drug induced hyperthermia and their management in ICU.

1. Hyperthermic Syndrome In
ICU and Their Management
DR Sumeet Singh
SR Neurology
GMC Kota
Heat not a furnace for your foe so hot that you singe yourself.
William Shakespeare Henry VIII

2. Some basics………
• Normal Body Temperature
The traditional norm of 37°C (98.6°F) is a mean value derived from a
study of axillary temperatures in 25,000 healthy adults, conducted in
the late 19th century .
However, axillary temperatures can vary by as much as 1.0°C (1.8°F)
from core body temperatures , and axillary temperatures are not
advised in ICU patients .
 Core body temperature can be 0.5°C (0.9°F) higher than oral
temperatures (6), and 0.2 – 0.3°C lower than rectal temperatures .
O’Grady NP, Barie PS, Bartlett J, et al. Guidelines for the evaluation of new fever in critically ill adult patients: 2008 update from the
American College of Critical Care Medicine and the Infectious Disease Society of America. Crit Care Med 2008; 36:1330–1349

3.  Elderly subjects have a mean body temperature about 0.5°C
(0.9°F) lower than younger adults .
 Body temperature has a diurnal variation, with the nadir in the
early morning (between 4 and 8 a.m.) and the peak in the late
afternoon (between 4 and 6 p.m.).
The most accurate measurements of temperature are obtained with
thermistor equipped catheters placed in the pulmonary artery,
esophagus, or urinary bladder.
Marion GS, McGann KP, Camp DL. Core body temperature in the elderly and factors which influence its measurement.
Gerontology 1991; 37:225–232.

4. • Definition of Fever in ICU
• 1. A body temperature of 38.3°C (101°F) or higher represents a fever,
and deserves further evaluation.
• 2. A lower threshold of 38.0°C (100.4°F) can be used for
immunocompromised patients, particularly those with neutropenia.
Peres Bota D, Lopes Ferriera F, Melot C, et al. Body temperature alterations in the critically ill. Intensive Care Med 2004; 30:811–816.

5. • The Febrile Response
• Fever is the result of inflammatory cytokines (called endogenous
pyrogens) that act on the hypothalamus to elevate the body
temperature.
• Fever is a sign of inflammation, not infection, and about 50% of ICU
patients who develop a fever have no apparent infection .
• The severity of the fever does not correlate with the presence or
severity of infection.
Saper CB, Breder CB. The neurologic basis of fever. N Engl J Med 1994; 330:1880–1886

6. Infectious causes of fever in ICU

7. Richards MJ, Edwards JR, Culver DH, Gaynes RP. The National Nosocomial Infections Surveillance System. Nosocomial infections in
combined medicalsurgical intensive care units in the United States. Infect Control Hosp Epidemiol 2000; 21:510–515

8. Some non infectious causes of fever

9. Blood transfusion
• Febrile non-hemolytic transfusion reactions occur in 0.5% of
erythrocyte transfusions.
• The fever usually appears during, or up to 6 hours after, the
transfusion.
• Fever is much more common with platelet transfusions; i.e., the
reported incidence is as high as 30%.
• Caused by antibodies to donor leukocytes.

10. Drugs causing fever
Mackowiak PA, LeMaistre CF. Drug fever: a critical appraisal of conventional concepts. Ann Intern Med 1987; 106:728

11. Approach to management of fever in ICU
• To determine whether the source is infectious or non-infectious.
• Blood cultures are recommended for all cases of ICU-related fever
where a noninfectious source is unlikely
• 20 – 30 mL of blood is withdrawn from each venipuncture site.
• Three blood cultures drawn over a 24-hour period will detect a
majority (> 90%) of bacteremia.

12. Relationship between the number of blood cultures drawn over a
24- hour period (20 mL per blood culture) and the detection rate
for bacteremia.

