According to the well-known definition, fever is a rise in body temperature above 38 degrees Celsius. In the postoperative setting, an accurate differential diagnosis must be performed in order to find the precise etiology of the fever. This brief literature review starts with a classification that groups fever into five categories, according to the time elapsed from the surgical intervention. Another important reminder is the list of five words – with mnemotechnic value – regarding the main causes of postoperative fever: “wind” (pneumonia, atelectasis), “water” (urinary tract infections), “wound” (surgical wound infection or inflammation), “wonder drugs” (malignant hyperthermia), “walk” (phlebitis). In the second part of this literature review, special considerations are described, relating fever to the main types of interventions from different surgical specialties. The article ends with a table that helps with practical tips on how to perform a general check-up when we have a feverish patient in our care.
immediate postoperative fever, early postoperative fever, late postoperative fever, delayed postoperative fever, subacute postoperative fever
Conform definiţiei bine cunoscute, febra este o creştere a temperaturii corpului peste 38 de grade Celsius. Postoperatoriu, trebuie efectuat un diagnostic diferenţial precis pentru a găsi etiologia exactă a febrei. Acest scurt review al literaturii începe cu o clasificare ce grupează febra în cinci categorii, în raport cu timpul scurs de la intervenţia chirurgicală. Un alt element important reamintit este lista de cinci cuvinte – cu valoare mnemotehnică – în ceea ce priveşte principalele cauze ale febrei postoperatorii: „vânt” (pneumonie, atelectazie), „apă” (infecţii ale tractului urinar), „rană” (infecţie sau inflamaţie a plăgii chirurgicale), „medicamente-minune” (hipertermie malignă), „mers” (flebită). În cea de-a doua parte a acestui review, sunt amintite consideraţii speciale, asociind febra cu principalele tipuri de intervenţii din diferite specialităţi chirurgicale. Articolul se încheie cu un tabel care oferă sfaturi practice legate de examenul general atunci când avem în îngrijire un pacient febril.
Being defined as a rise in body temperature above 38 degrees Celsius, the incidence of postoperative fever ranges between 14% and 91%, while infection as a direct cause of pyrexia is identified in less than 50% of the patients.
A classification of fever according to the time elapsed from the surgical intervention describes five groups:
1. Immediate postoperative fever, debuting on days 1-2 after surgery.
2. Early postoperative fever, debuting on days 3-5.
3. Late postoperative fever, appearing in days 5-8.
4. Subacute postoperative fever, debuting in the first four weeks.
5. Delayed/late postoperative fever, debuting after more than one month.
In trying to establish the etiology of postoperative fever, a focus is put on the diagnosis of “the five Ws”: wind, water, wound, walk, “wonder drugs”. Each is a mnemotechnic word symbolizing the triggering agent; for instance, “wind” can mean atelectasis or pneumonia, “water” stands for urinary tract infections, “walk” stands for deep venous thrombosis or phlebitis, “wound” refers to the surgical wound, and “wonder drugs” can mean any medication the patient might be on and which could cause fever.
If we are to refer to the “wind” category of factors, it is a well-known fact that anesthetics increase secretions, with the latter becoming viscous. In the postoperative setting, the cough reflex decreases, and the same does the ciliary activity, mucous plugs are thus formed and, consequently, they might cause airway obstruction. An increased risk of respiratory complications was described in patients with chronic obstructive pulmonary disease (COPD), chronic bronchitis and in smokers. Prevention can be done by avoiding smoking, performing physiotherapy, spirometry, and implementing protocols for early postoperative mobilization.
“Water” stands for urinary tract infections. These represent the most common nosocomial infections, with 75% of patients having a previous urinary tract maneuver or an intent (for instance, the intention of bladder catheterization or a urinary catheter “in place”). Elevated temperature, up to 39 or 40 degrees Celsius, is often accompanied by the clinical picture of chills. The judicious use of a urinary catheter (only if it is absolutely necessary), and the employment of an aseptic technique further ensure a decrease in the incidence of urinary tract infections.
“Walk” refers mainly to phlebitis. Sepsis can start from a peripheral intravenous/central venous catheter and, subsequently, cause deep venous thrombosis and lung embolism. Also, suppurative thrombophlebitis was also described in correlation with postoperative fever.
Surgical “wound” infections (after 5-8 postoperative days) can present as cellulitis or abscesses, with signs of erythema. They require an adequate drainage treatment and the administration of antibiotics.
