Author: Dr. R.S. Bhatia, Dr. Keerat Kaur Sibia, Dr. S.S. Sibia

Prevalence of global nosocomial infections in ICU is 25 percent and fever is the chief presentation. Apart from increased morbidity and mortality, cost burden and hospital stay, treating skills of best of physicians are put to test with the rise of temperature in a patient admitted in ICU1.

Fever is a leading cause of mortality in ICU if treatment is withheld or there is a delay in correct diagnosis in a critically ill patient. Nearly half of these are of infectious in origin, where pneumonia and intravenous line infection are common causes in patients admitted to I.C.U. The mortality rate of 20-50% in patients on mechanical respiratory is as higher as 60% in cases infected with pseudomonas aeroginosa. However, Nosocomial infection rate in ICU as respiratory infection – commonest being Acinibacter respiratory isolate and pseudomonas urinary isolate were commonest significant infections in ICU responsible for pyrexia in ICU, however not adversely affecting ICU mortality2. Non infectious causes of pyrexia such as infusion reaction, deep vein thrombosis and aspiration are also noted in many numbers of cases3. Infective endocarditis in developed nations, neoplastic disorders and non infectious causes are equally important in developing countries as important causes of fever. Non infective cardiac causes include myocardial infarction, ischemia, drug fever (clofibrate, nifedipine, hydralazine, hydrochlorthiazide, heparin, captopril, methyl dopa, procainamide, quinidine) 4. Nevertheless, many a times, over-investigations are done, adding economic burden to the patient; but at the same time, starting off antimicrobials with the onset of fever without diagnosing the infective etiology leads to emergence of drug resistant strains as well as expose the patients to unnecessary adverse drug effects.

Fever: Mean temperature of 98.4° F has an upper limit of 99° F of the normal body temperature, with one degree rise in the evening as a diurnal variation as again expected to be within normal range. Any pyrexia of more than 101° F or higher in the ICU has to be investigated as per guidelines of Society of Critical Care Medicine.5 Pattern of fever and its relation to pulse has been used as a significant diagnostic value6. Fevers higher than 1 06°F are of non-infectious origins. Certain pattern might give an etiological clue. Fever between 102°-106°F can be of both infectious & non infectious origin. Drug fever or gram negative infections give continuous pattern to fever. Fever in first 2-3 days in ICU mostly point towards non infectious cause and fever in patient on anti-microbials for over 2 weeks point towards drug resistant candida or fungi as causative organisms. Non infectious & infectious causes of cardio vascular & respiratory tract involvements are given in table 1.

Cardiopulmonary aetiology of fever in ICU - how to diagnose & treat
A systematic approach is always rewarding7. The attending physician must ask for basic queries; for example;

  1. Is there any history of chronic condition that predisposes to precipitation of bacterial infection, such as corticosteroid therapy, uncontrolled diabetes, chronic obstructive pulmonary disease, HIV disease etc. Non resolving pneumonia may be confused with graft versus post-disease and should figure recurrence of original clinical impression8.
  2. Has the patient been admitted with an acute condition that is self explanatory for aetiology of fever such as myocarditis, pulmonary embolism, ARDS, atelectasis, aspiration pneumonia?
  3. Any invasive procedure, if, has been carried out for diagnostic or therapeutic purposes, that might have lead to the entry of ICU organisms that could result in pyrexia e.g. bronchoscopy9, venous catheterization, tracheal intubation or tissue biopsy.
    1. If temperature is more than 106°F, consider drug fever, if any newer drug has recently been added.
    2. If temperature is <102°F, consider phlebitis, deep vein thrombosis, pulmonary embolism, atelectasis, or myocardial infarction.
    3. Temperature between 102-106°F, consider catheter related fever, drug fever, sinusitis in ICU, ventilator associated pneumonia, invasive tissue biopsy site infection etc.
  4. Physician must correlate the specific organ involvement from localizing signs present if any.

Diagnosis and treatment: Localizing signs often help in contributing to conclusive diagnosis. Difficult arises only when localizing signs are difficult to locate and such a challenging situation is often tackled with an empirical antimicrobial therapy guided by probable site of infection. This has to be strictly reviewed both clinically as well as lab wise after 48 hours if pyrexia has settled or not. Certain guidelines have to be followed;

  1. Empirical antimicrobial should be selected for suspected organism, target specific & has to be initiated with full dose, after taking samples for routine & culture investigations.
  2. In view of growing threat of ESBL's, the choice of antibiotic must be done after considering the antibiotic resistance pattern10.
  3. The accuracy and quality of testing must be ensured in the hospital setting and regularly reviewed, so that the authenticity of reports help intensive care specialist to rationally utilize the reports and make suitable changes in the initial therapy started on the basis of clinical experience.11
  4. Attending specialist must consider the pharmacologic activity (MIC valve) & pharmacokinetic property (tissue distribution, metabolism & excretion of drug) before selecting any anti-microbial drug.
  5. Protocol of withdrawing & replacing antimicrobial agent must be followed, to avoid emergence of drug resistant micro-organisms12.
  6. Treating Pseudomonas aeruginosa must utilize combination therapy, keeping in view multi-drug resistant nature of the organism.
  7. Over duration of use of anti-microbials must be checked to save money, adverse drug effects and emergence of drug resistance and other infections. Drug monitoring includes drug dose, duration, interaction, serum levels and adverse effects, in addition to clinical response and systemic response and functioning.
  8. Patient must be shifted to oral routine as soon as clinical stability is achieved.

