Traumatic brain injury (TBI) is a major medical and socio-economic problem, and is the leading cause of death in children and young adults. The critical care management of severe TBI is largely derived from the "Guidelines for the Management of Severe Traumatic Brain Injury" that have been published by the Brain Trauma Foundation. The main objectives are prevention and treatment of intracranial hypertension and secondary brain insults, preservation of cerebral perfusion pressure (CPP), and optimization of cerebral oxygenation. In this review, the critical care management of severe TBI will be discussed with focus on monitoring, avoidance and minimization of secondary brain insults, and optimization of cerebral oxygenation and CPP. However, secondary brain insults are often amenable to prevention or reversal.The intensive care management of patients with severe TBI is a dynamic process, starts in the pre-hospital period, at the scene of the accident. During the early stages of hospital care, the patients may be managed in a variety of locations including emergency department, the radiology department, and the operating room before they are admitted to the Intensive Care Unit (ICU). The continuum of acute care, during the "GOLDEN HOUR", from the time of injury through the start of definitive care, should be ensured and based on the guidelines and recommendations previously mentioned. This review outlines the fundamental principles of critical care management of patients with severe TBI during their stay in the ICU. See Figure 1Prior to arrival to the ICU, patients with severe TBI are usually received, resuscitated and stabilized in emergency department or operating room. Once the severely head-injured patient has been transferred to the ICU, the management consists of the provision of high quality general care and various strategies aimed at maintaining hemostasis with:- Stabilization of the patient, if still unstable- Prevention of intracranial hypertension- Maintenance of an adequate and stable cerebral perfusion pressure (CPP)- Avoidance of systemic, secondary brain insults (SBI)- Optimization of cerebral hemodynamic and oxygenationMonitoring of patients with severe TBI is essential for the guidance and optimization of therapy. The rationale of monitoring is early detection and diagnosis of secondary brain insults, both systemic and intracranial. Therefore, monitoring of patients with severe TBI must comprise both general and specific neurologic monitoring.2), capnography , arterial blood pressure , central venous pressure (CVP), systemic temperature, urine output, arterial blood gases, and serum electrolytes and osmolality. Invasive or non-invasive cardiac output monitoring may be required in hemodynamically unstable patients who do not respond to fluid resuscitation and vasopressors.During neurointensive care of patients with severe TBI, general parameters that are regularly monitored include electrocardiography (ECG monitoring), arterial oxygen saturation  should be monitored in all salvageable patients with a severe TBI and an abnormal computed tomography (CT) scan". Also, "ICP monitoring is indicated in patients with severe TBI with a normal CT scan if two or more of the following features are noted at admission: age over 40 years, unilateral or bilateral motor posturing, or systolic blood pressure (BP) < 90 mm Hg" [Currently, available methods for ICP monitoring include epidural, subdural, subarachnoid, parenchymal, and ventricular locations. Historically, ventricular ICP catheter has been used as the reference standard and the preferred technique when possible. It is the most accurate, low-cost, and reliable method of monitoring ICP . It alsoAlthough there is no randomized, controlled trial (RCT) that has been performed demonstrating that ICP monitoring improves outcome or supporting its use as standard; ICP monitoring has become an integral part in the management of patients with severe TBI in most trauma centers. However, there is contradicting evidence about whether ICP monitoring improves outcome. Several studies have demonstrated that ICP monitoring reduced the overall mortality rate of severe TBI -21. Othe2) is an indicator of both cerebral oxygenation and cerebral metabolism, reflecting the ratio between cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO2). A retrograde catheterization of the internal jugular vein (IJV) is used for SjvO2 monitoring. As the right IJV is usually dominant [2 can be either continuous via a fiberoptic catheter or intermittent via repeated blood samples. In a prospective study of patients with severe acute brain trauma and intracranial hypertension, Cruz concluded that continuous monitoring of SjvO2 was associated with improved outcome [2, in a normal awake subject, is 62% with a range of 55% to 71%. A sustained jugular venous desaturation of < 50% is the threshold of cerebral ischemia and for treatment [2 monitoring can detect clinically occult episodes of cerebral ischemia, allowing the prevention of these episodes by simple adjustment of treatment. In TBI, jugular venous desaturation is mostly related to CBF reduction secondary to decreased CPP  or hypocapnia-associated cerebral vasoconstriction. Studies showed that a sustained reduction of the SjvO2 < 50% was associated with poor outcome, and an independent risk factor for poor prognosis [2 monitoring is essential for adjustment of ventilation during the medical treatment of an established intracranial hypertension. However, the benefit of SjvO2 monitoring on severe TBI patients' outcomes has not been confirmed in a RCT.The jugular venous oxygen saturation  monitoring measure cerebral oxygenation, however, SjvO2 measures global cerebral oxygenation and PbtO2 measures focal cerebral oxygenation using an invasive probe (Licox). Rosenthal et al. documented that, measurements of PbtO2 represent the product of CBF and the cerebral arteriovenous oxygen tension difference rather than a direct measurement of total oxygen delivery or cerebral oxygen [2 provides a highly focal measurement, it is mainly used to monitor oxygenation of a critically perfused brain tissue. PbtO2 is the most reliable technique to monitor focal cerebral oxygenation in order to prevent episodes of desatuartion. However, global cerebral oxygenation alterations may not be observed. The normal PbtO2 ranges between 35 mm Hg and 50 mm Hg [2 < 15 mm Hg is considered a threshold for focal cerebral ischemia and treatment [2-based therapy may be associated with reduced patient mortality and improved patient outcome after severe TBI [2-based therapy is associated with improved patient outcome after severe TBI [2-based therapy, 38.8% had unfavorable and 61.2% had a favorable outcome. Among the patients who received ICP/CPP-based therapy 58.1% had unfavorable and 41.9% had a favorable outcome. Overall PbtO2-based therapy was associated with favorable outcome . These results suggested that combined ICP/CPP- and PbtO2-based therapy is associated with better outcome after severe TBI than ICP/CPP-based therapy alone [2 is an independent outcome predictor and is associated with poor short-term outcome after severe TBI independently of elevated ICP, low CPP, and injury severity. PbtO2 may be an important