Cardiac Tamponade in Patients Treated with Direct Oral Anticoagulants.

BACKGROUND: Direct oral anticoagulants (DOACs) are the treatment of choice for patients with non-valvular atrial fibrillation; however, bleeding risk remains significant. We reported a single-center experience with 11 patients who presented with hemorrhagic cardiac tamponade while treated with DOACs. OBJECTIVES: To evaluate the characteristics and clinical outcomes of patients under DOACs with cardiac tamponade. METHODS: We retrospectively identified 11 patients treated with DOACs admitted with pericardial tamponade in our cardiology unit during 2018-2021. RESULTS: The mean age was 84 ± 4 years; 7 males. Atrial fibrillation was the indication for anticoagulation in all cases. DOACs included apixaban (8 patients), dabigatran (2 patients), and rivaroxaban (1 patient). Urgent pericardiocentesis via a subxiphoid approach under echocardiography guidance was successfully performed in 10 patients. One patient was treated with urgent surgical drainage with a pericardial window. Reversal of anticoagulation using prothrombin complex concentrate and idarucizumab was given before the procedure to 6 patients treated with apixaban and one patient treated with dabigatran. One patient, initially treated with urgent pericardiocentesis, underwent pericardial window surgery due to re-accumulation of blood in the pericardium. The pericardial fluid analysis demonstrated hemopericardium. Cytology tests were negative for malignant cells in all cases. Discharge diagnoses regarding the cause of hemopericardium included pericarditis (3 patients) and idiopathic (8 patients). Medical therapy included non-steroidal anti-inflammatory drugs (1 patient), colchicine (3 patients), and steroids (3 patients). No patient died during hospitalization. CONCLUSIONS: Hemorrhagic cardiac tamponade is a rare complication of DOACs. We found good short-term prognosis following pericardiocentesis.

Systemic Thrombolysis Therapy is Associated With Improved Outcomes Among Patients With Acute Pulmonary Embolism and Respiratory Failure.

BACKGROUND: Thrombolytic therapy is widely accepted for massive pulmonary embolism (PE) due to the high mortality risk associated with standard anticoagulation alone. Its role in submassive PE, however, has remained controversial. We aimed to evaluate whether the selective use of systemic thrombolytic therapy with intravenous tissue plasminogen activator (IV-tPA) improves the survival of patients with submassive PE at increased risk for clinical deterioration. METHODS: A total of 184 consecutive patients diagnosed with acute PE by chest thoracic angiography (CTA) were included in a retrospective study. Pulmonary artery obstruction and right/left ventricular dysfunction were evaluated by CTA and echocardiography. Medical history and simplified PE Severity Index (sPESI) were assessed at diagnosis. Hemodynamic and respiratory status were recorded at diagnosis, admission to pulmonary unit and prior to thrombolytic therapy. Patient survival was assessed at 30 of 90 days from diagnosis by CTA. RESULTS: All low risk patients (36%) per sPESI survived. Among the 117 remaining patients, 31% received IV-tPA. Respiratory failure was associated with decreased age-adjusted survival (P = 0.005). Among patients with respiratory failure selected for IV-tPA, age-adjusted survival was improved significantly compared to others (P = 0.043). CONCLUSIONS: Thrombolytic therapy for hemodynamically stable PE patients with respiratory failure may improve survival. TRIAL REGISTRATION: MMC-0216-14.

The Effect of Admission Renal Function on the Treatment and Outcome of Patients with Acute Coronary Syndrome.

