HYPERTHERMIA IN PATIENTS WITH CENTRAL NERVOUS SYSTEM DAMAGE Tokmakov K.A.1,2, Gorbacheva S.М.1, Unzhakov V.V.2, Gorbachev V.I.1
1Irkutsk State Medical Academy of Postgraduate Education, the branch of Russian Medical Academy of Continuous Professional Education, Irkutsk, Russia,
2Regional Clinical Hospital No.2, Khabarovsk, Russia
The high body temperature is a quite common symptom in critically ill patients. According to the literature data, high body temperature is observed in 26-70 % of patients in the intensive care unit [7, 11, 18, 36, 47, 55]. The rate is even higher in patients of neurocritical profile [3, 56]. So, the body temperature > 38.3 °C is noted in 72 % of patients with subarachnoidal hemorrhage after cerebral aneurysm rupture [33, 69], the body temperature > 37.5 °C – in 60 % of patients with severe traumatic brain injury [57]. The causes of high temperature can be different. Centrogenous hyperthermic response (or neurogenic fever) is one of the causes in the patients with primary traumatic brain injury (TBI) (4-37 %) [67].
Classification of hyperthermic conditions
High body temperature is a distinct sign of hyperthermic states. From the perspective of pathophysiology, hyperthermia is a typical form of heat exchange disorder after high temperature influence and/or disorders of heat exchange processes in the body. It is characterized by breakdown of heat regulation processes and the body temperature exceeding the normal values [38]. There is not any generally accepted classification of hyperthermia. The Russian literature describes the following hyperthermic states: 1) body overheating (hyperthermia), 2) heat stroke, 3) sun stroke, 4) fever, 5) various hyperthermic responses [38]. The English language literature distributes the hyperthermic states into hyperthermia and fever (pyrexia). Hyperthermia includes heat shock, drug-induced hyperthermia (malignant hyperthermia [16], neuroleptic malignant syndrome [40], serotonin syndrome [9]), endocrine hyperthermia (thyrotoxicosis, pheochromocytoma, sympathoadrenal crisis) [66]. In such cases, the body temperature increases to 41 °C and higher, but traditional antipyretic pharmacotherapy is usually ineffective. Fever is classified according to two principles: infectious and non-infectious; outhospital and intrahospital (48 hours and later after hospital admission) [23].
Such patients are characterized by lesser body temperature increase, and traditional pharmacotherapy is efficient for them. Therefore, excitation of the thermoregulation center neurons and the associated regions of the cerebral cortex and the brainstem in injuries to the corresponding brain regions causes (according to the Russian literature) the centrogenous hyperthermic response (one of the forms of hyperthermic responses), as well as neurogenic fever (according to the foreign literature) [46].
Influence of high body temperature on neurocritical patients
It has been proved that hyperthermic states are more common for critically ill patients with acute cerebral injury as compared to patients of the general intensive care unit [3, 56]. Also it was suggested that fever in patients of the general intensive care unit can be a useful response to an infection [8, 43], but aggressive decrease in temperature should be contraindicated and can be accompanied by increasing risk of death [59]. One of such studies showed that administration of antifever agents had increased the mortality in septic patients, but not in non-infected patients [37]. The controlled randomized study included 82 patients with various injuries (except for TBI) and the body temperature ≥ 38.5 °C. The patients were distributed into two groups: the first group received aggressive antipyretic therapy (650 mg of acetaminophen (paracetomol) each 6 hours at the body temperature ≥ 38.5 °C and physical cooling at the body temperature ≥ 39.5 °C); the second group received the permissive therapy (only after reaching the body temperature ≥ 40 °C; acetaminophen was introduced and physical cooling for achieving the body temperature < 40 °C was conducted). The study was stopped when the mortality had reached seven cases in the group of “aggressive” therapy to one case in the group of “permissive” therapy [62].