Surgical infections can be: 1) superficial infections of the incision (which affect the skin and the subcutaneous tissue); 2) deep infections of the incision (affecting deep soft tissues, fascia and muscles); 3) infections of different organs and anatomical spaces (for instance, mediastinitis or endocarditis). The germs most frequently encountered at the level of an infection of a surgical site are Staphylococcus aureus, E. coli, Enterococcus spp. and P. aeruginosa. The main risk factors associated with surgical wound infection are considered: the degree of contamination of the intervention, the duration of the intervention, and tissue manipulation.
“Wonder drugs”. The condition generally known as malignant hyperpyrexia, a rare cause of postoperative death, as it was also mentioned by Prescott et al.(1), can manifest as very high fever, status epilepticus, and terminal acute renal failure with myoglobinuria, debuting after surgery. This is a genetically inherited disorder which can be triggered by certain anesthetic agents. The triggering substances produce excessive calcium release from the sarcoplasmic reticulum and may encourage extracellular calcium entry into the myoplasm, resulting in skeletal muscle rigidity, glycogenolysis and increased cellular metabolism, producing heat and excess lactate. Acidosis, hypercapnia, tachycardia, hyperthermia, muscle rigidity, compartment syndrome, rhabdomyolysis with subsequent increase in serum creatine kinase (CK) concentration, hyperkalemia with a risk of cardiac arrhythmia or even cardiac arrest, and myoglobinuria with a risk of renal failure are all symptoms experienced by those who are affected.
The first signs of malignant hyperthermia (tachycardia and tachypnea) appear almost always in the operating room; however, the signs can also appear in the early postoperative period. There is growing evidence that some people with malignant hyperthermia syndrome will acquire malignant hyperthermia as a result of exercise or exposure to hot surroundings. The mortality is exceedingly high without good and quick treatment with dantrolene sodium.
The fever that occurs between 7 and 30 days after surgery has been associated with: surgical bed infections, also with infections having as a source a central venous catheter, with urinary tract infections, pneumonia, sinusitis, diarrhea associated with the use of antibiotics (C. difficile), drug fever (beta-lactam antibiotics, sulfonamides, anti-H2, heparin, procainamide, phenytoin) and postoperative deep venous thrombosis/pulmonary thromboembolism, the latter two complications being associated with a low degree of patient mobilization.
The fever that occurs more than 30 days postoperatively is in correlation with posttransfusion viral infections, such as CMV, HIV, HBV or HCV, or with parasitic infections, such as toxoplasmosis or malaria. Other etiologic factors were infectious endocarditis and surgical wound infection.
One of the laboratory parameters that can help in the clinical management is C-reactive protein – with increased values in the postoperative period (normal values: below 3 mg/L). For instance, in the case of colonic operations, after three days postoperatively, an increase in C-reactive protein usually indicates the presence of an intraabdominal infection. Another laboratory parameter that can represent an aid to enhance clinical judgement in a patient with fever is procalcitonin (normal values: below 0.5 ng/ml), harvested on days 1 (PCT1) and 2 (PCT2) after the rehabilitation of an intraabdominal septic outbreak: PCT1/PCT2>1.03 implies success and a ratio below 1.03 might suggest that the eradication of the infectious focus was not effective enough.
Examples of particular situations in which fever and its many facets were studied:
A. Breast surgery
As shown in a research performed by Yan et al.(2), postoperative fever has been linked to relapse in individuals with node negative breast cancer. The phenomenon suggests that changes in the host environment caused by fever may hasten the formation of micrometastatic foci. For the evaluation of the relapse risk, nevertheless, combining tumor and host-related parameters may be more exact.
B. Urologic surgery
Research was performed to compare the risk of fever after percutaneous nephrolithotomy (PNL) from different types of lithotrites(3). No fragmentation, ultrasonic, laser, pneumatic, and combined ultrasonic/pneumatic lithotrites were all tested. The risk of fever was correlated, using multivariate logistic regression, with: diabetes, steroid usage, a history of positive urine culture, the presence of staghorn calculi or a preoperative nephrostomy, stone burden and lithotrite. In this trial, the risk of post-PNL fever was not found to be statistically different among the various lithotrites used.
The objective of a study described by Wu et al.(4) was to assess the clinical effectiveness of mini-tract percutaneous nephrolithotomy (MPCNL) versus standard-tract percutaneous nephrolithotomy (SPCNL) to see if MPCNL is related with both increased RPP (renal pelvic pressure) and postoperative fever. A total of 228 kidney stone patients were randomly assigned to the MPCNL (n=114) and SPCNL (n=114) groups. RPP and the time it took for RPP to reach 30 mmHg, as determined by logistic regression, had a significant impact on the incidence of postoperative fever. When compared to SPCNL, MPCNL was associated with higher RPP and with a higher risk of postoperative fever.