BACKGROUND: Chronic kidney disease is a frequent comorbidity among patients with acute coronary syndrome (ACS). We aimed to evaluate treatment characteristics in ACS patients according to their renal function and to assess the effect of differences in therapy on clinical outcomes. METHODS: Included were patients with ACS enrolled in the biennial Acute Coronary Syndrome Israeli Surveys (ACSIS) during 2000-2013. Excluded were patients with cardiogenic shock at presentation. The estimated glomerular filtration rate (eGFR) was calculated using the simplified Modification of Diet in Renal Disease (MDRD) formula. The distribution of the eGFRs was divided into 4 categories (<45, 45-59.9, 60-74.9, and ≥75 mL/min/1.73 m2). The primary endpoint was all-cause mortality at 1 year. RESULTS: A total of 13,194 patients with ACS were included. Patients with a reduced eGFR were less likely to be admitted to a coronary care unit and had lower rates of coronary angiograms and subsequent percutaneous coronary interventions. Furthermore, as the eGFR was lower, the patients were less frequently treated with aspirin, clopidogrel, ß-blockers, and ACE inhibitors/angiotensin receptor blockers. We demonstrated an inverse association between renal function and 1-year mortality, with the highest mortality rates observed in the group with the lowest eGFR (HR = 3.8, 95% CI 2.9-4.9, p < 0.0001). Differences in mortality remained significant following a multivariate analysis for all the baseline characteristics as well as for invasive and medical treatment (HR = 2.7, 95% CI 1.9-3.7, p < 0.0001). CONCLUSIONS: ACS patients with chronic kidney disease represent a high-risk group with an increased mortality risk. Despite this high risk, these patients are less frequently selected for an invasive treatment strategy and are less commonly treated with guideline-based medications. However, reduced renal function was associated with higher mortality regardless of the variations in therapy.

Admission plasma glucose levels within the normal to mildly impaired range and the outcome of patients with acute coronary syndrome.

BACKGROUND: Elevated admission plasma glucose levels >140 mg/dl are associated with adverse clinical outcomes in both diabetic and non-diabetic patients admitted with acute coronary syndrome (ACS). We aimed to evaluate the association between admission plasma glucose levels <140 mg/dl and the outcome of non-diabetic patients admitted with acute coronary syndrome. METHODS: The study population consisted of patients with acute coronary syndrome included in the Acute Coronary Syndrome Israeli Survey during 2000-2013. Diabetic patients were excluded. The primary endpoint was all-cause mortality at one year. RESULTS: The 452 0 patients had a mean age of 61.7±13.5 years and were stratified into four quartiles according to admission plasma glucose (60-94, 95-105, 106-119, 120-140 mg/dl). Patients with higher admission plasma glucose were older and included a higher percentage of smokers. In addition, the higher the glucose so also did they have a poorer risk factor profile including a higher body mass index, total and low-density lipoprotein cholesterol and triglyceride levels, and lower high-density lipoprotein cholesterol levels. During the first year 5.2% of patients died. A comparison of one-year mortality according to admission plasma glucose quartiles demonstrated a significant and progressive increase in mortality risk as admission plasma glucose rose (3.5%, 4.1%, 6.1%, 6.4%, respectively, p=0.001). However, this association lost its clinical significance following a multivariate analysis ( p=0.08). CONCLUSIONS: High admission plasma glucose levels within the normal to mildly impaired range are associated with increased one-year mortality in non-diabetic acute coronary syndrome patients. However, the higher glucose level is probably not the cause for the adverse outcome but rather a marker for high risk. Our findings support the definition of 140 mg/dl as the cutoff for clinically acceptable admission glucose levels in patients with acute coronary syndrome.

Impact of Point-of-Care Ultrasound Examination on Triage of Patients With Suspected Cardiac Disease.

Complementing the physical examination with a point-of-care ultrasound study (POCUS) can improve patient triage. We aimed to study the impact of POCUS on the diagnosis and management of outpatients and hospitalized patients with suspected cardiac disease. In this multicenter study, a pocket-sized device was used to perform POCUS when the diagnosis or patient management was unclear based on anamnesis, physical examination, and basic diagnostic testing. Eighteen physicians (cardiac fellows 49%, cardiologists 30%, and echocardiographers 21%) performed physical examinations extended by POCUS on 207 patients (inpatients 83% and outpatients 17%). POCUS findings resulted in a change in the primary diagnosis in 14% of patients. In patients whose diagnosis remained unchanged, POCUS results reinforced the initial diagnosis in 48% of the cases. In 39% of the patients, the diagnostic plan was altered, including referral (16%) or deferral (23%) to other diagnostic techniques. Alteration in medical treatment (drug discontinuation or initiation) occurred in 11% of the patients, and in 7% POCUS results influenced the decision whether to perform a therapeutic procedure. Hospitalization or discharge was determined after POCUS in 11% of the patients. In conclusion, during patient triage, extension of the physical examination by POCUS can cause physicians to alter their initial diagnosis, resulting in an immediate change of diagnostic and therapeutic procedures. Based on POCUS results, physicians altered the diagnostic plan either by avoiding or referring patients to other diagnostic procedures in almost half of the studied population.

