and phagocytosis.[ 8 ]

The patients who received therapeutic hypothermia were intubated for a longer period or extubated late than the normothermic group, it is reported in one of the studies that in low temperature, the lung functions were altered; low respiratory rate and VT and hypothermia-induced acidosis which lungs cannot compensate without external support.[ 7 ] In another study, lung edema is reported as an effect of hypothermia.[ 15 ] All these factors can be the cause of delayed extubation in the hypothermic group.

Cardiovascular events such as bradycardia and cardiac arrhythmias were found in the rewarming phase, hypothermia causes significant changes in the hemodynamic parameters leading to loss of cardiac contractility and decreased heart rate. In hypothermia, there is blood volume shifting from the periphery to the central vascular system which leads to sinus bradycardia.[ 28 ] Shivering is also reported in one of the articles and is documented as a normal physiological response to hypothermia, it is used to generate heat when the body temperature is low.[ 28 ]

In one study, gastric retention, N/V, GI bleeding, and stress hyperglycemia were reported in hypothermia patients, which are also mentioned in an article that hypothermia induces insulin resistance leads to hyperglycemia.[ 28 ] Hypothermia causes Wischnewsky spots on gastric mucosa which are dark brown colored, ranging 1–5 mm in diameter, which leads to gastric mucosa erosion and GI bleeding.[ 9 ]

Leukocytopenia is also reported in one of the studies in the rewarming phase in patients with therapeutic hypothermia which is comparable to the result of a previous study that reported that in hypothermia, there is a risk of intravascular thrombosis and cytopenia from splenic sequestration and thrombocytopenia, especially during rewarming.[ 10 ] Hypothermia leads to disruption in the platelet functions, slowing down of coagulation enzymes,[ 35 ] which explain the occurrence of bleeding in the hypothermic group.

Rewarming is associated with hypovolemic shock/rewarming shock which is due to fatal circulatory derangement and posts hypothermic circulatory instability which is caused by cardiac insufficiency and alteration of the peripheral vascular bed, cellular calcium overload leads to change in the myocardial responsiveness to cellular calcium. All these factors contribute to the maintenance of low cardiac output, hence, hypovolemic shock.[ 34 ] In the rewarming phase, an abrupt increase in the ICP was seen, probably due to cerebral vasospasm. In one study, the rate of CSF drainage was higher which was a consequence of elevated ICP. In one of the studies, the neurological complications were higher in the hypothermic group which is contrary to the findings of the study where the neurological outcomes were better in the hypothermic group.[ 17 ]

CONCLUSION

Treating IHT with therapeutic hypothermia may be beneficial according to a few studies but it is also associated with many adverse effects. The patients in the control group also suffered from a few adverse events but the incidence was toward the higher end in the hypothermic group. The present review provides information about the adverse effects of therapeutic hypothermia in neurosciences patients which has not got much emphasis so far. Although, the adverse effects were not of much severity and can be easily managed in any health-care setting. The comprehensive knowledge of the adverse effects of hypothermia to neurosciences team working with neurosciences patients can minimize the side effect of hypothermia and will enhance the quality of care of patients treated with hypothermia.

Limitations

Meta-analyses were not done.

Recommendations

Although therapeutic hypothermia is practiced in various settings for reducing IHT, there is no high-quality evidence available for its beneficial effects. Hence, it can be used cautiously.

Declaration of patient consent

Patient’s consent not required as patient's identity is not disclosed or compromised.

Financial support and sponsorship

Publication of this article was made possible by the James I. and Carolyn R. Ausman Educational Foundation.

Conflicts of interest

There are no conflicts of interest.

Acknowledgment

I wish to acknowledge Mrs. Lalita Dheer, Assistant Library and Information Officer, Dr. Tu lsi Da s Li brary, Po stgraduate Institute of Medical Education & Research, Chandigarh, India for helping in retrieving the full manuscript of included studies.

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