For large (2 cm) renal calculi, percutaneous nephrolithotomy (PCNL) remains the standard technique; nonetheless, up to a quarter of PCNL patients develop postoperative problems. The purpose of the study conducted by Amri et al.(5) was to look at the factors that could affect bleeding and fever after percutaneous nephrolithotomy. Diabetes was the only independent predictor of postoperative bleeding, according to the multivariate stepwise regression analysis. Postoperative fever was predicted by: staghorn lithiasis, prone position, and operation time above 95 minutes. The conclusion of the aforementioned study was that, after percutaneous nephrolithotomy, prone position was found to be substantially related with fever.
To get an insight into PCNL management, it was described as highly important by Yu et al.(6) to assess the risk factors for fever in patients receiving PCNL. A total of 276 patients undergoing PCNL were included in the study, with a 19.39% incidence of postoperative fever. There were no significant differences in gender, BMI, alcohol use, smoking, hypertension, hyperlipidemia, intraoperative blood infusion or length of hospital stay between fever patients and patients without fever. There were significant differences in age, diabetes, stone size and surgery time between fever patients and patients without fever. Fever was associated with age above 60 years old, diabetes, stone size of 2 cm, and surgery duration of 100 minutes in PCNL patients. The top three pathogenic bacteria in urine culture were Escherichia coli, Staphylococcus aureus and Candida albicans. One of the most prevalent side effects of PCNL is fever. Patients with high-risk variables should receive full attention and follow appropriate risk-based preventive measures.
The goal of an analysis made by Hu et al.(7) was to describe the distinct characteristics of absorption fever in patients who have a hematoma following percutaneous renal biopsy (PRB) and to distinguish it from subsequent hematoma infection. Fever is prevalent in people who have had a hematoma due to a kidney biopsy, and it is usually noninfectious. Patients with post-biopsy fever must be evaluated in order to rule out any obvious infection sources. If no focus is found, empiric antibiotic therapy should not be started, and prophylactic antibiotics should not be continued for a longer period. Without special medicinal interventions, absorption fevers will settle over time.
Li et al.(8) examined the characteristics of the patients, looking at the retrograde intrarenal surgery (RIRS) in order to find out what factors predict postoperative fever and systemic inflammatory response syndrome (SIRS). Finally, large stone burden, extended surgical duration, positive stone culture, high preoperative CRP and diabetes mellitus, all increased the risk of fever or SIRS after RIRS for kidney stone.
A history of obstructive pyelonephritis prior to ureteroscopic lithotripsy (URSL) has been linked to a higher risk of fever urinary tract infection (f-UTI)(9). In patients with obstructive pyelonephritis, f-UTI following URSL might be avoided by using a ureteral stent with a placement term of 21 days or less and an operation time of 75 minutes or less.
C. Orthopedic surgery
In a study(10) assessing the epidemiology of postoperative fever in adult orthopedic patients and its association with infection, after the statistical data were analyzed, the conclusion was that fever, even up to the seventh postoperative day, was not substantially helpful in distinguishing infection from general inflammation in clean orthopedic surgery.
Sivakumar et al.(11) conducted a study to see if blood cultures could be used to diagnose early postoperative fever in hip fracture patients who had no other signs of infection. Among the results, the authors found that the risk of bacteremia in patients with postoperative fever, but with no other symptoms of infection, is low. Therefore, routine procurement of blood cultures in such patients is ineffective and of limited utility.
Karam et al.(12) implemented a multimodal pain management regimen for total joint arthroplasty (TJA), which used acetaminophen, pregabalin and celecoxib or Toradol® (looking also at the antipyretic features of this medication), and speculated that this protocol could influence the incidence of postoperative pyrexia. The conclusion of the implementation of the new treatment regimen was that the multimodal analgesia strategy has the hidden benefit of lowering the temperature response to the surgical insult of TJA, in addition to fewer side effects and better pain control. Furthermore, the lower rate of postoperative fever prevents unneeded anxiety for the patient and the treating team, as well as lowering the use of healthcare resources caused by postoperative fever.