Prevalence and Significance of Unrecognized Renal Dysfunction in Patients with Acute Coronary Syndrome.

BACKGROUND: Unrecognized renal insufficiency, defined as estimated glomerular filtration rate <60 mL/min/1.73 m(2) in the presence of normal serum creatinine, is common among patients with acute coronary syndrome. We aimed to determine the prevalence and clinical significance of unrecognized renal insufficiency in a large unselected population of patients with acute coronary syndrome. METHODS: The study population consisted of patients with acute coronary syndrome included in the Acute Coronary Syndrome Israeli biennial Surveys during 2000-2013. The estimated glomerular filtration rate was calculated using the simplified Modification of Diet in Renal Disease formula. Patients were stratified into 3 groups: 1) normal renal function (estimated glomerular filtration rates ≥60 mL/min/1/73 m(2)); 2) unrecognized renal insufficiency (estimated glomerular filtration rates <60 mL/min/1/73 m(2) with serum creatinine ≤1.2 mg/dL); and 3) recognized renal insufficiency (estimated glomerular filtration rates <60 mL/min/1/73 m(2) with serum creatinine ≥1.2 mg/dL). The primary endpoint was all-cause mortality at 1 year. RESULTS: Included in the study were 12,830 acute coronary syndrome patients. Unrecognized renal insufficiency was present in 2536 (19.8%). Patients with unrecognized renal insufficiency were older and more frequently females. All-cause mortality rates at 1 year were highest among patients with recognized renal insufficiency, followed by patients with unrecognized renal insufficiency, with the lowest mortality rates observed in patients with normal renal function (19.4%, 9.9%, and 3.3%, respectively, P <.0001). Despite their increased risk, patients with renal insufficiency were less frequently referred for coronary angiography and were less commonly treated with guideline-based cardiovascular medications. CONCLUSIONS: Acute coronary syndrome patients with unrecognized renal insufficiency should be considered as a high-risk population. The question of whether this group would benefit from a more aggressive therapeutic approach should still be evaluated.

Increased hypoxemia in patients with COPD and pulmonary hypertension undergoing bronchoscopy with biopsy.

BACKGROUND AND OBJECTIVE: Patients with pulmonary hypertension (PH) are considered to be at risk for complications associated with flexible bronchoscopy (FB), but data concerning the degree of PH are often lacking. We investigated whether COPD patients with PH who undergo bronchoscopy are at greater risk for complications. METHODS: This prospective study included 207 consecutive COPD patients undergoing FB. All underwent an echo-Doppler to evaluate pulmonary artery pressure on the day of the bronchoscopy procedure. Pulmonologists were blinded to the echocardiogram results. RESULTS: A total of 167 patients (80.7%) had normal pulmonary pressure. The remaining 40 patients (19.3%) had PH: 27 (13.0%) mild, eight (3.9%) moderate, and five (2.4%) severe. Noninvasive hemodynamic parameters between groups before and after FB were similar. Two patients with normal pulmonary pressure developed supraventricular tachycardia. None developed hemodynamically significant dysrhythmia. Bleeding episodes between groups in bronchoalveolar lavage (BAL) and transbronchial biopsy (TBB) did not differ. PH patients who underwent BAL and TBB had decreased O2 saturation during the procedure compared with the non-PH group (23.5% vs 6.9%, P=0.033). No deaths were attributable to FB. CONCLUSION: PH is common among COPD patients undergoing FB. PH patients undergoing BAL and TBB are at higher risk of decreased O2 saturation than those without PH. Further studies should assess the risk among COPD patients with moderate-to-severe PH.

Comparison of mortality in patients with coronary or peripheral artery disease following the first vascular intervention.