therapeutic target after severe TBI [2 has been documented to be superior to SjvO2, near infrared spectroscopy [2 monitoring is a promising, safe and clinically applicable method in severe TBI patients; however, it is neither widely used nor available. The combinations of ICP/PbtO2 intra-parenchymal monitoring are important and helpful modalities in the management of severe TBI.Both SjvOl oxygen . As PbtO50 mm Hg . A valuereatment . Severalvere TBI -42. In avere TBI . Among ppy alone . Oddo etvere TBI . PbtO2 htroscopy , and regtroscopy  in detecCerebral microdialysis (MD) is a recently developed invasive laboratory device, bedside monitor to analyze brain tissue biochemistry . UsuallyCharacteristically, cerebral hypoxia or ischemia results in a significant increase in the lactate: pyruvate ratio (LPR) . A LPR >Transcranial Doppler (TCD) is a non-invasive method to measure CBF velocity. It is increasingly utilized in neurocritical care including TBI. It is a clinically useful tool in the diagnosis of complications that may occur in patients with TBI such as vasospasm, critical elevations of ICP and decreases in CPP, carotid dissection, and cerebral circulatory arrest (brain death). TCD can predict post-traumatic vasospasm prior to its clinical manifestations. Since ICP monitoring is an invasive procedure with potential risk of associated complications, TCD has been suggested as a non-invasive alternative technique for assessment of ICP and CPP ,51. The Electroencephalogram (EEG) is a clinically useful tool for monitoring the depth of coma, detecting non-convulsive  seizures or seizures activity in pharmacologically paralyzed patients, and diagnosing brain death ,55. ContSensory-evoked potentials (SEP) can yield data on current brain function in very severe TBI patients; however, their use is very limited in the initial management of TBI.Near infrared spectroscopy (NIRS) is a continuous, direct, and non-invasive monitor of cerebral oxygenation and cerebral blood volume (CBV). In cerebral tissue, the two main chromophores (light-absorbing compounds) are hemoglobin (Hb) and cytochrome oxidase. NIRS is based on the differential absorption properties of these chromophores in the NIR range, i.e., between 700 and 1,000 nm. At 760 nm, Hb occurs primarily in the deoxygenated state (deoxyHb), whereas at 850 nm, it occurs in the oxygenated state (oxyHb). Hence, by monitoring the difference in absorbency between these two wavelengths, the degree of tissue deoxygenation can be evaluated.2, NIRS is less accurate in determining cerebral oxygenation [In comparison with the SjvOgenation . AlthougAfter head trauma, a temperature gradient in brain temperature compared with body temperature of up to 3°C higher in the brain has been reported. Elevated temperature is a common secondary systemic insult to the injured brain. Both invasive   and non-Guidelines for the management of severe TBI are widely available and should constitute the main background and cornerstone for the development of institutional clinical practice guidelines-based management protocols. Several studies have demonstrated the importance and the impact of implementation of such protocols on the outcomes of patients with severe TBI -7. We reIn severe TBI patients, endotracheal intubation, mechanical ventilation, trauma, surgical interventions (if any), nursing care and ICU procedures are potential causes of pain. Narcotics, such as morphine, fentanyl and remifentanil, should be considered first line therapy since they provide analgesia, mild sedation and depression of airway reflexes (cough) which all required in intubated and mechanically ventilated patients. Administration of narcotics is either as continuous infusions or as intermittent boluses.2 consumption, CMRO2, and CO2 production; improves patient comfort; and prevents harmful movements. The ideal sedative for TBI patient would be rapid in onset and offset, easily titrated to effect, and lack active metabolites. It would be anticonvulsant, able to lower ICP and CMRO2, and to preserve the neurologic examination. Finally, it would lack deleterious cardiovascular effects. No commonly used sedative is ideal. Propofol is the hypnotic of choice in patients with an acute neurologic insult, as it is easily titratable and rapidly reversible once discontinued. These properties permit predictable sedation yet allow for periodic neurologic evaluation of the patient. However, propofol should be avoided in hypotensive or hypovolemic patients because of its deleterious hemodynamic effects. Moreover, propofol infusion syndrome  is a potential complication of prolonged infusions or high doses of propofol administration. Benzodiazepines such as midazolam and lorazepam are recommended as continuous infusion or intermittent boluses. In addition to sedation, they provide amnesia and anticonvulsive effect. Prolonged infusion, high dose, presence of renal or hepatic failure, and old age are risk factors for accumulation and oversedation.Adequate sedation potentiates analgesics; provides anxiolysis; limits elevations of ICP related to agitation, discomfort, cough or pain; facilitates nursing care and mechanical ventilation; decrease ORoutine use of neuromuscular blocking agents (NMBAs) to paralyze patients with TBI is not recommended. NMBAs reduce elevated ICP and should be considered as second line therapy for refractory intracranial hypertension. However, the use of a NMBA is associated with increased risk of pneumonia and ICU length of stay (LOS), and with neuromuscular complications.2 saturation < 90%, or PaO2 < 60 mm Hg, should be avoided [2 < 25 mm Hg is not recommended [2 30-35 mm Hg is recommended to treat acute neurological deterioration reflecting increased ICP. Longer periods of hyperventilation might be required for intracranial hypertension refractory to all treatments including sedation, paralytics, CSF drainage, hypertonic saline solutions (HSSs) and osmotic diuretics. However, when hyperventilation is used, SjvO2 or PbtO2 measurements are recommended to monitor cerebral oxygenation and avoid cerebral ischemia.Patients with severe TBI are usually intubated and mechanically ventilated. Hypoxia, defined as O avoided . Prophylommended . Within ommended . Excessi2) of 95% or greater and/or PaO2 of 80 mm Hg or greater and to achieve normoventilation (eucapnia) with PaCO2 of 35 to 40 mm Hg. Mascia et al. reported that high tidal volume ventilation is an independent predictor and associated with acute lung injury (ALI) in patients with severe TBI [The ventilatory settings should be adjusted to maintain a pulse oximetry  = 1.0, and administration of additional sedation are recommended to avoid desaturation and sudden increase in the ICP. Suctioning ETT must be brief and atraumatic.Prior to suctioning the patient through the endotracheal tube (ETT), preoxygenation with a fraction of inspired oxygen , with an incidence of ALI/ARDS reported between 10% and 30% -64. EtioHemodynamic instability is common in patients with severe TBI. Hypotension, defined as SBP < 90 mm Hg or MAP < 65 mm Hg, is a frequent and detrimental secondary systemic brain insult and has been reported to occur in up to 73% during ICU stay . StudiesIt is unlikely that an isolated TBI by itself would cause