Thermal disorders

Chapter 74 Thermal disorders



Body temperature is normally very tightly controlled by a balance between heat production and heat loss, through a complex feedback mechanism involving the thermoregulatory centre in the hypothalamus. In the intensive care unit (ICU), fever (pyrexia) is usually due to resetting of the thermoregulatory set-point at a higher level by activation of heat-conserving mechanisms, whereas hyperthermia is due to failure of effector mechanisms to maintain body temperature at the normal set-point.


Although the pathogenesis of hyperthermia varies between different aetiologies, the complications are similar:










THERMOREGULATION


Control of body temperature, like most complex biological systems, is maintained by a complicated system of sensors and controls. The target set-point varies by <1°C per day on a circadian basis, and by <½°C monthly in women. However, at any given time the core temperature is within a few tenths of 1°C of the set-point.


The three major components of the thermoregulatory system are:





Temperature is sensed by A-δ fibres (most cold signals) and unmyelinated C fibres (most warm signals). These sensors are distributed throughout the body but the largest contribution is from the thermal core (deep abdominal and thoracic tissues, and neuraxis).


Signals from these sensors ascend via the spinothalamic tracts in the anterior spinal cord to the thermoregulatory centre located in the preoptic region of the hypothalamus near the floor of the third ventricle. This region contains heat-sensitive neurones but also receives neural input from other thermoreceptors. The preoptic region receives afferent information from peripheral thermoreceptors, determines the thermoregulatory set-point and coordinates appropriate responses.


Temperature is then regulated by a variety of central structures that compare integrated thermal inputs from skin, neuraxis and deep tissues with reference temperatures for each thermoregulatory response.


The most important effector response in humans against extreme environments is behavioural, and outweighs autonomic changes. At extremes of age, hypothalamic temperature regulation is impaired and less effective.


Humoral mediators from the circulation act to alter temperature primarily via the organum vasculosum of the lamina terminalis (OVLT), an area of fenestrated capillaries in the hypothalamus that permits cytokine access to neuronal receptors. Cytokines appear to be the endogenous pyrogens, with interleukin-6 (IL-6) and prostaglandin-E2 (PGE2) being a final common pathway. In addition to elevating body temperature, several cytokines also reduce the thermoregulatory set-point, and are known as endogenous cryogens.1


Patients in the ICU are likely to have disturbance of both heat production and heat loss. Heat is produced as a result of metabolic activity and energy expenditure. Inflammation or infection as part of an acute phase response results in an increase in body temperature and energy expenditure. Pyrexia in turn results in an increased metabolic rate; however, reducing activity with sedation and muscle relaxation reduces energy expenditure.


Regulation of heat loss, which is the predominant effector of thermoregulation, is usually disturbed in the ICU population. Patients are usually nursed semi-naked, bed-bathed frequently, sedated and sometimes paralysed, and infused with drugs and fluids at ambient temperature. This effect is particularly pronounced during renal replacement therapy. Peripheral blood flow may be affected by vasopressors and the ability to shiver abolished by muscle relaxants. Behavioural defences may be compromised by sedative use. All of these effects play a variable part and, together with the method of temperature measurement, should be considered when evaluating fever in the ICU.



FEVER IN THE ICU


Fever is defined by a regulated hyperthermia, that is, it is a regulated elevation in the preoptic set-point temperature. Endogenous pyrogens as well as other mediators inhibit warm-sensitive neurones that normally facilitate heat loss and suppress heat production. This elevates the set-point temperature for all thermoregulatory responses and activates cold defences such as vasoconstriction and shivering, which decrease heat loss and increase metabolic heat production respectively. The set-point temperature returns to normal when pyrogen concentrations decrease, triggering heat loss by vasodilatation and sweating.2


Fever may reflect a wide variety of pathological processes including infection, inflammation, trauma, malignancy and connective tissue diseases (Table 74.1), necessitating a systematic and comprehensive diagnostic approach.3 It is often assumed that a patient presenting with a fever should be treated, regardless of the presence or absence of other symptoms. However, the evidence that anti-fever treatments lead to an improvement in morbidity or mortality, or even patient comfort, is lacking.4


Table 74.1 Causes of fever in the ICU





























































































































System Infectious aetiology Non-infectious aetiology
Cardiovascular Endocarditis Myocardial infarction
  Catheter-related infection Deep-vein thrombosis
  Pacemaker infection Pericarditis
Respiratory Pneumonia Atelectasis
  Empyema Chemical pneumonitis
  Sinusitis Pulmonary emboli
Alimentary Abdominal abscess Inflammatory bowel disease
  Biliary infection Acalculous cholecystitis
  Peritonitis Pancreatitis
  Diverticulitis Ischaemic colitis
  Viral hepatitis Non-viral hepatitis
  Antibiotic-related colitis Gastrointestinal haemorrhage
Renal Pyelonephritis  
  Urinary tract infection  
Central nervous Meningitis Cerebral haemorrhage/infarct
  Encephalitis Seizures
Rheumatological Septic arthritis Connective tissue disease
  Osteomyelitis
  Gout Vasculitis
     