13. Empiric Antimicrobial Therapy
• Empiric coverage with an antibiotic that is active against Gram-negative
aerobic bacilli such as the carbapenems (imipenem or meropenem),
piperacillin/tazobactam, or cefepime
• Coverage for staphylococci (S. aureus and coagulase-negative
staphylococci) should be included if vascular catheter-related septicemia is
a possibility. Vancomycin is the antibiotic-of-choice for this purpose.
• An antifungal agent should be considered when unexplained fever persists
for longer than 3 days after the start of empiric antibiotics.
• For patients with long hospital stay, recent antimicrobial therapy,
immunosuppressed, Candida colonizing multiple sites, Fluconazole is
adequate for most patients, while an alternative agent (e.g., caspofungin)
is recommended for neutropenic patients.

14. ANTIPYRETIC THERAPY
• Acetaminophen is usually given orally or by rectal suppository in a
dose of 650 mg every 4 – 6 hrs, with a maximum daily dose of 4
grams.
• Iv preparation of 1000mg iv every 8 hour can be used alternately.
• Ibuprofen provides safe and effective antipyresis at an intravenous
dose of 400 – 800 mg every six hours.

15. Hyperthermia vs Fever
• Hyperthermia is the result of a defect in temperature regulation.
• Fever results from normal thermoregulatory system operating at a
higher set point.
• The antipyretic agents are ineffective in treating hyperthermia.
Keel CAm Neil E, Joels N. Regulation of body temperature in man. In: Samson Wright’s Applied Physiology, 13th ed. New York:
Oxford University Press, 1982:346.

16. Response to Thermal Stress
• The maintenance of body temperature in conditions of thermal stress
(e.g., hot weather, strenuous exercise) is primarily achieved by
enhanced blood flow to the skin (convective heat loss) and the loss of
sweat (evaporative heat loss).

17. Hyperthermic syndromes
• Heat-related illnesses are conditions where the thermoregulatory
system is no longer able to maintain a constant body temperature in
response to thermal stress.
• Some conditions with hyperthermia:
1. Heat exhaustion
2. Heat stroke
3. Malignant hyperthermia
4. Neuroleptic malignant syndrome
5. Serotonin syndrome.

18. Heat Exhaustion
• Heat exhaustion is the most common form of heat-related illness.
• Patients with heat exhaustion experience flu-like symptoms that include
hyperthermia (usually < 39°C or 102°F), muscle cramps, nausea, and
malaise.
• The hallmark of this condition is volume depletion without signs of
hemodynamic compromise.
• The volume loss can be accompanied by hypernatremia (from sweat loss)
or hyponatremia (when sweat loss is partly replaced with water intake).
• There is no evidence of significant neurologic impairment.
• The management of heat exhaustion includes volume repletion and other
general supportive measures. Cooling measures to reduce body
temperature are not necessary.
Lugo-Amador NM, Rothenhaus T, Moyer P. Heat-related illness. Emerg Med Clin N Am 2004; 22:315–327.

19. Heat stroke
• Heat stroke is a life-threatening condition characterized by extreme
elevations in body temperature (≥ 41°C or 106°F)
• Severe neurologic dysfunction (e.g., delirium, coma, and seizures)
• Severe volume depletion with hypotension, and multiorgan
involvement that includes rhabdomyolysis, acute kidney injury,
disseminated intravascular coagulopathy (DIC)
• Marked elevation in serum transaminases, presumably from liver.
• The inability to produce sweat (anhidrosis) is a typical, but not
universal, feature of heat stroke .
Glazer JL. Management of heat stroke and heat exhaustion. Am Fam Physician 2005; 71:2133–2142.