As the majority of studies on postoperative fever (POF; 38°C) after total knee arthroplasty (TKA) have only looked at the first few days after surgery (PODs), another category of studies (among those, the one conducted by Ishii et al.(13)) were designed. The premise was to assume that a four-week follow-up period will reveal differences in POF and fever-related variables between a normal inflammatory response and an early acute infection-related response. At 2-4 weeks postoperatively, the presence of POF, as well as increased C-reactive protein and local suggestive symptoms may indicate the necessity for a positive fever workup to detect an early acute periprosthetic infection.
Several studies have reported diagnostic values for the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) in a variety of disorders, including oncological, inflammatory and viral diseases. These laboratory measures’ predictive usefulness for early periprosthetic joint infections (PJIs) have not yet been described. The target of the research of Zhao et al.(14) was to investigate the postoperative NLR, PLR and LMR predictive values for the diagnosis of PJIs. Due to their persistent high values following arthroplasty, ESR (erythrocyte sedimentation rate) and CRP appear to be insensitive for the detection of early PJI. The ability of the postoperative NLR at the suspected time to predict early PJI still remains to be studied.
D. Gynecologic surgery
Blood cultures, urine cultures, and chest X-ray evaluations of postoperative fever were performed in women who had major gynecologic surgery(15). Early-onset fever and advanced age indicated positive urine cultures, but late-onset fever and advanced age predicted pneumonia. Moreover, patients with pneumonia were symptomatic in 80% of cases. There were no infections or pathologic processes found in 92% of the patients with postoperative fever. The conclusion of the research was that, although blood cultures, urine cultures and chest X-rays are often used to diagnose postoperative fever, positive results are rare.
The purpose of the research conducted by Çinar et al.(16) was to see if there was a link between obesity and complications and the clinical characteristics in 273 women who had abdominal myomectomy over the study period. The clinical factors were assessed based on demographic, preoperative and postoperative data. Age, gravidity, diameter of fibroid (DOF), postoperative hemoglobin, length of hospital stay and complications represented all statistically significant differences between the obese and non-obese groups. Obese patients had a higher DOF and more sequelae, including bleeding, postoperative fever, wound infection and ileus.
In a study performed by Lin et al.(17), examining the possible prospective correlation between bacterial vaginosis in infection after major gynecologic surgery, it was found that the link between bacterial vaginosis and postoperative febrile morbidity is unsure. More so, due to other variables, it may be prudent, nevertheless, for the surgeon to identify patients with bacterial vaginosis and treat them prior to surgery.
E. Vascular surgery
A comparative study(18) was developed and applied in order to evaluate endovascular versus open surgery of abdominal aortic aneurysms. Parameters such as postoperative fever, bowel ischemia and cytokine response were measured and compared. The fact that TPEG (transfemorally placed endoluminal grafting) patients had less evident perioperative intestinal ischemia is a benefit of the procedure. Postoperative fever, as well as the IL-6 and TNF responses were not linked to splanchnic ischemia.
In theory, it is known that a common symptom of acute aortic dissection is fever. The onset and persistence of fever in individuals with aortic dissection after a percutaneous endovascular stent-graft were studied by Yu et al.(19) The data of 64 patients with type B acute aortic dissection who underwent percutaneous endovascular stent-graft were gathered and evaluated in this retrospective analysis. After the stent-graft, 55 patients (85.9%) developed fever. The majority of patients’ fevers began during the first two days following the interventional procedure (92.7%), and most patients’ fevers lasted no longer than seven days after stent placement. The appearance of fever before stent implantation was linked to the onset of fever after stent implantation, but not to the length of the fever.
The initial Body Mass Index (BMI) is regarded as a significant risk factor in cardiovascular surgery. In patients who underwent off-pump coronary artery bypass grafting (OPCAB), a piece of research presented by Sabzi and Faraji(20) established a historical cohort study to assess perioperative complications associated to BMI (OPCAB). Among the conclusions of the study, we mention that reintubation, increased intubation length and ICU stay were all strongly associated with having a low BMI (which is linked to starvation and respiratory muscle weakness). On the other hand, postoperative atelectasis and fever were also linked to the obese group.
With an incidence rate of 0.3-1.2% per patient-year, prosthetic valve endocarditis (PVE) is a rare but serious complication of valve replacement surgery, as stated by Liu et al.(21), PVE is now caused by staphylococci, which are the most common causal bacterium. There have been reported and also confirmed cases of late PVE caused by Mycobacterium tuberculosis in a mechanical aortic valve.