Endocrine   Adrenocortical insufficiency
    Alcohol and drug withdrawal
    Hyperthyroidism
Skin/soft tissue Cellulitis Burns
  Decubitus ulcer Intramuscular injections
  Wound infections
    Haematoma
Other Parotitis Drug fever
  Pharyngitis Transfusion reaction
  Otitis media Neoplasms

The development of fever in response to infection may be a protective adaptive response, and appears to be a phylogenetically preserved evolutionary response because of its survival value.5 In mammalian models, increasing body temperature results in enhanced resistance to infection. In humans, retrospective clinical trials have shown a positive correlation between maximum temperature on the day of bacteraemia and increased survival in patients with Gram-negative bacteraemia and spontaneous bacterial peritonitis.6 Also, septic patients with hypothermia have a poorer outcome than those who develop fever, although this causality is less clear. Both local and systemic hyperthermia has been used to facilitate cancer treatment. The protective effects of fever result from increased immune and cytokine functions.710


Temperature elevation has been shown to enhance:







In addition, elevated temperatures inhibit some pathogens, such as Streptococcus pneumoniae.11


Moderate fever is a common occurrence in ICU patients, but approximately half of these are non-infectious in origin.1214 The presence of fever frequently results in the performance of diagnostic tests and exposes the patient to unnecessary invasive procedures and inappropriate use of antibiotics.15


Whilst very high fevers (> 40°C) are dangerous, it is less clear whether moderate elevation of body temperature is detrimental and, indeed, may be protective.4 Moreover, artificially lowering the temperature of a febrile patient may mask the signs of infection and make diagnosis and monitoring more difficult. Any decision to adopt anti-fever measures, physical or pharmacological, must take into consideration the variable response by this patient population. Antipyretics may be ineffective.The usual concern about external cooling measures inducing peripheral vasoconstriction, reducing heat loss and making the pyrexia worse by shivering and hypermetabolism, may not be observed in sedated ICU patients.16 The most likely cause for this response is the drugs used to maintain sedation.17,18


Pyrexia is associated with a number of deleterious physiological effects. Cardiac output, oxygen consumption, carbon dioxide production and energy expenditure are all increased, particularly in the presence of shivering. Oxygen consumption is increased on average by 10%/°C.2 These changes are poorly tolerated by patients with limited cardiorespiratory reserve, and this group of patients would probably derive benefit from cooling measures. Other patient groups that require special consideration include those with immunosuppression, prosthetic implants and acute brain injury. Recent trials of therapeutic moderate hypothermia and traumatic brain injury indicate that hypothermia is a complicated treatment that is likely to benefit only a subgroup of patients with traumatic brain injury.1921



HEAT STROKE


A diagnosis of heat stroke is suggested when hyperthermia is associated with neurological abnormalities after exposure to high ambient temperature and/or vigorous exercise. Rectal temperature is usually greater than 42°C. Two distinct forms are recognised, and the spectrum of injury includes milder forms of thermal injury often termed heat stress.


Exertional heat stroke is a consequence of prolonged, intense exercise in warm humid environments, often seen in athletes and military recruits. Classic heat stroke is commonly seen in sedentary, elderly patients with underlying illnesses during heat waves. Factors predisposing to heat stroke are listed in Table 74.2. About 80% of heat stroke deaths occur in people aged 50 years and older, because of the diminished ability of the older body to compensate for increased core temperatures. Heat stroke is estimated to be the cause of approximately 1700 deaths each year in the USA.22 The European heat wave of 2003 was responsible for > 14 000 excess deaths within 2 weeks in France alone, of which a third were attributed to heat stroke, hyperthermia or dehydration.23,24 A high mortality rate of > 62% was reported for this cohort, which is higher than that for leading killers in ICUs such as acute respiratory distress syndrome (ARDS) and septic shock.25 Furthermore, there is a late mortality contributed by survivors who have sustained neurological injury. A study of former heat stroke patients suggests that susceptible individuals have a poorer physiological response to heat stress in terms of core temperature, heart rate and sweat response.