However there are some convincing results that hyperthermic response increases the possibility of death in patients with brain injury [43, 20, 60, 17, 25, 54]. It was shown that the mortality increased in patients with TBI, stroke, if they demonstrate the high body temperature within the first 24 hours from admission to the critical care unit. But such feature was not found in patients with central nervous system (CNS) infection [60]. Another study examined 390 patients with acute cerebral perfusion disorder. The analysis was directed to the relationship between the high body temperature and the mortality, a degree of neurologic deficiency in survivors and cerebral lesion size. It was found that each degree of temperature elevation caused 2.2-fold increase in the risk of unfavorable outcome (including death). Also the hyperthermic state was associated with bigger sizes of cerebral lesion [54]. Among 580 patients with subarachnoid hemorrhage (SAH) 54 % of the patients had the high body temperature and showed the worst outcomes of the disease [70]. The metaanalysis of 14,431 medical records from the patients with acute brain injury (mainly stroke) showed a relationship between the high body temperature and the worst outcome for each estimated value [25]. Finally, the analysis of 7,145 medical records from the patients with TBI (including 1,626 with severe TBI) showed that the possibility of unfavorable outcome (and death), which was estimated with Glasgow Coma Scale, was higher in the patients with the high body temperature within three days of stay in the intensive care unit; moreover, duration of fever made the direct influence on the outcome [30].
There are several possible explanations for the fact that hyperthermic states increase the mortality in patients with brain injury. It is known that the brain temperature is slightly higher than the internal body temperature, but the difference increases with increasing internal body temperature [57]. Hyperthermia increases the metabolic requirements (temperature increase by 1° C leads to increasing metabolism by 13 %) and it is harmful for ischemic neurons [28]. The increasing brain temperature is accompanied by the increase in the intracranial pressure [57]. Hyperthermia worsens the edema and inflammation in the injured cerebral tissues [4]. Other possible mechanisms of brain injury are disordered integrity of hematoencephalic barrier, disarrangement of protein structures stability and their functional activity [25]. The estimation of metabolism in 18 patients with SAH in hyperthermia and induced normothermia identified the decrease in lactate/ pyruvate ratio and the lower number of cases with lactate/pyruvate > 40 (metabolic crisis) in patients with the normal body temperature [49].
Considering the high body temperature influence on the injured brain, it is very important to precisely determine the etiology of the hyperthermic state and to initiate the appropriate treatment. It is certainly that appropriate antibacterial agents are the life saving measures in presence of indications. However the early and precise diagnostics of centrogenous hyperthermia can prevent the unnecessary prescription of antibiotics and concurrent complications.
Hyperthermic states in neurosurgical intensive care units
According to Badjatia N. (2009), 70 % of patients with brain injury demonstrate the high body temperature in the intensive care unit, but in patients in the general intensive care unit – only 30-45 %. Moreover, only a half of the cases included fever (caused by infection) [3]. Among patients in the neurosurgical ICU, patients with SAH demonstrated the highest risk of the hyperthermic state, including both fever (infectious origin) and centrogenous hyperthermic response (non-infectious origin) [12].
Other risk factors of centrogenous hyperthermia are catheterization for cerebral ventricles and duration of stay in ICU [13]. Among 428 patients in the neurosurgical ICU, 93 % of the patients with length of stay > 14 days showed the high temperature. 59 % of the patients with SAH experienced the body temperature elevation above the febrile figures [33]. In its turn, among the patients with SAH, the highest risk of the hyperthermic response was in the patients with high value of Hunt&Hess, with intraventricular hemorrhage and bigger size of aneurism [20].
Fever of non-infectious origin
Infectious etiology as the cause of fever is identified in not all patients. For patients in the neurosurgical ICU the infectious origin is identified in only 50 % of cases with fever [3]. In the general ICU the most common cause of non-infectious fever is so called postsurgical fever [7]. Other possible non-infectious causes of fever are pharmaceuticals, venous thromboembolism and non-calculous cholecystitis. Almost each medication can cause fever, but the most common agents in the ICU are antibiotics (especially β-lactams), anticonvulsants (phenytoin) and barbiturates [31].