Regarding the postoperative fever syndrome in association with COVID-19 infection in cardiovascular surgery, a study performed by Cerillo et al.(22) showed that a group of 18 patients who contracted the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection after cardiac surgery had a surprisingly benign course. During the initial lockdown period of the COVID-19 pandemic, all patients were operated on urgent or emergency basis (acute aortic syndrome – 3; refractory heart failure –12; endocarditis – 3). The average age of the patients was 70 years old, and 12 of them were men. The patients were treated according to the most recent recommendations after being diagnosed with COVID-19. Eleven patients who were asymptomatic were sent home or to a COVID-19 hotel and were closely monitored. The patients who had fever, dyspnea or a significant increase in polymerase chain reaction levels were admitted to the hospital, and antivirals, antibiotics and hydroxychloroquine were administered.
Postoperative fever (POF), which is usually associated with posterior cranial fossa (PCF) surgery, is a possible cerebral infection indicative, as shown by Wang et al.(23) The effectiveness of current preventative techniques for balancing the risk of brain infection versus antibiotic misuse is questionable. Despite the fact that POF is a common symptom following PCF tumor removal, a confirmed cerebral infection is uncommon. When routine preventative precautions have been carefully followed, a high body temperature and considerable aberrant cerebrospinal fluid (CSF) profiles may not be a precise and adequate indicator of intracranial infection to warrant upgrading antibiotic therapy.
In the context of spinal lumbar surgery, postoperative meningitis is a rare complication. After spinal surgery, patients with the clinical triad of fever, neck stiffness and consciousness disturbance should have a high index of suspicion for meningitis, as described by Lin et al.(24) The most important predictor is an intraoperative accidental durotomy. A positive outcome can be achieved with early diagnosis and proper antibiotic treatment.
G. General surgery and surgical oncology
1. Esophageal surgery
Looking into the outcome of ICU patients with esophageal cancer, a new oral hygiene care routine(25) was found to lower the postoperative oral bacteria count and the number of days with increased fever in the postoperative period (after esophageal surgery). A new oral hygiene regimen with benzethonium chloride, interdental brushes and hydrogen peroxide significantly reduced the number of oral bacteria and the days with increased temperature in patients with esophageal cancer when compared to conventional oral hygiene.
2. Gastric surgery
Preoperative pulmonary function testing was used by Feng et al.(26) to screen surgical candidates and forecast the likelihood of problems after surgery. A total of 1210 gastric cancer patients were enrolled in this trial (949 males and 261 females). The percentage of expected values for forced vital capacity (FVC) and maximal voluntary ventilation (MVV) were calculated. Low FVC is associated with a worse prognosis and with a higher incidence of postoperative fever in gastric cancer patients, according to these findings.
The occurrence of in-hospital postoperative complications in gastric surgery can be significantly linked to BMI index(27), as described by Li et al.(28), and was an independent predictor of worse five-year overall survival rate after the radical resection of gastric cancer.
3. Pancreatic surgery
Major surgery is associated with significant morbidity and death, as shown in experimental(29) and clinical research, with 30% of patients experiencing early postoperative adverse events (POAE) during the first 30 days. TruCulture® whole blood technique(30) was studied in order to examine the preoperative immune function in a group of patients undergoing pancreaticoduodenectomy (PD). The research assumed that patients who developed inflammatory POAE – defined as leukocytosis, fever or a high (above median) area under the curve (AUC) C-reactive protein (CRP) in the first postoperative week – would have a compromised preoperative immune function. In comparison to patients without inflammatory POAE, patients with inflammatory POAE had lower preoperative stimulated values of IL-12p40, IFN, IL-6, and IL-10, as well as a higher TNF response.
4. Liver and biliary surgery
A prospective observational trial, as described by Kang et al.(31), looked into the usefulness of procalcitonin (PCT) in identifying bacterial infection and guiding antibiotic therapy for patients with fever, following transarterial chemoembolization (TACE) and/or radiofrequency ablation for hepatocellular carcinoma (HCC-RFA). The patients with bacterial infections had a substantially higher PCT on day 0 of fever than those without infection (p=0.035). As also mentioned in the general section of the article, PCT could be a biomarker for identifying infection and guiding antibiotic treatment in individuals with fever following TACE and/or RFA.
H. Marrow harvesting
The detailed experience of extracting marrow for allogeneic transplantation on 1270 occasions from 1160 normal donors at a single facility was further described, together with a study of – largely – all donor problems. Ten percent of the donations were linked by Buckner et al.(32) to an unidentified temporary postoperative fever.
In the end, we conclude with a practical take-home message from the present article concerning fever and its etiology: how to perform a routine infection screening (Figure 4), as recommended by various surgery manuals(33-37).
Conflict of interests: The authors declare no conflict of interests.
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