Table 74.2 Predisposing factors to heat stroke






























































Age Elderly
Environmental High ambient temperature and humidity
Heat waves
Poor ventilation
Behavioural Lack of acclimatisation
Salt and water deprivation
Obesity
Underlying conditions Infection/fever
Diabetes
Malnutrition
Alcoholism
Hyperthyroidism
Impaired sweat production
Healed burns
Ectodermal dysplasia
Impaired sweating
Cardiovascular disease
Fatigue
Potassium deficiency
Drugs Anticholinergics
Antiparkinsonians
Antihistamines
Butyrophenones
Phenothiazines
Tricyclics
Diuretics
Sympathomimetics

There are two autonomic responses to heat stress: sweating and active precapillary vasodilatation. Sweating is extremely effective and can dissipate up to 10 times the basal metabolic rate, provided that environmental conditions such as ambient temperature, humidity and wind speed are optimal. The resemblance between heat illness and the effects of antimuscarinic drugs, which produce a central anticholinergic syndrome, is explained by the postganglionic, cholinergic sympathetic innervation of sweat glands. Vascular responses to heat stress include vasodilatation of peripheral vascular beds and vasoconstriction of splanchnic and renal beds. During severe heat stress, blood flow through the top millimetre of skin can be equal to the entire resting cardiac output.



PATHOGENESIS


The pathogenesis of multiple organ failure in heat stroke is complex. Although direct cellular damage from increased temperature constitutes the initiating insult,26 the precise sequence of injury and responsible mediators are poorly understood. At the cellular level, thermal injury results in increased membrane permeability, which in turn stimulates membrane enzymes such as Na+K+-ATPase to maintain membrane integrity. This ATP-consuming enzyme activity is also responsible for nerve impulse conduction, which ismarkedly curtailed when ATP is depleted. This results in tissue oedema, reduced oxygen extraction and neuronal injury. High temperatures ameliorate ATP synthesis leading to fatigue.


Recent evidence suggests that the pathways for tissue injury in heat stroke share many features with that of sepsis, endotoxaemia and systemic inflammation. Increased levels of circulating endotoxin and cytokines have been identified in patients with heat stroke.27,28 The use of anti-endotoxin antibodies in primate models of heat stroke suggests that endotoxin at least in part mediates the tissue injury associated with hyperthermia. There was also a significant correlation between plasma IL-6 concentration and the severity of heat stroke. Since this cytokine is known to modulate the hypothalamic set-point, the ramifications of such a response in an already hyperthermic patient are obvious.


Activation of coagulation factors29 and release of endothelin and adhesion molecules30,31 from activated or injured endothelium have also been demonstrated in heat stroke. These recent observations lead to the speculation that certain mediators that are implicated in the pathogenesis of acute organ injury are also elevated in heat stress, but become intense when heat stroke develops and are not normalised upon cooling.



CLINICAL PRESENTATION


Heat stroke induces multiple organ failure and the clinical presentation reflects this. The first clinical signs may be neurological, and include restlessness, delirium, pupillary abnormalities, seizures and coma. Brainstem reflexes may be lost in the presence of brainstem-evoked potentials. There may be focal pathology including cerebellar injury, which may remain permanent. Lumbar puncture may show increased protein, xanthochromia and lymphocytic pleocytosis.


The signs of distributive shock, with a hyperdynamic haemodynamic profile not dissimilar to that of sepsis, are present in a large number of patients. The marked hyperventilation results in respiratory alkalosis, and hypoxaemic respiratory failure may be due to cardiac failure or acute lung injury.


Dehydration follows excessive insensible losses although sweating is generally absent in the terminal stages of classic heat stroke, leaving a hot, dry skin. Hypovolaemia is a consequence of dehydration and fluid redistribution, and results in reduced organ perfusion. A severe metabolic (lactic) acidosis is present. The major biochemical abnormalities include hyperglycaemia, hypophosphataemia, and raised serum enzymes and acute phase proteins (Table 74.3). Haematological findings include leukocytosis, thrombocytopenia, and activation of coagulation and fibrinolysis.


Table 74.3 Biochemical differences between classic and exertional heat stroke



































  Classic heat stroke Exertional heat stoke
Arterial gases Mixed respiratory alkalosis Severe metabolic acidosis
Serum electrolytes Na+, Mg2+, Ca2+ are usually normal HyperkalaemiaHypocalcaemia
  Hypophosphataemia Hyperphosphataemia
Blood glucose Hyperglycaemia Hypoglycaemia
Creatinine kinase Moderately increased Markedly increased
Hepatic enzymes Markedly increased Moderately increased
Acute phase proteins Markedly increased Moderately increased

Exertional heat stroke differs slightly in that additional findings include rhabdomyolysis and acute renal failure that is associated with hyperkalaemia, hyperphosphataemia and hypocalcaemia (Table 74.3).