hypotension unless the patient has become brain dead. Intravascular volume depletion due to hemorrhage from associated injuries such as scalp, neck, vessels, chest, abdomen, pelvis and extremities, or due to polyuria secondary to diabetes insipidus, are the most common causes of hypotension in patients with severe TBI. Other potential reasons for hypotension in patients with severe TBI are myocardial contusion resulting in primary pump failure, and spinal cord injury with spinal shock . An often missed cause of hypotension in patients with TBI is the use of etomidate for intubation. It has been reported that even a single dose of etomidate may cause adrenal insufficiency resulting in hypotension .Appropriately aggressive fluid administration to achieve adequate intravascular volume is the first step in resuscitating a patient with hypotension following severe TBI. The CVP may be used to guide fluid management and is recommended to be maintained at 8 - 10 mm Hg. In patients who respond poorly to adequate volume expansion and vasopressors, demonstrate hemodynamic instability, or have underlying cardiovascular disease, a pulmonary artery catheter or non-invasive hemodynamic monitoring may be considered. The pulmonary capillary wedge pressure should be maintained at 12 - 15 mm Hg. Several reliable predictors of fluid responsiveness such as pulse pressure variation, systolic pressure variation, stroke volume variation, and collapse of inferior vena cava have been suggested to guide fluid management. Isotonic crystalloids, specifically normal saline (NS) solution are the fluid of choice for fluid resuscitation and volume replacement. HSSs are effective for blood pressure restoration in hemorrhagic shock; however, with no survival benefit . The NatAnemia is a common secondary systemic brain insult and should be avoided, with a targeted hemoglobin ≥100 g/L or hematocrit ≥0.30. Brain tissue is reach in thromboplastin and cerebral damage may cause coagulopathy . CoagulaPrior to the insertion of an ICP monitoring, a MAP ≥80 mm Hg is recommended. The rationale for a MAP ≥80 mm Hg is to maintain a CPP ≥60 mm Hg for a treatment threshold of ICP > 20 mm Hg . FollowiOccasionally, targeted CPP or MAP may not be achieved despite appropriate fluid resuscitation and adequate intravascular volume. Excessive and inappropriate fluid administration to achieve intended CPP or MAP is associated with fluid overload and ARDS, and should be avoided. Vasopressors should be used to achieve targeted CPP or MAP if these could not be obtained with adequate fluid resuscitation. Norepinephrine, titrated through a central venous line (CVL), is recommended. Dopamine causes cerebral vasodilatation and increase ICP, however, can be used initially via a peripheral intravenous cannula until a CVL is inserted ,77. PhenHypertension, defined as SBP > 160 mm Hg or MAP > 110 mm Hg, is also a secondary systemic brain insult that can aggravate vasogenic brain edema and intracranial hypertension. However, hypertension may be a physiological response to a reduced cerebral perfusion. Consequently, and prior to ICP monitoring, hypertension should not be treated unless a cause has been excluded or treated, and SBP > 180-200 mm Hg or MAP > 110-120 mm Hg. Lowering an increased BP, as a compensatory mechanism to maintain an adequate CPP, exacerbates cerebral ischemia. Following placement of an ICP monitoring, the management of MAP is guided by the CPP.2 monitoring has been suggested to identify individual optimal CPP [Cerebral ischemia is considered the single most important secondary event affecting outcome following severe TBI. CPP, defined as the MAP minus ICP, (CPP = MAP - ICP), below 50 mm Hg should be avoided . A low Cimal CPP . In the imal CPP .2O. The prophylactic administration of mannitol is not recommended [2O. Osmotic diuresis should be compensated by adequate fluid replacement with isotonic saline solution to maintain euvolmia. The effective dose is 0.25-1 g/kg, administered intravenously over a period of 15 to 20 minutes. The regular administration of mannitol may lead to intravascular dehydration, hypotension, pre-renal azotemia and hyperkalemia [Mannitol administration is an effective method to decrease raised ICP after severe TBI . Mannitoommended . Prior trkalemia . Mannitorkalemia ,83. MannHSSs have been suggested as alternative to mannitol. HSS has a number of beneficial effects in head-injured patients, including expansion of intravascular volume, extraction of water from the intracellular space, decrease in ICP, and increase in cardiac contractility. HSS produces osmotic dehydration and viscosity-related cerebral vasoconstriction. Prolonged administration of a HSS was associated with lowered ICP, controlled cerebral edema, with no adverse effects of supraphysiologic hyperosmolarity such as renal failure, pulmonary edema, or central pontine demyelination ,85. In aModerate systemic hypothermia at 32°C to 34°C, reduces cerebral metabolism and CBV, decreases ICP, and increases CPP . EvidencPost-traumatic seizures are classified as early occurring within 7 days of injury, or late occurring after 7 days following injury . ProphylPhenytoin is the recommended drug for the prophylaxis of early post-traumatic seizures. A loading dose of 15 to 20 mg/kg administered intravenously (I.V.) over 30 minutes followed by 100 mg, I.V., every 8 hours, titrated to plasma level, for 7 days, is recommended. Patients receiving antiseizures prophylaxis should be monitored for potential side effects.Severe TBI patients are at significantly high risk of developing venous thromoembolic events (VTEs) including deep vein thrombosis (DVT) and pulmonary embolism. The risk of developing DVT in the absence of prophylaxis was estimated to be 20% after severe TBI .Mechanical thromboprophylaxis, including graduated compression stockings and sequential compression devices, are recommended unless their use is prevented by lower extremity injuries. The use of such devices should be continued until patients are ambulatory. In the absence of a contraindication, low molecular weight heparin (LMWH) or low dose unfractionated heparin should be used in combination with mechanical prophylaxis. However, the use of pharmacological prophylaxis is associated with an increased risk for expansion of intracranial hemorrhage. Although, evidence to support recommendations regarding the timing of pharmacological prophylaxis is lacking, most experts suggest initiating pharmacologic prophylaxis as early as 48 to 72 hours after the injury, in the absence of other contraindications .Severe TBI is a well-known risk factor for stress ulcers (Cushing's ulcer) in the ICU. Prophylaxis includes early enteral feeding, and pharmacological prophylaxis such as H2- blockers, proton-pump inhibitors and sucralfate ,96.Severe TBI patients are usually in hypermetabolic, hypercatabolic and hyperglycemic state, with altered G.I. functions. There is evidence suggesting that malnutrition increases mortality rate in TBI patients . StudiesAlthough, the BTF recommended 140% of resting metabolic expenditure in non-paralyzed patients and 100% in paralyzed patients to be replaced, there is growing body of evidence suggesting the benefit of a lower caloric intake -102.In