A patient with infectious fever can be suspected of fungal infections, if becomes febrile despite on being broad spectrum anti-biotics. Consider for fungal blood culture and stop antibiotics therapy. Systemic antifungal therapy is indicated.

In an immunocompromised patient, with diabetes, neutropenia, corticosteroids therapy or HIV disease, disseminated candidiasis in suspected and may require systemic amphotericin B or voriconzole. In an immune-compromised patient the susceptibility to infections is higher and signs are often not typical. Pulmonary opportunistic infections demand urgent routine investigations, chest x-ray, bronchoscopy and BAL and CT guided percutaneous biopsy especially in cases of localized non peripheral lung lesions13. Lung ultrasound rules out quickly the pulmonary oedema, consolidation, atelectasis and pleural effusion14.

Rapid microbiological diagnostics and prompt institution of antimicrobial therapy is always rewarding. Newer tests such as Genexpert and Bectec culture for MTB, galactomannan assay for aspergillus and 1,3 p-D-glucan for pneumocystitis jirobecii help in timely diagnosis of pulmonary opportunistic infections15.

I.V. catheter septicemia is suspected if inflammation or purulence is seen at insertion site. Semi quantative culture of catheter tip and blood cultures both for bacterial and fungal growth are sent. Line is removed, antimicrobials are considered for persistent bacteremia, high risk patients need vancomycin for MRSA, cloxacillin for sensitive staphylococci and a cover for gram negative organisms and even candida.

In Indian set up, gram negative pathogens pose a great challenge in patients suffering from chronic lung disease with acute exacerbation and those with ventilatory support16. In ventilator associated pneumonia, history of purulent secretions, bronchial breathing on X-ray, with and new or progressive chest infiltrates worsening of Pa 02/Fi 02 and systemic inflammatory response, urgently require gram stain and culture of tracheal secretions, BAL fluid analysis17 and qualitative culture of PCP, CMV & AFB. Predisposing factors include old age, coexisting fatal diseases, intubation and H2 blocker therapy18. Piperacillin tazobactam or carbapenem broad spectrum antibiotic should immediately be started, modified according to culture reports and weaning of the patient should be urgently considered as soon as patient's condition improve. One must consider non infectious causes of fever such as congestive heart failure, ARDS and atelectasis in the differential diagnosis.

In a patient suspected of infective endocarditis, fever with heart murmur, an unexpected heart failure19 embolic phenomenon must arouse suspicion of infection and blood cultures should be sent urgently and transthoracic echocardiography should be requested for. Antimicrobials covering gram negative and staphylococcal organisms should be started.

Patients with pyrexia should be given antipyretic measures only when temperature is more than 1 06°F, patients with poor cardio-pulmonary reserves20 and incase of pregnancy, since hyperpyrexia can worsen the outcome underlying or associated disorder.

Paracetamol is preferred drug; except in cases of fulminant hepatic failure; physical cooling induces shivering that further increases cardiac output and oxygen demand. Fever is a coordinated neuroendocrine, autonomic and behavioral acute phase, adaptive, response to an immune stimulus or tissue injury21. Fever is a host response to challenge with bacterial affection; the synthesis & release of pyrogenic cytokines trigger in turn the release of PGE2, resulting in fever. But it must be kept in mind that fever itself, acts as a thermal ceiling to protect against the effects of high temperature of 106°F that is partly mediated by endogenous cryogens22. At the same time, fever enhances immune functions, antibody production, T-Cell activation, cytokines production and functions of neutrophils and macrophages6. But the deleterious effects of hyperthermia such as increased cardiac output, increased BMR, increased oxygen consumption may be difficult to tolerate by those with poor cardio respiratory reserve23.