Drug therapy is an exclusion diagnosis. There are not any specific signs. In some cases fever is accompanied by relative bradycardia, rash and eosinophilia [39]. There is a temporary relationship between prescription of a medical agent and development of fever or between drug cancellation and disappearance of the high temperature. The possible mechanisms of development are hypersensitivity responses and idiosyncratic reactions [31]. According to PIOPED (Prospective Investigation of Pulmonary Embolism Diagnosis), 14 % of patients with diagnosed pulmonary embolism showed the body temperature ≥ 37.8 °C without any association with other alternative cause [64]. Venous thromboembolism-associated fever is usually short term, with insignificant temperature elevations. Fever disappears after initiation of anticoagulant therapy [48]. Venous thromboembolism-associated fever is accompanied by the increasing risk of 30-day mortality [6]. Spontaneous ischemic or inflammatory injury to the gall bladder can happen in a critically ill patient. Gallbladder duct occlusion, cholestasis and secondary infection can cause gangrene or perforation of the gall bladder [29]. The diagnosis can be suspected in patients with fever, leukocytosis and pain in the right hypochondrium. The gall bladder ultrasonic examination is characterized by sensitivity and specificity > 80 %. The diagnostic significance of spiral computer tomography (SCT) is higher for the gall bladder region [32].
Centrogenous hyperthermic reaction
Even after proper examination, etiology of fever cannot be estimated in some patients. The origin of the high body temperature remains an enigma in 29 % of neurologic ICU patients [50, 53]. According to the data from Oliveira–Filho J., Ezzeddine M.A. et al. (2001), among 92 examined patients with SAH, 38 patients had the febrile temperature, including 10 (26 %) of the patients with a non-identified infection source [50]. Among patients with TBI, 4-37 % of cases show the centrogenous hyperthermia (after excluding other causes) [67]. The pathogenesis of centrogenous hyperthermia has not been researched properly [34]. Hypothalamus injury with increasing levels of PgE makes the foundation for the origin of centrogenous hyperthermia [58]. The study involving the rabbits identified hyperthermia and the high levels of PgE in the cerebrospinal fluid (CSF) after administration of hemoglobin into the cerebral ventricles [22]. It correlates with many clinical observations, when intraventricular blood is a risk factor of development of non-infectious fever [20, 12].
Centrogenous hyperthermic reactions demonstrate the tendency to appear in the beginning of the treatment, confirming the fact the initial injury is centrogenous [53]. Among patients with TBI, patients with diffuse axonal injury (DAI) and damage of the frontal lobes present the risk group of centrogenous hyperthermia [67]. Possibly, these types of TBI accompany a hypothalamus injury. A cadaveric study showed that hypothalamus injuries were in 42.5 % of TBI cases with hyperthermia [68]. Also it is believed that one of the causes of centrogenous hyperthermia can be so called disbalance of neuromediators and neurohormones participating in the thermoregulation processes (noradrenaline, serotonin, dopamine) [34]. The deficiency of dopamine causes the persistent centrogenous hyperthermia [34]. A number of the studies were directed to identification of the predictors of centrogenous hyperthermia. One of the predictors is time of fever appearance. Non-infectious fever is characterized by early development at the early stages of admission to the ICU. So, a study showed that development of hyperthermia and SAH during 72 hours after admission are the main predictors of non-infectious origin of fever [53]. A study of 526 patients showed that SAH and intraventricular hemorrhage (IVH) cause hyperthermia within 72 hours from the moment of admission to the ICU, but long term fever is a predictor of centrogenous hyperthermia [27]. Another study showed a relationship between long tern stay in ICU, ventricular catheterization and SAH with non-infectious origin of fever [12]. The authors of the study concluded that blood in the ventricles was a risk factor, because ventricular catheterization often happens in intraventricular bleeding.