patients with severe TBI, stress hyperglycemia is a common secondary systemic brain insult. Studies showed that hyperglycemia has repeatedly been associated with poor neurological outcome after TBI -108. AltSteroids administration is not recommended for improving the outcome or reducing ICP in patients with severe TBI. Moreover, steroids may be harmful after TBI. The CRASH trial, a multicentre international collaboration, aimed to confirm or refute such an effect by recruiting 20000 patients. In May, 2004, the data monitoring committee disclosed the unmasked results to the steering committee, which stopped recruitment at 10008 patients. Compared with placebo, the risk of death from all causes within 2 weeks was higher in the group allocated corticosteroids . The authors concluded that there was no reduction in mortality with methylprednisolone in the 2 weeks after head injury. The cause of the rise in risk of death within 2 weeks was unclear . Hence, Barbiturate is proven as efficient therapy for refractory intracranial hypertension. Barbiturates reduce cerebral metabolism and CBF, and lower ICP . High-doPentobarbital: 10 mg/kg over 30 min, then5 mg/kg/h for 3 hours, then1 mg/kg/hAs alternative, sodium thiopental might be used as follows:2.5-10 mg/kg IV, slow bolus, then0.5-2 mg/kg/hThe goal of fluid management is to establish and maintain euvolemia to moderate hypervolemia . Negative fluid balance has been shown to be associated with an adverse effect on outcome, independent of its relationship to ICP, MAP, or CPP . Isotoni+ up to 150 - 155 mEq/L may be acceptable [+ > 150 mmol/L) in patients with TBI are central or neurogenic diabetes insipidus, osmotic diuresis (mannitol), and the use of HSS. Correction of severe hypernatremia (Na+ > 160 mmol/L) should be gradual, as abrupt changes in serum osmolarity and rapid fall of serum sodium concentration would worsen cerebral edema. Fluid resuscitation of hypovolemic hypernatremic TBI patients should be initially only with NS. Management of electrolytes disturbances should follow complete volume restoration. Hyponatremia is detrimental and major secondary systemic brain insult in patients with severe TBI, as it leads to exacerbation of brain edema and an increase in ICP. It is usually secondary to cerebral salt wasting syndrome [In severe TBI patients with increased ICP or brain edema, a serum sodium level Naceptable . Howeversyndrome , or to tsyndrome ,123.The "Lund therapy" of severe TBI is based on physiological principles for cerebral tissue and blood volume regulation. The therapy aims at preventing cerebral hypoxia simultaneously with taking measures that counteract transcapillary filtration. The Lund concept is more beneficial if the blood brain barrier is disrupted and more appropriate if pressure autoregulation is lost. The therapy has two main goals: first to reduce or prevent an increase in ICP , and second to improve perfusion and oxygenation around contusions  by maintaining normal blood oxygenation, normovolemia and normal hematocrit. The treatment protocol, to reduce an increased ICP, includes preservation of a normal colloidal absorbing force , a reduction of intracapillary pressure through reduction of systemic blood pressure by antihypertensive therapy  and a simultaneous, moderate constriction of precapillary resistance vessels with low-dose thiopental and dihydroergotamine. A few studies have reported that Lund therapy was associated with improved clinical outcome Similar to other patients in the intensive care, TBI victims should receive the usual daily care as follows:- Raising head of bed to 30° - 45°: that would reduce ICP and improves CPP ; and low- Keeping the head and neck of the patient in a neutral position: this would improve cerebral venous drainage and reduce ICP.- Avoiding compression of internal or external jugular veins with tight cervical collar or tight tape fixation of the endotracheal tube that would impede cerebral venous drainage and result in an increase in the ICP.- Turning the patient regularly and frequently with careful observation of the ICP .- Providing eye care, mouth and skin hygiene- Implementing all evidence-based bundles for prevention of infection including VAP  and cent- Administrating a bowel regimen to avoid constipation and increase of intra-abdominal pressure and ICP.- Performing physiotherapySurgical decompressive craniectomy has been suggested as a promising therapeutic approach for patients with acute severe TBI at risk to develop severe brain edema. Decompressive craniectomy and hemicraniectomy, both are well accepted for the surgical treatment of intractable intracranial hypertension in cases in which medical management fails. Decompressive surgery is performed as a life-saving procedure when death is imminent from intracranial hypertension. Though the operation is being increasingly used, evidence regarding its overall effects on outcomes is contradicting. Albanèse et al, in a retrospective cohort study in 40 patients with intractable intracranial hypertension and at very high risk of brain death, decompressive craniectomy allowed 25% of patients to attain social rehabilitation at 1 yr . Cooper The early prediction of outcome after TBI is important. A few predictive models for patient outcomes after severe TBI have been proposed ,132. A rThe management of severe TBI centers on meticulous and comprehensive intensive care that includes multi-model, protocolized approach involving careful hemodynamic support, respiratory care, fluid management, and other aspects of therapy, aimed at preventing secondary brain insults, maintaining an adequate CPP, and optimizing cerebral oxygenation. This approach clearly requires the efforts of a multidisciplinary team including neurointensivists, neurosurgeons, bedside nurses and respiratory therapists, and other members of the medical team. While such management can be challenging, it is by all means rewarding considering the age of the victims and the socio-economic impact of the problem.2: Brain tissue oxygen tension; PEEP: Positive end expiratory pressure; SBP: Systolic blood pressure; SIADH: Syndrome of inappropriate anti-diuretic hormone secretion; SjvO2: Jugular venous oxygen saturation; TBI: Traumatic brain injury.BTF: Brain Trauma Foundation; CBF: Cerebral blood flow; CBV: Cerebral blood volume; CPP: Cerebral perfusion pressure; CSF: Cerebral spinal fluid; CVP: Central venous pressure; EEG: Electroencephalogram; GCS: Glasgow coma scale; HSS: Hypertonic saline solution; ICP: Intracranial pressure; MAP: Mean arterial pressure; NS: Normal saline; PbtOThe authors declare that they have no competing interests.SHH performed literature review and wrote the initial draft of the manuscript. YMA edited and rewrote portions of the manuscript. All authors read and approved the final manuscript.Samir H. Haddad, MD, is Head Section of Surgical Intensive Care Unit; and Consultant in the Intensive Care Department at King Abdulaziz Medical City, Riyadh, Saudi Arabia.Yaseen M. Arabi, MD, FCCP, FCCM, is Chairman, Intensive Care Department; and Medical Director, Respiratory Services at King Abdulaziz Medical City, Riyadh, Saudi Arabia. He is also Associate Professor at College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.