Fever has diagnostic value as well as fever creates a state of emergency both for patient’s attendants and attending physician in an ICU. A unified approach would reveal that fever is a blessing as well as curse. Instead of creating a chaos, starting with basics, following the guidelines, pyrexia can be diagnosed in most of the cases of cardiorespiratory aetiology and can be managed in the ICU. No hurry in bringing down temperature with anti-pyretics, or using cooling blankets in routine should be attempted. Physical cooling induces by shivering, thus further increases oxygen demand, thus causing more of patient discomfort24. Higher mortality has been observed in patients of septic shock, who were hypothermic than those who were febrile25. And absence of fever in sepsis results in greater fatality, thus giving a wonderful clue that fever might have a protective function. Fever should be considered as a marker of some underlying problem that needs to be redressed. No need to hyper-react to hyperpyrexia; treat fever more as a friend than as a foe. Appropriate diagnosis and suitably dealing with the underlying cause is always rewarding, since half of the patients with cardiopulmonary problems in ICU have pyrexia of non infectious origin26. In case of infectious aetiology, identification of source of infection as well as causative organism and choice of antimicrobial must be made considering the factors such as site of infection, predisposing factors, pathogen variety, and pattern in that hospital setting and whether to use single antibiotic or in combination. Recent care of post partum said to be nosocomial infection which kept the patient in ICU on ventilator life support along with use of fourth generation antimicrobials and responding to some old drug (though with more of ADRS) disturbed all those involved in patient care and also lead to the inference of naming it community acquired resistant possibly exhibiting the overuse antibiotics in a sub-therapeutic dose and for a very short period (one or two doses / or for one/two days) in outdoor practice. This adds a new dimension to issue an advisory to strictly control the use of drugs, especially the use of antimicrobials only by qualified doctors in the hospital OPD / clinical practice with an additional advice to each patient to neither to reduce the drug dose, nor to cut short the recommended duration, particularly of antimicrobials.

Prevention: Fever as sequalae to infections of cardiopulmonary origin demands a strong motivation for promotion of strict infection control programmes in Indian hospitals27, similar to hospitals abroad where it is mandatory to seek accreditation. This will help those seeking medicine insurance where reimbursement for diagnosis related group of diseases such as pneumonia will be entertained and no payments shall be made for nosocomial infections.

A core committee of microbiologist, physician and surgeon has to target at three levels28. A good data of hospital organisms, anti-microbial resistance pattern and the changing trend of hospital flora should be continuously monitored29. Secondly, specific surveillance30 at infections should be carried out for ICU related infections and ventilator pneumonia, post cardiac surgery wound infections, antibiotic resistant bacteria and vascular access related infections. Spot surveillance should be carried, which is quicker & cheaper. Strict implementation of order to examine the patient after soap and water scrub hand wash or using alcohol rub solution31. This third level of mandatory hand washing preventive action32 is the single most important infection check practice33 because not only tap water in India has Ecoli or legionella, at times improperly diluted disinfectant solutions can harbor pseudomonas organism. Cardiopulmonary infections in ICU have increased by increased use of invasive devices and the cost is more than what government spends on total health care of the community. Even with an active infection control program, any hospital can be expected to record a 5-10% incidence of hospital acquired infections because of today's aggressive approach to cardio-respiratory sick patients in ICU.

Fever can well be prevented by strict isolation of a patient in a negative air pressure room, strict respiratory preventions for attending health workers and quarantine for any contact health care worker running high temperature.34 That level of health care discipline, has yet to be achieved in India.

To cut down both economic burden as well as infection risk in ICU, guidelines have been set by Cardiology Societies to reuse cardiac catheters after through cleansing and sterilization, only to reuse for limited three occasions. The never ending efforts to check fever of cardiopulmonary origin in ICU shall see the core team of microbiologist, physicians and intensive care specialist, struggling hard in the coming years to face more and more non infectious and infectious aetiologies, especially with the increasing population with immunocompromise and utilization of more and more invasive techniques.

  1. Mishra AP; ICU infection, IN: SR Joshi; ed; Medicine Update, API 2014:24;144-70.
  2. Pradhan NP; etal; Nosocomial infections in the medical ICU. JAPI 2014;6218-21.
  3. Soni NK, Ohri K; Nosocomial infections in the ICU; IN, SR Joshi; ed; Med Update API; 2014;24:627-43.
  4. Maitra; Fever of unknown origin; IN; SB Gupta; ed; Pu Med; API; 2014;28:570-82.
  5. O' Grady NP, Barie PS, Bartlett JG, et al. Practice guidelines for evaluating new fever in critically ill adult patients. Task Force of the Society of Critical Care Medicine and the Infectious Disease Society of America. Clin Infect Dis 1998; 26: 1042-59.
  6. Malacarne P; etal,Epidemology of nosocomial infection in 125 Italian Intensive care units: Minerva Anaesthesiol: 2010;67: 13-23.
  7. Rizoli SB, Marhall JC, Saturday Night Fever: finding and controlling the source of sepsis in critical illness. Clin Infect Dis 2002;2: 137-44.
  8. Sorabjee J, Mishra V; Non resolving Pneumonia; IN: SB Gupta, ed; PG Medicine API 2014;28:556-69.
  9. Bhatia R S; Sibia SS; Therapeutic use of FOB; Lung India; 1994; 12:138-39.
  10. AK O, Batirel; etal; Nosocomial infections and risk factors in the intensive care unit of a teaching and research hospital; A prospective cohort study; Med Sci Monit; 2011;17:PH29-34