OBJECTIVES: Patients with peripheral artery disease (PAD) less frequently achieve secondary prevention goals compared with patients with coronary artery disease (CAD). We aimed to compare mortality rates in patients with PAD and CAD following first vascular intervention. PATIENTS AND METHODS: Patients 18 years of age or older without a history of cardiovascular disease, who underwent first coronary or lower limb vascular intervention between 2002 and 2010, were included in this study. The primary endpoint was all-cause mortality. RESULTS: Of the 9950 participants, 8242 (82.8%) underwent first coronary revascularization and 1708 (17.2%) received first peripheral vascular intervention. During a mean follow-up period of 5.6±2.3 years, 1283 (12.9%) participants died. Compared with CAD patients, patients with PAD had significantly worse long-term prognosis with an increased risk for all-cause mortality (hazard ratio=2.95, 95% confidence interval 2.6-3.3, P<0.0001). This association remained statistically significant following a multivariable analysis (hazard ratio=1.86, 95% confidence interval 1.6-2.1, P<0.0001). Furthermore, PAD patients were less frequently treated with cardioprotective medications including statins, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, aspirin, and clopidogrel (P<0.001). CONCLUSION: Patients with PAD have worse outcome compared with patients with CAD, even in the specific group of patients following first vascular intervention. These findings demand more effort to improve secondary prevention guidelines in all patients with cardiovascular diseases, but especially in PAD patients.

Lipid control in patients with coronary heart disease treated in primary care or cardiology clinics.

BACKGROUND: Guidelines recommend low-density lipoprotein-cholesterol (LDL-C) target of <70 mg/dL in patients with coronary disease. However, this goal is not achieved in many patients. OBJECTIVES: We compared LDL-C control in patients with coronary disease treated by a primary care physician or with the addition of a cardiologist. METHODS: Included were patients with coronary disease who had full lipid profile. Primary end points included the percentage of patients who achieved the LDL-C goals of <100 mg/dL and <70 mg/dL. RESULTS: Of the 27,172 patients, 12,965 (47.7%) were followed only by a primary care physician and 14,207 (52.3%) were also followed by a cardiologist. Overall, 18,366 patients (67.6%) achieved the LDL-C goal of <100 mg/dL, and 6517 patients (24%) achieved the LDL-C goal of <70 mg/dL. Patients followed by a cardiologist more frequently achieved the LDL-C goal of <100 mg/dL (74.3% and 60.3%; P < .0001, in patients treated by a cardiologist or by a primary care physician, respectively), as well as the lower LDL-C goal of <70 mg/dL (27.2% and 20.4%; P < .0001, in patients treated by a cardiologist or by a primary care physician, respectively). Differences in LDL-C control remained significant after a multivariate adjustment. Patients followed by a cardiologist were more commonly treated with highly potent statins and with non-statin cholesterol-lowering drugs. CONCLUSIONS: Among patients with coronary disease, those followed by a cardiologist receive a more aggressive antilipid treatment and more frequently achieve lipids goals. Nevertheless, the disappointingly poor lipid control in both groups warrants an effort to improve adherence for guidelines in both primary care and cardiology clinics.

Comparison of lipid control in patients with coronary versus peripheral artery disease following the first vascular intervention.

Peripheral arterial disease (PAD) is a strong risk factor for cardiovascular morbidity and mortality. Therefore, target low-density lipoprotein (LDL) cholesterol level in patients with PAD is ≤70 mg/dl, similar to patients with coronary artery disease (CAD). However, despite their high cardiovascular risk, patients with PAD less frequently achieve LDL cholesterol goals compared to patients with CAD. We aimed to compare LDL cholesterol control in patients after first coronary or peripheral vascular intervention. Included were patients ≥18 years of age without a history of cardiovascular disease who underwent first coronary or peripheral vascular intervention from 2004 through 2010. Primary end points were percentage of patients who achieved the LDL cholesterol goal of <100 and <70 mg/dl. Of 9,138 patients available for analysis, 7,512 (82.2%) underwent first coronary revascularization and 1,626 (17.8%) underwent first peripheral revascularization. Patients after first coronary revascularization were treated more frequently with any statin and with highly potent statins. Furthermore, they more frequently achieved the LDL cholesterol goals compared to patients after first peripheral intervention. This was true for the LDL cholesterol goal of <100 mg/dl (65% and 46.7%, p <0.0001) and for the lower LDL cholesterol goal of <70 mg/dl (23.3% and 13.3%, p <0.0001). Differences in LDL cholesterol control between the 2 groups remained statistically significant after multivariate adjustment. In conclusion, lipid control in patients with PAD is poor and significantly inferior to that of patients with CAD even after the first vascular intervention.

Mortality and coronary heart disease in euthyroid patients.