In this study we tested the hypothesis that, assuming a constant VCO2 and under fixed ventilation, PETCO2 can track changes in CO induced by PLR and can be used to predict fluid responsiveness.The passive leg-raising (PLR) maneuver provides a dynamic assessment of fluid responsiveness inducing a reversible increase in cardiac preload. Since its effects are sudden and transitory, a continuous cardiac output (CO) monitoring is required to appropriately assess the hemodynamic response of PLR. On the other hand, changes in partial end-tidal COThirty-seven mechanically ventilated patients with acute circulatory failure were monitored with the CardioQ-ODM esophageal Doppler. A 2-minutes PLR maneuver was performed. Fluid responsiveness was defined according to CO increase (responders ≥ 15%) after volume expansion.2 were strongly correlated . The areas under the receiver-operating characteristics (ROC) curve for a PLR-induced increase in CO and PETCO2  were not significantly different. An increase ≥ 5% in PETCO2 or ≥ 12% in CO during PLR predicted fluid responsiveness with a sensitivity of 90.5% (95% CI: 69.9 to 98.8%) and 95.2% (95% CI: 76.2 to 99.9%), respectively, and a specificity of 93.7% (95% CI: 69.8 to 99.8%).PLR-induced increases in CO and PETCO2 during a PLR maneuver could be used to track changes in CO for prediction of fluid responsiveness in mechanically ventilated patients with acute circulatory failure, under fixed minute ventilation and assuming a constant tissue CO2 production.Induced changes in PETCO The passive leg-raising (PLR) maneuver provides a dynamic assessment of preload dependence inducing a transient and reversible increase in cardiac preload. The abrupt transfer of blood contained in the venous reservoir of the legs and splanchnic compartment while moving the patient from a semirecumbent to supine position with legs elevated increases cardiac preload as a 'self-volume challenge' and, when both ventricles are operating in the steep part of the Frank-Starling curve, also improves cardiac output (CO) . This ma2 pressure (PETCO2) has been known for decades [2 has been proposed to confirm the restoration of spontaneous circulation in patients with cardiac arrest [2 is mainly determined by tissue CO2 production (VCO2), alveolar ventilation and CO  [2 have been shown to correlate strongly with changes in CO in experimental [2 has been suggested as a noninvasive alternative for continuous assessment of CO in different shock states [The relationship between CO and partial end-tidal CO decades ,14, so mc arrest , but alsc arrest . Moreoveod flow) , when strimental -24 and crimental ,26 settik states .2 monitoring can track changes in CO induced by PLR and can be used as a noninvasive surrogate for predicting fluid responsiveness in mechanically ventilated patients with acute circulatory failure requiring fluid administration.The aim of the present study, therefore, was to assess whether PETCOThis study was prospectively conducted in a 17-bed adult multidisciplinary Intensive Care Unit of the Hospital del SAS Jerez de la Frontera. The study protocol was approved by the Institutional Ethics Committee of the Hospital Jerez of the Andalusian Health Service and endorsed by the Scientific Committee of the Spanish Society of Intensive Care, Critical and Coronary Units (SEMICYUC). Written informed consent was obtained from each patient's next of kin.Inclusion criteria were patients with controlled mechanical ventilation and for whom the attending physician decided to give fluids due to the presence of at least one of the following signs of circulatory failure: systolic blood pressure ≤ 90 mmHg or a decrease ≥ 50 mmHg in a previously hypertensive patient; the need of vasopressor drugs; urine output ≤ 0.5 ml/kg/hr during at least two hours; heart rate > 100 beats/minute; and presence of skin mottling or delayed capillary refilling. Exclusion criteria were age < 18 years, pregnancy, any contraindication for the use of esophageal Doppler  or to perform PLR .To avoid changes in alveolar ventilation, patients were ventilated in volume control mode and spontaneous respiratory movements were temporally suppressed with a neuromuscular blockade agent (0.1 mg/kg vecuronium bromide) if detected in airway pressure trace in the respiratory monitor.2 was continuously measured at the tip of the endotracheal tube using a sidestream infrared gas analyzer  integrated into the patient monitor  and recorded online in a laptop computer every 10 seconds using proprietary data acquisition software . The validation of this compact modular metabolic monitor for use in mechanically ventilated patients in the ICU has been published elsewhere [2 measurements was calculated as twice its coefficient of variation (CV = SD/mean), determined in all studied patients at baseline during stable hemodynamic and respiratory conditions. The least significant change (LSC) was calculated as the precision × √2, which sets the minimum percentage change between successive measurements that can be considered not due to random error and therefore representing a real change in PETCO2 [2 measurements was also calculated, which refers to the ability to detect a change over time, providing an estimation of the 'sensitivity to change' of a measurement tool [2. A GRI value ≥ 0.8 is considered a high responsiveness [PETCOlsewhere . The pren PETCO2 . Since aent tool . We calcsiveness .Hemodynamic monitoring was performed using the CardioQ-ODM™ esophageal Doppler monitor . This device allows minimally invasive real-time CO monitoring by measuring aortic blood flow velocity at the descending thoracic aorta, assuming a constant aortic diameter  and that a constant proportion of the CO flows through the descending aorta . This moAll Doppler measurements were performed by the same observer (MIMG). The intraobserver reproducibility for CO measurements was determined using the Bland-Altman test analysis in ten randomly selected patients over a one-minute period and described as bias ± limits of agreements (1.96SD), and presented as percentages and absolute values (in brackets). We also calculated precision and LSC for Doppler CO measurements at pre-infusion and post-infusion stages. Since Doppler parameters were averaged during one minute before and after fluid administration, precision was determined by the coefficient of error  and LSC as 2√2 × CE .2 measurements during each protocol period were expressed as an average of the measurements collected during one minute, except for the PLR stage, in which they were recorded at the moment at which they reached their maximum values [The study protocol was performed in four sequential stages Figure . A firstm values .Supportive therapies, ventilatory settings and vasopressor therapy were kept unchanged throughout the study period.2 were normally distributed. The results are expressed as means ± SD or as median and the interquartile range (IQR), as appropriate. Sample size was calculated for detection of differences of 0.10 with known expected area under the ROC curve [t-test for hemodynamic parameters and by the Mann-Whitney U test for PETCO2 measurements. The effects of fluid administration on hemodynamic parameters were assessed using a paired Student's t-test and by Wilcoxon rank sum test for PETCO2 measurements. The relationships between variables were analyzed using a linear regression method. The ability of PETCO2 to track directional changes in CO (trending capability) during PLR and fluid administration was tested using a concordance analysis. Concordance was defined as the percentage of data in which the direction of change was in agreement [PLR) and PETCO2 (ΔPETCO2-PLR), and pre-infusion FTc according to volume expansion (VE) response were calculated and compared using the Hanley-McNeil test. ROC curves are presented as area ± SE . A P value < 0.05 was considered statistically significant. All statistical analyses were two-tailed and were performed using MedCalc software for Windows version 11.6.1.0 .Normal distribution of data was tested using the D'Agostino-Pearson test. All variables except PETCOOC curve . We seleOC curve . PatientOC curve . To valiOC curve . Differegreement . The areFrom January to May 2011, 37 consecutive patients were included. Two patients were excluded because of inability