Differential diagnosis
An ability to differentiate between infectious and non-infectious causes of fever plays a crucial role for treatment of neurologic ICU patients. A proper examination with orientation to identification of infection source should be conducted. If the infection risk is high or patient is unstable, then antibiotic therapy should be initiated immediately [41]. One of the possible instruments for identification of non-infectious origin of fever is serum biomarkers of infection. Procalcitonin (one of such markers) was properly researched as an indicator of sepsis. The metaanalysis was conducted in 2007 (based on 18 studies). It showed specificity and sensitivity of the procalcitonin test > 71 % [65].
Duration of antibiotic therapy (initiated after a positive result of the procalcitonin test) should decrease theoretically. The recent metaanalysis of 1,075 medical records (7 studies) showed that antibiotic therapy, initiated after a positive result of the procalcitonin test, did not influence on mortality, but reduced the duration of antibiotic therapy significantly [52]. Non-significant difference (< 0.5 °C) between basal and peripheral temperatures (isothermy) is supported for identifying the difference between centrogenous hyperthermia and infectious inflammatory fever [34]. Temperature survey is conducted in the various points (axillary and rectal).
There is an interesting clinical observation that the extremely high body temperature (> 41.1 °C) in patients in the neurosurgical ICU usually has the non-infectious origin and can be a manifestation of centrogenous hyperthermic response, malignant hyperthermia, malignant neuroleptic syndrome and drug fever [14]. Besides identification of infectious origin of fever it is also required to exclude the drug origin of hyperthermia [31]. The temperature to heart rate ratio can be an important criterion of differential diagnosis of hyperthermic states. Usually heart rate increases along with increasing body temperature (with the body temperature increase by 1 °C heart rate increases approximately by 10 contractions per minute). If the pulse rate is lower than a predicted value for such temperature (> 38.9 °C), then relative bradycardia takes place, except for cases when a patient receives β-blockers, verapamil, diltiazem or when a cardiostimulator is installed.
After consideration of these exclusion criteria, relative bradycardia in patients with hyperthermia in the neurosurgical ICU indicates (with high probability) the non-infectious origin, particularly, centrogenous hyperthermic response or drug fever. Moreover, in rare cases, relative bradycardia is noted in high temperature patients at the background of nosocomial pneumonia and ventilator-induced pneumonia as results of intrahospital legionellosis in general intensive care units [15].
Drug fever encounters in approximately 10 % of patients in the ICU. Its development does not exclude a possibility of an infectious disease or other condition accompanied by hyperthermia. From the classical point of view, such patients look quite well for such temperature values. Patients with drug fever inevitably demonstrate relative bradycardia, but if the body temperature is lower than 38.9 °C, pulse deficit can demonstrate lower obviousness. In laboratory conditions such patients demonstrate the unexplainable leukocytosis with leftwards shift (infectious process imitation), eosinophilia, increasing ESR, but blood culture for sterility does not identify the signs of infectious origin of hyperthermia. Also the levels of aminotransferase and immunoglobulin E can increase. As a rule, such patients demonstrate the burdened allergic anamnesis, particularly, drug anamnesis. A quite common misbelief is absence of drug fever, when a patient consumes a medical agent for a long time, and without any signs of allergy previously. In most cases the cause of fever is a drug that a patient takes for a long period [14].
When the high body temperature is persistent, despite of antibiotics administration, or microbial source is not identified, one should conduct the screening for venous thrombosis with use of clinical and instrumental methods (ultrasonic examination of the veins in the lower and upper extremities) [71]. Atelectasis was often mentioned as a cause of non-infectious fever, but several studies did not identify any particularities [19]. Non- calculous cholecystitis can be a life threatening condition after considering the quite unclear symptoms in patients with coma [51]. Ultrasonic abdominal examination can be efficient for diagnostics. Centrogenous hyperthermia can be diagnosed only after appropriate exclusion of an infection or the above mentioned non-infectious causes of fever in neurological ICUs. As it was mentioned before, some nosologies indicate higher predisposition to hyperthermia [12, 67, 27]. Aneurysmatic SAH is the most significant risk factor, the second one is IVH [28]. Patients with DAI and frontal lobes damages present the risk group among patients with TBI [67]. Ongoing fever, despite the treatment [27] and its development within 72 hours after ICU admission [27, 53], also indicates centrogenous hyperthermia. Sometimes centrogenous hyperthermia is not accompanied by tachycardia and sweating (usual for infectious fever) and can be resistant to action of antipyretics [68]. Therefore, the diagnosis “centrogenous hyperthermic reaction” is a diagnosis of exclusion [41]. Although it is desirable to prevent prescription of antibiotics without indications owing to development of side effects, refusal from antibacterial therapy can be fatal for septic patients.