BACKGROUND: Subclinical thyroid dysfunction is associated with increased mortality and cardiovascular risk. It is unknown whether this association remains within normal thyroid function range. METHODS: The study was conducted using the computerized database of the Sharon-Shomron district of Clalit Health services. Included were subjects aged ≥40 years with normal thyroid function. Patients with a history of thyroid or cardiovascular diseases or diabetes were excluded. The primary end points were all-cause mortality and the need for coronary revascularization with either percutaneous coronary intervention or coronary artery bypass grafting. RESULTS: The 42,149 participants were stratified into 3 groups of equal thyrotropin intervals (0.35-1.6, 1.7-2.9, and 3-4.2 mIU/L). During a mean follow-up of 4.5±2.1 years, 4239 (10.1%) participants died and 1575 (3.7%) underwent coronary revascularization. For both women and men, the lowest mortality rates were observed in the intermediate thyrotropin group. Nevertheless, only for the low thyrotropin group, mortality risk remained significantly higher as compared with the intermediate thyrotropin group, even following multivariate model adjusted for the conventional cardiovascular risk factors, in both women (odds ratio 1.22; 95% confidence interval, 1.09-1.36 for the low thyrotropin group, compared with the intermediate group) and men (odds ratio 1.14; 95% confidence interval, 1.01-1.3 for the low thyrotropin group, compared with the intermediate group). There was no significant difference in the need for coronary revascularization among the 3 thyrotropin groups in both men and women. CONCLUSIONS: Low thyrotropin level within the reference range is associated with increased risk for all-cause mortality.

Primary angioplasty in patients following coronary artery bypass surgery: trends in application and outcome. Results from the acute coronary syndrome Israeli Survey (ACSIS) 2000-2008.

OBJECTIVES: We aimed to study the trends in management and outcome of post CABG patients presenting with acute MI. BACKGROUND: Primary angioplasty is the treatment of choice in patients with acute myocardial infarction. Saphenous vein grafts used for CABG are large-diameter conduits that tend to accumulate a large mass of thrombus when they are the culprit artery for acute myocardial infarction (MI). We hypothesized that performing PCI in these patients is more complex and possibly results in worse outcome compared to non-CABG patients. METHODS: Data for patients with STEMI was obtained from five acute coronary syndromes Israeli biennial Surveys (ACSIS) during 2000-2008. Baseline characteristics, management and outcome of post-CABG patients were compared to non-post CABG patients during 2006-2008 surveys. RESULTS: A total of 9,781 patients were included. About 1,002 (10.2%) were post-CABG. Reperfusion therapy for post-CABG patients (34-48%) was consistently lower compared to non-CABG patients (57-65%). Angiographic outcome in patients with STEMI who underwent primary PCI (17 post-CABG, mean age 66.6 ± 9.1 and 821 non-CABG, age 60.1 ± 12.9) was successful (TIMI flow 3) in 86 and 88%, respectively. Thirty-day mortality was 5.9 and 5.1% (P = 0.89) and MACE rates were 17.6 and 12.5%, respectively (P = 0.54). CONCLUSIONS: Use of primary PCI in post-CABG patients was lower than in non-CABG patients but increased steadily and to a similar extent in both groups. Angiographic and clinical outcome was similar despite assumingly larger thrombus burden in post CABG patients. Therefore, primary angioplasty is appropriate also in post-CABG patients presenting with STEMI.

USage of chitosan for Femoral (USF) haemostasis after percutaneous procedures: a comparative open label study.

AIMS: To test the efficacy and safety of a chitosan pad for femoral haemostasis as an adjunct to manual compression. Haemostasis of the femoral artery after coronary angiography by manual compression is time consuming and uncomfortable for the patient. Closure devices are costly and do not reduce vascular complication rate. The HemCon(r) pad is used by the US army to control traumatic bleeding. It consists of chitosan, a positively charged carbohydrate that attracts the negatively charged blood cells and platelets and promotes clotting. METHODS AND RESULTS: Patients undergoing percutaneous coronary angiography were 1:1 randomised for manual compression with regular or HemCon(r) pad. All patients were catheterised with 6 Fr sheath and received 2500 u of heparin. Time to haemostasis, incidence of minor and major bleeding, haematoma size, post-procedural stay at the hospital and level of satisfaction were compared between the two groups. Seventy patients in the HemCon group and 66 patients in the regular pad groups were recruited. Activated clotting time (ACT) before manual compression was similar, 183.9 ± 43.4 and 178.3 ± 34.2 seconds in the HemCon(r) and regular pad groups respectively. Time to haemostasis was 5.6 ± 2.1 and 8.4 ± 3.5 minutes in the HemCon® and regular pad groups, respectively (p<0.001). Haematoma developed in 6% and 14.8% of patients in the HemCon(r) and regular pad group, respectively (p=0.14). CONCLUSIONS: The HemCon(r) pad significantly decreased time-to-haemostasis compared to the regular pad. The total incidence of haematoma tended to be lower in the HemCon(r) pad compared to the regular pad group.