to acquire an adequate Doppler signal. Patients' characteristics are summarized in Table 2 measurements, the precision and mean LSC were 1.3%  and 1.84% , respectively. The responsiveness of the gas analyzer according to Guyatt's Responsiveness Index was 1.58 .The intraobserver variability for esophageal Doppler CO measurements was 0.6 ± 4.9% (-0.02 ± 0.21 L/min). At pre-infusion, the precision and mean LSC for Doppler CO measurements were 2.3%  and 3.2% , respectively; at post-infusion, these values were 1.9%  and 2.6% . For PETCOP < 0.0001), stroke volume (SV) by 15.5 ± 10.2% , FTc by 8.4 ± 6% , mean arterial pressure (MAP) by 5.4% , arterial pulse pressure (PP) by 10.1% , and PETCO2 by 5.32 ± 3.09% . Neither heart rate nor Acc changed during PLR.Overall, the PLR maneuver increased CO by 15.9 ± 9.1%  with an absolute increase of 2.54 ± 0.99 mmHg (95% CI: 2.09 to 2.99 mmHg), whereas in non-responders, this value was 2.66 ± 1.69% (95% CI: 1.76 to 3.56%), with an absolute increase of 0.92 ± 0.61 mmHg (95% CI: 0.59 to 1.24 mmHg). All volume responders showed a ΔPETCO2-PLR greater than their individual baseline LSCs.In fluid-responder patients, ΔPETCO2-PLR  but was weaker with PLR-induced changes in arterial PP  , SV by 17.4% ; FTc by 8.4 ± 8.7% , MAP by 4.7% ; arterial PP by 12.5% ; and PETCO2 by 1.69 ± 3.55% . All the VE-responder patients exhibited an increase in CO after VE greater than their individual LSC values for Doppler CO measurements.In the entire study population, VE increased CO by 18.9 ± 17.1% . Changes between VE-induced increases in PETCO2 and CO showed a 59% concordance. Furthermore, CO increase after fluid administration was also correlated with ΔCOPLR and ΔPETCO2-PLR  .The VE-induced increase in CO was correlated with changes in PETCO) Figure . So, the2 measurement throughout the four stages are summarized in Table The hemodynamic and PETCOPLR  and ΔPETCO2-PLR  was not significantly different but was higher than for pre-infusion FTc  and baseline PP  , metabolic CO2 production (VCO2) and alveolar ventilation; so PETCO2 varies directly with VCO2 and CO and inversely with alveolar ventilation [2 should predominantly reflect variations in pulmonary blood flow and thus, indirectly, changes in CO. The strong relationship observed between changes in PETCO2 and CO during PLR supports this hypothesis and it is also in agreement with numerous studies performed under similar conditions [2 has been advocated as a simple and noninvasive parameter of the circulatory status for monitoring the resumption of spontaneous circulation and the efficacy of chest compressions during cardiac arrest [Exhaled or end-tidal COtilation . Therefonditions -26. For c arrest  but alsoc arrest  and emerc arrest .2 induced by PLR could be explained at least by two mechanisms. First, if PLR increases venous return and pulmonary blood flow, then CO2 delivery to the lungs  and CO2 removal should be increased. Second, by increasing pulmonary perfusion pressure, PLR could recruit previous collapsed pulmonary vessels and reduce alveolar spaces with high ventilation-to-perfusion mismatch or alveolar dead space. This latter phenomenon could be particularly striking in patients with severely impaired pulmonary perfusion pressure, as seen in deep hemorrhagic shock [et al. [2 pressure, we cannot estimate the relative influence of changes in dead space during PLR. In any case, according to the above explanation, whatever the underlying mechanism, the increase in PETCO2 is determined ultimately to an effective increase in pulmonary blood flow and improved efficiency of alveolar CO2 excretion [According to previous observations ,25, the ic shock ,19,21,23ic shock . In this [et al.  demonstrxcretion ,25.2 was initially described as linear [2 should be expected [2 at low CO values might be attributed not only to limited CO2 elimination, but also to changes in metabolic CO2 production during oxygen supply dependency [2, and thus, changes in PETCO2 would not reflect its variations but mainly the adequacy of alveolar ventilation [2 suggests that, under the conditions described by the study protocol, this relationship remains valid over the wide range of studied CO values. Furthermore, the moderate magnitude of transient changes in CO produced by PLR  and 2 variations should potentially share the same limitations as interpreting CO changes during PLR, since in this context the former is in essence just a surrogate for the latter. Therefore, any condition that could affect the ability of PLR to predict fluid responsiveness  [2 changes. Second, to prevent fluctuations in minute ventilation, all the patients were mechanically ventilated in volume control mode, deeply sedated and fully adapted to the ventilator with no inspiratory efforts. Consequently, in spontaneously breathing patients, the unpredictable variations in alveolar ventilation could make the analysis of changes in PETCO2 more difficult. For this reason, this population was deliberately excluded from the study and extrapolation of our results to this clinical condition cannot be recommended. Third, the assessment of PETCO2 variations is also based in the assumption that no significant changes in metabolic CO2 production have been produced while performing the PLR maneuver. If the metabolic rate varies considerably , the observed changes in PETCO2 could not be attributed solely to modifications in CO and thus the ability of PETCO2 variations to predict fluid responsiveness could be diminished. However, the maximum hemodynamic effects of PLR take place primarily during the first minute [2 after fluid administration. However, even under these circumstances, the VE-induced increase in CO still accounted for more than 50% of the observed changes in PETCO2. Finally, the 5% cutoff found for changes in PETCO2 represents an increase of no more than 2 mmHg, which a priori could be attributed to a low signal-to-noise ratio and easily interpreted as a measurement error. Nonetheless, we effectively confirmed that this value is almost three times the LSC for PETCO2 measurement, so under the same conditions, an increase above this threshold should represent an actual increase in PETCO2 and the presence of fluid responsiveness. Despite these considerations, PETCO2 measurement could offer an easily available, totally noninvasive method for the assessment of fluid responsiveness with similar performance as measuring CO, but without the need of any hemodynamic monitoring device, when similar clinical conditions are present .Before drawing conclusions from our results, some considerations should be mentioned. First, the assessment of fluid responsiveness using PETCOtension)  should at minute , so it i2 effectively tracked changes in CO during the PLR maneuver and predicted fluid responsiveness in patients with acute circulatory failure with fixed minute ventilation, assuming a constant tissue CO2 production.In our study we demonstrated that PETCOPLR: Passive leg raising-induced changes in cardiac output (%); ΔPETCO2-PLR: Passive leg raising-induced changes in partial end-tidal CO2 pressure (%); ΔPP-PLR: Passive leg raising-induced changes in arterial pulse pressure (%); Acc: Mean acceleration of aortic blood velocity; ARDS: Acute respiratory distress syndrome; CE: Coefficient of error; CI: Confidence interval; CO: Cardiac output; CV: Coefficient of variation; FTc: Corrected flow time; GRI: Guyatt's Responsiveness Index; IQR: Interquartile range; LSC: Least significant change; MAP: Mean arterial pressure; PEEP: Positive end-expiratory pressure; PETCO2: Partial end-tidal CO2 pressure; PLR: Passive leg raising; PP: Arterial pulse pressure; SV: Stroke volume; VCO2: Metabolic CO2 production; VE: Volume expansion.ΔCOMIMG has received consulting fees from Edwards Lifesciences. The other authors have no competing interests to disclose.MIMG, AGC and JCDM conceived the study. MIMG designed the study, participated in the recruitment of patients, performed the statistical analysis, interpreted the data and drafted the manuscript. AGC participated in the study design, interpreted data and helped draft the manuscript. MGR, RMP and VPM participated in patient recruitment, data collection and technical support. All authors contributed to the critical review of the manuscript and approved the final manuscript.