MANAGEMENT


Heat stroke is a medical emergency. The principal therapeutic objectives are rapid cooling to below 40°C and support of vital organ systems. Heat is dissipated by:




Evaporation is considerably more effective. Pharmacological treatment with antipyretic agents, or dantrolene,32 is ineffective. Prevention of vasoconstriction and shivering by overcooling is important because of the danger of subsequent rebound hyperthermia. Core and skin temperature monitoring is useful, but measurement of rectal temperature should be avoided because it lags considerably during cooling. Cooling can be stopped when core temperature reaches below 39°C. However, despite cooling, about 25% of patients experience failure of one or more organ systems.


Fluid and electrolyte imbalance, and acid–base disturbances must be corrected cautiously with appropriate fluids tailored to the individual and guided by measurements of filling pressure, serum electrolytes and haematocrit.


The mechanism of acute renal failure is multifactorial but rhabdomyolysis is the major component. Early institution of alkaline diuresis and mannitol may obviate the need for renal replacement therapy.


Oxygen therapy and controlled ventilation may be indicated, and anticonvulsants required. Prophylactic antibiotics and steroids are not recommended. Blood glucose must be controlled aggressively. Finally, any underlying illness should be sought and treated accordingly.




DRUG-INDUCED HYPERTHERMIAS


In contrast to fever, the thermoregulatory set-point during hyperthermia remains unchanged at normothermic levels; however, body temperature increases in an uncontrolled fashion and overrides the ability of effector mechanisms to dissipate heat. Although a raised body temperature is not necessarily due to increased heat production but rather due to an imbalance between heat production and loss, most hyperthermias result as a consequence of net heat gain. Hyperthermia can result in dangerously high core temperatures by two mechanisms:




The numerous causes of hyperthermia are listed in Table 74.4. This section will review the relatively common causes of drug-induced hyperthermias, including malignant hyperthermia, neuroleptic malignant syndrome, and the sympathomimetic and anticholinergic syndromes.


Table 74.4 Causes of hyperthermia





































































Disorders of excessive heat production Exertional hyperthermia
  Heat stroke (exertional)
  Malignant hyperthermia
  Neuroleptic malignant syndrome
  Lethal catatonia
  Thyrotoxicosis
  Phaeochromocytoma
  Salicylate intoxication
  Sympathomimetic drug abuse
  Delirium tremens
  Seizures
  Tetanus
Disorders of diminished heat dissipation Heat stroke (classic)
  Dehydration
  Autonomic dysfunction
  Anticholinergic poisoning
  Neuroleptic malignant syndrome
Disorders of hypothalamic function Cerebrovascular accidents
  Encephalitis
  Trauma
  Granulomatous diseases
  Neuroleptic malignant syndrome


MALIGNANT HYPERTHERMIA


Malignant hyperthermia (MH) is a rare pharmacogenetic myopathy usually manifested when a susceptible individual is exposed to anaesthetic triggering agents. It is characterised by an intense hypermetabolic state and skeletal muscle rigidity upon exposure to volatile anaesthetics and depolarising muscle relaxants. In extreme cases, body temperature may exceed 42°C and the arterial pH reach 6.8, and can be rapidly fatal. The incidence of an MH reaction during general anaesthesia varies between 1/60 000 when succinylcholine is used, and 1/250 000 when only volatile agents are used. It is more frequent in children (1/15 000), with more than 50% of cases occurring before the age of 15 years.



PATHOGENESIS


Skeletal muscle is the principal tissue involved in an MH reaction. The primary defect is thought to be in the sarcolemma, and in particular the calcium release channel also termed the ryanodine receptor (RYR1). In MH, exposure of skeletal muscle to triggering agents depolarises the muscle hypersensitively to release massive amounts of calcium ions from the sarcoplasmic reticulum (SR), thus vastly increasing its cytoplasmic concentration. It is believed that the altered kinetics of the ryanodine receptor is due to exaggerated release of calcium by small increases in cytoplasmic calcium concentration (calcium-induced calcium release), as well as a decrease in inhibitory effects of high calcium concentrations. ATP-dependent membrane pumps (Ca2+-ATPase) attempt to return the calcium back to the SR, resulting in a sustained glycolytic and aerobic metabolism. Recovery of calcium by the SR is often incomplete, causing prolonged excitation–contraction coupling and leading to muscle rigidity. Muscle contractures impede blood flow and perturb nutrient supply and waste removal from this hypermetabolic reaction. Eventually, oxidative phosphorylation is uncoupled, metabolism becomes anaerobic, and a severe lactic and respiratory acidosis develops. As muscle constitutes about 40% of body mass and is a major source of body heat, increased activity results in hyperthermia.


Membrane phospholipase A2 is also activated by calcium, leading to an increase in mitochondrial and sarcoplasmic permeability, with further loss of calcium regulation and release of intracellular contents (potassium [K+], calcium [Ca2+], creatinine kinase (CK) and myoglobin) into the circulation.

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Jul 7, 2016 | Posted by in CRITICAL CARE | Comments Off on Thermal disorders

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