Therapeutic possibilities
As fever is caused by prostaglandin-induced displacement of “adjustment temperature” of hypothalamus, then appropriate therapy should block this process. The common antipyretics (including paracetamol and non-steroidal anti-inflammatory drugs) prevent synthesis of prostaglandins [4]. Some studies have shown their efficiency for management of fever [44, 26], but without influence on mortality. Also the studies have shown that centrogenous hyperthermic reactions more or less persistent to conventional drug therapy [68, 61]. Only 7 % of patients with TBI and 11 % of patients with SAH showed the decreasing body temperature after administration of antipyretics [2]. There is not any generally accepted technique for management of centrogenous hyperthermic reactions. Some medical agents were offered: continuous intravenous infusion of clonidine as a part of so called neurovegetative stabilization, [35], use of dopamine receptors agonists – bromocriptine in combination with amantadine [34], propranolol [42], continuous infusion of low dosages of diclofenac [13]. The physiotherapeutic treatment techniques were offered, particularly, contact electromagnetic impact on the region between the spinous processes C7-Th1. A study also showed that decompensated hemicraniectomy for severe TBI promoted the cerebral temperature decrease that was possibly by increasing conductive heat exchange [45]. A clinical study of 18 children (age from 1 week to 17 years) with severe TBI in most cases used management of hyperthermia by means of 10-15 minutes intravenous infusion of cold saline (4 °C) with the average volume of 18 ml/kg. The authors concluded that such technique is safe and efficient [21]. Similar studies were conducted for adult patients with severe TBI and showed their efficiency [5]. Physical cooling is used, when drug therapy is insufficient. Theoretically, all medical technique of hypothermia can be divided into two categories: invasive and non-invasive. General external cooling can cause muscle tremor that decreases the efficiency of the technique and increases the metabolic requirements of the body [4]. Deep sedation with muscle relaxants can be used for prevention. Some studies offer an alternative technique with use of selective craniocerebral hypothermia [10] and non-invasive intranasal hypothermia [1, 63], although the results of these studies relating to patients with severe TBI are contradictory, mainly regarding the efficiency of this technique.
The endovascular (invasive) devices were developed for rapid stimulation of hypothermia. After comparison of efficiency and safety of the endovascular cooling devices for external hypothermia one can note that both techniques are similarly efficient for induction of hypothermia, and there are not any confirmed differences in rates of side effects, mortality and unfavorable outcomes. However external cooling shows the lower accuracy in the phase of hypothermia support [24].
CONCLUSION
The high body temperature in critically ill patients is a common symptom. The injured brain is very sensitive to hyperthermia. Multiple experimental and clinical studies show the unfavorable outcomes in patients with TBI and the high body temperature regardless of its origin. Besides fever, a cause of increasing body temperature in patients with acute brain injury can be so called centrogenous hyperthermia (neurologic disease in other words).
Subarachnoidal hemorrhage, intraventricular hemorrhage and some types of TBI are the risk factors of development of the last one. Centrogenous hyperthermia is a diagnosis of exclusion that should be confirmed only after proper examination with identification of infectious or non-infectious causes of fever. Both fever and centrogenous hyperthermia should be managed in patients with acute brain injury. Pharmacological antipyretics (efficient for fever, and less efficient for centrogenous hyperthermia) and physical techniques of cooling (efficient both for fever and centrogenous hyperthermia) can be used. Considering the current absence of a uniform technique for management of centrogenous hyperthermia, the future attempts should be oriented to higher amount and better quality of clinical studies for identification of an efficient and safe technique for management of centrogenous hyperthermia.
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