Hypertension is the most important preventable risk factor for premature death worldwide. It increases the risk of ischemic heart disease, strokes, peripheral vascular disease, and other cardiovascular diseases, including heart failure, aortic aneurysms, diffuse atherosclerosis, and pulmonary embolism. In childhood, hypertension can be determined according to a table adjusted for height, age and gender . A graphWe used a computerized calculation method to develop high-resolution graphics containing curves with 5,841 points each, to depict the main percentiles associated with high blood pressure for girls from 1 to 17 years old in the 50th percentile of height. Each point represents the calculation of the polynomial equation that includes the statistical processing of the last Report on Blood Pressure [Six monotonic curves of systolic BP for girls representing the 50th, 75th, 90th, 95th, 99th, and 99th +5 percentiles were built Figure . In relaThe correction of systolic BP for height is of little significance, and this updated graphic can be used to diagnose high systolic blood pressure for girls. Clinical studies are necessary to determine the systolic BP percentile that better represents clinically significant hypertension.


Intracellular heat shock protein (Hsp) 27 is a potent anti-apoptotic factor that, among other activities, prevents the binding of membrane receptor Fas to its ligand FasL. However, the potential role of extracellular Hsp27 and possibilities to control it have not been clarified. Moreover, there are no data on relations between Hsp27, sFas/sFasL system, matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in patients with chronic kidney disease (CKD)—neither children nor adults. The aim of this study was to evaluate serum concentrations of Hsp27 and their potential regulators  in children with CKD and on chronic dialysis. Twenty-six CKD children stage 5 still on conservative treatment, 19 patients on hemodialysis (HD), 22 children on automated peritoneal dialysis (APD), and 30 controls were examined. Serum concentrations of Hsp27, sFas, sFasL, MMP-7, and TIMP-1 were assessed by ELISA. Median values of Hsp27 were significantly elevated in all dialyzed patients vs. those in pre-dialysis period and vs. controls, the highest values being observed in subjects on HD. Regression analysis revealed that MMP-7, TIMP-1, sFas, and sFasL were the best predictors of Hsp27 concentrations in dialyzed patients. Children with CKD are prone to Hsp27 dysfunction, aggravated by the dialysis commencement, and more pronounced in patients on hemodialysis. Correlations between Hsp27 and examined parameters suggest the potential role for Hsp27 as a marker of cell damage in the pediatric population on chronic dialysis. Chronic inflammation, immune system activation, and enhanced apoptosis are characteristic features of chronic kidney disease (CKD), additionally aggravated by the dialysis procedure and the membrane type   and their tissue inhibitors (TIMPs), have been known in the case of sFas/sFasL. sFasL is proteolytically shed from its membrane-bound form by MMPs , their tissue inhibitors (TIMP-1), markers of inflammation , and endothelial damage (sE-selectin) in the pediatric population with CKD.2)  contained 26 patients  aged 2.0–16.5 years  with CKD stage 5, yet on conservative treatment (median glomerular filtration rate (GFR) calculated according to the Schwartz formula 13 ml/min/1.73 mThe second group consisted of 22 children  aged 4.0–15.5 years  on automated peritoneal dialysis , five of them having residual renal function. Mean Kt/V value was 1.4. The patients had five to eight exchanges of dialysis fluid during the night and, if necessary, one or two during the day. Peritoneal fluids used in our patients had glucose concentrations of 1.36 % or 2.27 %. The causative factors in CKD were chronic pyelonephritis (seven), chronic glomerulonephritis (six), polycystic kidney disease (two), neurogenic bladder (three), hemolytic uremic syndrome (two), and unknown (two).2, the dialyzers were not reused. The water, purified by reosmosis, was regularly checked for contamination. Mean Kt/V value was 1.3. All patients were on stable anticoagulation regimen using non-fractionated or low-molecular weight heparin. The causative factors in chronic renal failure were chronic glomerulonephritis (seven cases), chronic pyelonephritis (seven), neurogenic bladder (two), polycystic kidney disease (one), and unknown (two).The third group included 19 patients  aged 10.5–17.0 years , hemodialyzed on polysulfone membranes, only three out of them with residual kidney function. Hemodialysis (HD) sessions (3.5–4 h) were performed three times a week, using bicarbonate dialysate, the blood flow ranged from 150 to 200 ml/min, dialysate flow did not exceed 500 ml/min. The membrane area was between 1.0 and 1.6 mThirty children  aged 5.5–15.5 years  with primary nocturnal enuresis and normal kidney function, served as controls.None of the patients showed clinical evidence of infection, had diabetes, malignancies or vasculitides, smoked, took antibiotics, statins, corticosteroids, or immunosuppressive therapy. They were also free of such comorbidities as diabetes, cardiovascular disease, peripheral vascular disease, or obesity. In the CKD group, blood pressure was well controlled either without medication (18 children) or with the use of calcium channel blockers (five patients) and β-blockers (three children). All APD children had their blood pressure values below the 90th percentile, adjusted for gender and age, according to the criteria of the fourth report on high blood pressure in children and adolescents National  and did Informed consent was obtained from the subjects and their parents, if necessary. The research project has been approved by the university ethics committee in accordance with the Helsinki declaration.Blood samples were drawn after an overnight fast from peripheral veins in CKD and APD patients and in controls, in HD subjects twice—from the afferent line of the first-use dialyzer before starting an HD session and after finishing it. Samples were clotted for 30 min, centrifuged at 4°C for 10 min, and then serum was stored at −20°C until assayed.Serum concentrations of Hsp27, sFas, sFasL, MMP-7 (matrilysin), and TIMP-1 were evaluated by commercially available ELISA kits . Standards and serum samples were transferred to 96-well microplates pre-coated with recombinant antibodies to human Hsp27, sFas, sFasL, MMP-7, and TIMP-1. Each sample was tested in duplicate, and the arithmetical mean was considered a final result. Measurements were performed according to the manufacturer’s instructions; results were calculated by reference to standard curves.In all patients, high sensitivity CRP , interleukin (IL)-4 and sE-selectin (ELISA kits by R&D Systems) as markers of inflammation/endothelial dysfunction, were also evaluated.U, Wilcoxon). The relations between parameters were assessed by Spearman’s rank correlation coefficient and by linear regression analysis. The linear regression equations were calculated as y = βx + a . We presented only those equations where both regression coefficient and constant