20. Management
• Volume resuscitation
• Body cooling to reduce the body temperature to 38°C (100.4°F).
1. External cooling accomplished by placing ice packs in the groin and axilla, and covering the upper
thorax and neck with ice.
2.Internal cooling can be achieved with cold water lavage of the stomach, bladder, or rectum.
Hadad E, Rav-Acha M, Heled Y, et al. Heat stroke: a review of cooling methods. Sports Med 2004

21. DRUG-INDUCED HYPERTHERMIA
• Malignant hyperthermia(MH)
It is an inherited disorder with an autosomal dominant pattern
Characterized by excessive release of calcium from the sarcoplasmic
reticulum in skeletal muscle
The calcium release leads to uncoupling of oxidative phosphorylation
and a marked rise in metabolic rate.
Occurs in response to halogenated inhalational anaesthetic agents
(e.g., halothane, isoflurane, sevoflurane, and desflurane) and
depolarizing neuromuscular blockers (e.g., succinylcholine)
Rusyniakn DE, Sprague JE. Toxin-induced hyperthermic syndromes. Med Clin N Am 2005;89:1277–1296.

22. Cont…..
• Clinical manifestations
Muscle rigidity
Hyperthermia
Depressed consciousness(agitation to coma)
Generalized erythematous flush followed by mottled skin and cyanosis
Autonomic instability(cardiac arrhythmia, persistent hypotension)
Rise in end-tidal PCO2
Rhabdomyolysis
Myoglobinuric renal failure.
Litman RS, Rosenberg H. Malignant hyperthermia. J Am Med Assoc 2005; 293:2918–2924

23. Management of malignant hyperthermia
• Prompt immediate discontinuation of the offending anesthetic agent.
• Specific treatment:
• Dantrolene sodium, a muscle relaxant that blocks the release of
calcium from the sarcoplasmic reticulum.
• Regimen : 1–2 mg/kg as IV bolus, and repeat every 15 minutes if
needed to a total dose of 10 mg/kg. Follow the initial dosing regimen
with a dose of 1 mg/kg IV or 2 mg/kg orally four times daily for 3 days
• Given early in course it can reduce the mortality from 70% to less
than 10%
McEvoy GK, ed. AHFS Drug Information, 2001. Bethesda, MD: American Society of Health-System Pharmacists, 2001, pp. 1328–
1331.

24. Price in INDIA rupees 8/vial.

25. Neuroleptic malignant syndrome(NMS)
• NMS is associated with drugs that influence dopamine-mediated
synaptic transmission in the brain.
• NMS can be the result of therapy with drugs that inhibit
dopaminergic transmission (most cases), or can be triggered by
discontinuing drugs that facilitate dopaminergic transmission.
• There is no relationship between the intensity or duration of drug
therapy and the risk of NMS, so NMS is an idiosyncratic drug reaction
and not a manifestation of drug toxicity.
Bhanushali NJ, Tuite PJ. The evaluation and management of patients with neuroleptic malignant syndrome. Neurol Clin N Am 2004;
22:389–411.

26. Drugs causing NMS
Guze BH, Baxter LR. Neuroleptic malignant syndrome. N Engl J Med 1985; 313:163–166.

27. • Clinical features of NMS:
• Most cases of NMS begin to appear 24 – 72 hours after the onset of drug
therapy, and almost all cases are apparent in the first 2 weeks of drug
therapy.
• Muscle rigidity(lead pipe type)
• Hyperthermia (body temperature can exceed 41°C)
• Depressed mental status(agitation to coma)
• Autonomic instability( cardiac arrhythmias to persistent hypotension)
• Raised serum CK levels are higher than 1,000 Units/L and the leukocyte
count in blood can increase to 40,000/µL.
• The mortality rate in NMS is about 20% .
Otani K, Horiuchi M, Kondo T, et al. Is the predisposition to neuroleptic malignant syndrome genetically transmitted? Br J Psychiatry
1991; 158:850–853.