[Posture-dependent refractory hypoxemia].

Patent foramen ovate is a common finding in the general population. However, interatrial right to left shunt causing severe hypoxemia in the absence of pulmonary hypertension is a rare finding. The authors describe two such patients suffering from severe hypoxemia refractory to oxygen supplementation. The first, a 57-year-old mate, developed severe hypoxemia several months after right pneumonectomy. The second patient, an 83 year old lady was found with severe hypoxemia after an unrelated fall and the degree of hypoxemia was posture related. Regular transthoracic Doppler echocardiography did not explain the hypoxemia in either patient. One hundred percent oxygen breathing test suggested large right to Left anatomic shunt in both patients. Doppler echocardiography with intravenous agitated saline injection demonstrated the existence of interatrial right to left blood shunting in both patients in the absence of elevated systolic pulmonary artery pressure. Both patients underwent right heart catheterization. Pulmonary arterial hypertension was ruled out and the interatrial shunt was successfully occluded percutaneously by an Amplatzer device. In both patients, hypoxemia resolved immediately after the occlusion of the interatrial shunt and their quality of life improved remarkably. In cases of unexplained refractory hypoxemia, in the absence of acute lung disease, and especially if related to upright posture, one should consider platypnea-orthodeoxia syndrome and its most common cause, a right to left interatrial shunt. This can nowadays be successfully treated percutaneously.

Cardiovascular risk in patients with fasting blood glucose levels within normal range.

Fasting glucose levels elevated beyond the normal range have been associated with increased cardiovascular risk. However, it is unknown whether this association exists for variations of fasting glucose within the normal range. The present study was conducted using the computerized database of the Sharon-Shomron District of Clalit Health Services. Included in the present study were subjects with fasting glucose levels within the normal range (< 100 mg/dl). We excluded patients with a history of cardiovascular disease or diabetes. The primary outcome was the incidence of coronary revascularization with either percutaneous coronary intervention or coronary artery bypass grafting. The 28,263 participants (age 53.7 ± 12.2 years) were divided into quartiles according to the fasting glucose level (75.4 ± 4.5, 83.6 ± 1.7, 88.9 ± 1.4, and 95.1 ± 2.2 mg/dl). During a mean follow-up of 5.9 ± 0.7 years, 424 subjects required coronary revascularization. A progressive increase was seen in the risk of coronary revascularization as the fasting glucose levels increased within the normal range (hazard ratio 1.73, 95% confidence interval 1.3 to 2.3, p > 0.001, between the fourth and first quartiles). However, this association lost its statistical significance after adjustments for the conventional coronary risk factors (hazard ratio 1.17, 95% confidence interval 0.85 to 1.62, p = 0.328). In conclusion, elevated fasting glucose levels within the normal range were associated with an increased cardiovascular risk. This association was caused by the greater prevalence of the other conventional risk factors and not by the glucose level itself.

Neurologic manifestations as presenting symptoms of endocarditis.

The features of infective endocarditis include both cardiac and non-cardiac manifestations. Neurologic complications are seen in up to 40% of patients with infective endocarditis and are the presenting symptom in a substantial percentage. We describe in detail the clinical scenarios of three patients admitted to our hospital, compare their characteristics and review the recent literature describing neurologic manifestations of infective endocarditis. Our patients demonstrate that infective endocarditis can develop without comorbidity or a valvular defect. Moreover, our patients were young and lacked the most common symptom of endocarditis: fever. The most common neurologic manifestations were focal neurologic deficits and confusion. We conclude that infective endocarditis should always be considered in patients presenting with new-onset neurologic complaints, especially in those without comorbidities or other risk factors. A prompt diagnosis should be reached and antibiotic treatment initiated as soon as possible.