28. Management of NMS
• Immediate removal of the offending drug.
• If NMS is caused by discontinuation of dopaminergic drugs, the drug
should be restarted immediately, with gradual reduction of the drug
dosage at a later time.
• General measures for NMS include volume resuscitation.
• Dantrolene sodium 2-3 mg/kg as iv bolus and repeated if needed.
• Bromocriptine in a dose of 2.5 – 10 mg three times a day can improve
muscle rigidity.
• There is a heightened risk of venous thromboembolism during NMS
so heparin prophylaxis is recommended.
Khaldarov V. Benzodiazepines for treatment of neuroleptic malignant syndrome. Hosp Physician, 2003 (Sep

29. Serotonin syndrome
• Serotonin is a neurotransmitter that participates in sleep–
wakefulness cycles, mood, and thermoregulation.
• Overstimulation of serotonin receptors in the central nervous system
produces a combination of mental status changes, autonomic
hyperactivity, and neuromuscular abnormalities that is known as the
serotonin syndrome (SS).
Boyer EH, Shannon M. The serotonin syndrome. N Engl J Med 2005; 352:1112–1120. 18. Demirkiran M, J

30. Drugs causing serotonin syndrome
Demirkiran M, Jankivic J, Dean JM. Ecstacy intoxication: an overlap between serotonin syndrome and neuroleptic malignant syndrome. Clin
Neuropharmacol 1996; 19:157–16

31. Clinical manifestations
• Mental status changes (e.g., confusion, delirium, coma),
• Hyperthermia
• Autonomic hyperactivity (e.g., mydriasis, tachycardia, hypertension)
• Neuromuscular abnormalities (e.g., hyperkinesis, hyperactive deep tendon
reflexes, clonus, and muscle rigidity).
• The clonus is most obvious in the patellar deep tendon reflexes, and
horizontal ocular clonus may also be present.
• Severe cases of SS often present with delirium, hyperpyrexia (temperature
> 40°C), widespread muscle rigidity
Boyer EH, Shannon M. The serotonin syndrome. N Engl J Med 2005; 352:1112–1120

32. • Diagnostic worksheet of serotonin syndrome

33. Management :
• Removal of offending drug
• Sedation with benzodiazepines for controlling agitation .
• Cyproheptadine - a serotonin antagonist that can be given in severe
cases of SS
• The initial dose is 12 mg, followed by 2 mg every 2 hrs for persistent
symptoms. The maintenance dose is 8 mg every 6 hours.
• Neuromuscular paralysis may be required in severe cases of SS to
control muscle rigidity and extreme elevations of body temperature
(> 41°C).
• Nondepolarizing agents (e.g., vecuronium) should be used for muscle
paralysis because succinylcholine can aggravate the hyperkalaemia
that accompanies rhabdomyolysis .
Graudins A, Stearman A, Chan B. Treatment of serotonin syndrome with cyproheptadine. J Emerg Med 1998; 16:615–619.

35. Rhabdomyolysis
• Skeletal muscle injury (rhabdomyolysis) is a common complication of
hyperthermia syndromes
• Disruption of myocytes in skeletal muscle
• CK levels in plasma is used to determine the presence and severity of
rhabdomyolysis.
• Plasma CK levels above 15,000 Units/L indicate severe
rhabdomyolysis.
• Renal tubular injury from myoglobin results in acute renal failure in
about one-third of patients with rhabdomyolysis
Sharp LS, Rozycki GS, Feliciano DV. Rhabdomyolysis and secondary renal failure in critically ill surgical patients. Am J Surg 2004; 188:801–806.

36. CASE SCENARIO #1
• A 42 years male, in the post anesthesia care unit (PACU)
develops muscle rigidity and becomes tachypneic and
tachycardic.
• His blood pressure is 154/90 and his temperature, which
was 98° F (37° C) preoperatively and 100° F (38° C) at PACU
admission, has jumped to 104° F (40° C).

37. • He underwent arthroscopic repair of a torn anterior
cruciate ligament and arrived in the PACU about 5 minutes
ago.
• He has no significant medical or surgical history.
• Reviewing his medical record, he has received isoflurane
for general anesthesia. He's receiving supplemental oxygen
by nasal cannula.

38. • What do u think this condition is?
• MH
• Recognizing symptoms early and discontinuing
anaesthesia promptly are imperative. Goals of treatment
are to decrease metabolism, reverse metabolic and
respiratory acidosis, correct dysrhythmias, decrease body
temperature, provide oxygen and nutrition to tissues, and
correct electrolyte imbalance.

39. CASE SCENARIO # 2
• Male, 64, admitted with signs of a possible stroke.
• According to his family, he had become nonverbal and was
“sitting and staring into space.” Concerned that he might be
having a stroke, they brought him to ER after he became rigid
and nonresponsive.
• Upon admission , he remained unresponsive to verbal stimuli,
responding only to noxious stimuli with facial grimacing. His
Glasgow coma scale (GCS) score was 7 . His vital signs included
temperature, 104° F (40.0° C); sinus tachycardia- 137
respiratory rate, 28 breaths/minute; SpO2, 92% on
oxygen via nasal cannula at 2 L/minute; and BP, 158/88 mm Hg.
• Computed tomography of the brain was normal.

40. • He had a history of schizophrenia, hypertension and
dyslipidemia.
• His schizophrenia was managed with the antipsychotic
quetiapine. Recently, he had also been placed on lithium
and haloperidol to treat his psychosis characterized by
paranoia, hallucinations, thought disorganization, and
religious delusions.

41. • His physical assessment findings included profuse diaphoresis and
generalized muscular rigidity with superimposed tremor.
• The blood and urine specimen results showed no signs of an
infection, but his serum creatine kinase (CK) levels were
significantly elevated at 1,600 U/L (normal range, 38 to 174 U/L).
• A lumbar puncture ruled out meningitis, encephalitis, bleeding,
syphilis, and inflammatory disorders such as multiple sclerosis. He
was admitted to the ICU for further management.
• What could be the possible diagnosis?

42. • Potential causative factors may be the psychotropic drug regimen, which was
stopped immediately.
• Markedly elevated BP was lowered by administering clonidine or nitroprusside.
Bromocriptine mesylate, a dopamine agonist, was prescribed to restore lost
dopaminergic tone.26
• Patients was assessed for cardiomyopathy and VTE. Additionally, patient’s
respiratory status was closely monitored.
• Euthermia was maintained by reducing the room temperature and using ice packs,
ice water gastric lavage, antipyretics, and cooling blankets or garments such as
vests and leg wraps.
• Dantrolene sodium, a direct-acting skeletal muscle relaxant that inhibits calcium
release from the sarcoplasmic reticulum, was administered to prevent
rhabdomyolysis.
• CK-MM levels were monitored.
• Over next few days patient improved.

43. CASE SCENARIO # 3
• A 21-year-old female with a history of generalized anxiety disorder and major depression
presented with increased depressive symptoms over several months while taking fluoxetine
20 mg daily.
• Fluoxetine was discontinued without taper and replaced with paroxetine 10 mg daily, along
with hydroxyzine 50 mg twice daily as needed for anxiety.
• Within a week of starting the paroxetine, the patient reported increased anxiety, insomnia,
and constant shaking.
• The paroxetine continued to be used in dose 30 mg due to unremitting depressive
symptoms.
• One day later, the patient presented with tachycardia, generalized body aches, extreme
fatigue, weakness, uncontrollable twitching, tremor, and hyperreflexia.
• A widespread burning sensation accompanied by random hot flashes( temperature-104 F)
without diaphoresis was also noted.

44. • What could it be?
• With history of addition of SSRI and recent increase in dose
• Serotonin syndrome was diagnosed .
• Paroxetine was discontinued, and the patient’s physical
symptoms resolved within a week.

45. To conclude….
Fever and hyperthermia are not same.
 Fever is not a pathological condition, but is a normal adaptive
response that serves an antimicrobial defense mechanism.
Except for the early period following cardiac arrest or ischemic stroke,
fever provides a documented benefit in patients with infection.
 The professed harm of hyperpyrexia (≥ 40°C or ≥ 104°F) in a
nonischemic brain is more assumption than documented fact.

46. References
• Marinos The ICU Book
• Continuum journel
• Bradley’s 8th edition

47. Thank you
Give me the power to produce fever, and I will
cure all diseases.
Parmenides ca 500 B.C