term were statistically significant. Statistical analysis was performed using the package Statistica ver. 9.0. A p value < 0.05 was considered significant.Results are expressed as median values and interquartile ranges. Since the null hypothesis of normality of distribution was rejected by Shapiro–Wilk test, multiple comparisons and comparisons in pairs were evaluated by using nonparametric tests  the values of Hsp27 in the group of dialyzed patients  were observed. No correlations with selected parameters of dialysis adequacy, such as Kt/V, hemoglobin, albumin, urea, calcium, phosphate, or parathormone levels were noticed either.Our study describes for the first time the disturbed Hsp27 concentrations, and the potential role of sFas/sFasL, MMP-7 and TIMP-1 in their regulation, in children with chronic kidney disease treated conservatively and on chronic dialysis.Hsp27 serum levels were increased in our pre-dialysis patients, which is concordant with previous observations in adults, suggesting the progressive character of those changes and their dependence on the aggravation of renal failure  predicted Hsp27 concentrations in pediatric patients on dialysis. Moreover, our previous investigation has revealed that MMPs and TIMPs may well predict sFas/sFasL in dialyzed children (Musiał and Zwolińska All together, these connections strongly suggest the engagement of evaluated parameters in tissue homeostasis and regeneration following the cell damage. In the case of MMPs and TIMPs, such activity results from their functioning as proteolytic enzymes, degrading and remodeling the matrix components. The sFas/sFasL impact on apoptosis is also the tool for controlling tissue destruction and restoration. Thus, the fact that MMPs, TIMPs, sFas, and sFasL are Hsp27 predictors in dialyzed patients, suggests the potential role of Hsp27 as a marker of cell damage seen in patients with chronic kidney disease.However, some differences require careful attention. Both MMP-7 and TIMP-1 turned out to be useful predictors of Hsp27 concentrations in patients on dialysis, whereas no such link was observed in the case of pre-dialysis children with CKD stage 5. The same results concerned sFas and sFasL—they predicted very accurately Hsp27 concentrations in dialyzed subjects, but were ineffective as predictors of Hsp27 in the population of pre-dialysis CKD children. Such discrepancy may mean that factors triggering Hsp27 increase vary between those populations and uremic toxicity plays a paramount role in pre-dialysis patients, whereas in subjects on dialysis the therapy itself, with its bio-incompatibility and inadequacy above all, is able to trigger and aggravate dialysis-related stress reactions. Together with the discrepancies between HD and APD, favoring the latter, Hsp27 serum levels create a new quality in assessing biocompatibility of dialysis modalities. Surely, this theory needs to be verified in the course of future investigation performed on a bigger group of patients.Finally, the hypothetical chain of reactions can be built, starting with Hsp27 overexpression due to stress conditions characteristic for chronic kidney disease. The next step would be the stimulation of pro-inflammatory cytokines and NF-κB (Parcellier et al. Children with chronic kidney disease are prone to Hsp27 dysfunction, aggravated by the dialysis commencement and more pronounced in patients on hemodialysis. Correlations between Hsp27 and examined parameters suggest the potential role for Hsp27 as a marker of bio-incompatibility-related cell damage in the pediatric population on chronic dialysis.


Introduction. This study aimed to evaluate symptoms and signs, inflammation markers, electrolytes, and ECG signs of increased vagal tone as markers of colon perforation in sigmoid diverticulitis or appendicitis. Methods. The records of all patients older than fifty years (only these had routine ECG done) admitted to our emergency station between January 2008 and December 2010 with sigmoid diverticulitis  or appendicitis  were retrospectively evaluated. Pain score, heart rate, blood pressure, and body temperature were assessed at presentation. Before starting infusion therapy, blood was taken to do a blood count and to analyze CRP, the electrolytes, and creatinine levels. Then an ECG was done. Results. The perforation rate was 37% (n = 103). Body temperature, heart rate, sodium, CRP, and leukocytes correlated significantly with infectious colon perforation. However, only body temperature, CRP, and sodium correlated significantly with infectious colon perforation if compared by logistic regression analysis. The prevalence of hyponatremia (sodium level <136 mmol/L) was 29% in the group with infectious colon perforation and 16% in the group without (P = 0.013). Conclusion. Hyponatremia is a specific marker of infectious colon perforation in patients older than fifty years. Older patients with abdominal sepsis present with altered symptoms  and theiCRP is a known strong marker of infectious colon perforation , 4. HypoPeritonitis can lead to increased vagal tone  leading We aimed to evaluate symptoms and signs , laboratory values , and ECG signs of increased vagal tone  as markers of infectious colon perforation in patients older than 50 years.All patients older than fifty years with sigmoid diverticulitis or appendicitis admitted to our hospital between January 2008 and December 2010 were included in this study. Patients who were fifty years old or younger were excluded from the study. Patient identification was done by screening all radiology reports from this period with the search term “diverti*” and by screening all operation reports from this period with the search term “append*.” The presence of perforation was diagnosed by computer tomography  and/or by surgical exploration. n = 198) or with acute appendicitis (n = 84) were retrospectively analyzed.Finally, two hundred and eighty-two consecutive patients older than fifty years with sigmoid diverticulitis  to 10 (most severe pain), heart rate and blood pressure were measured using an automatic blood pressure machine, and body temperature was measured with a tympanic thermometer. Blood samples were taken before starting any infusion therapy in order to do a blood count and to analyze CRP, the electrolytes, and creatinine levels. Then a 12-lead ECG was done routinely.Normal CRP values were recorded as below 5 mg/L; for the analyses, we set the negative results to 2.5 mg/L in order to prevent a bias. The threshold for elevated leukocytes was set to >10/nL and the threshold for hyponatremia was set to <136 mmol/L. Vasovagal signs in ECG were defined as symmetroid T-waves longer than two-thirds of the R-wave in any ECG lead or presence of AV block.Stata 10.0 for Windows was used for computing statistical tests. The category data were summarized and a two-tailed Fisher's test was performed. The quantitative data was compared using the Wilcoxon rank sum test. A logistic regression analysis was performed to compare the diagnostic values of those markers that correlated significantly with colon perforation in univariate analysis. The study has been reviewed by the Ethics committeeof Basel (Ref.-Nr. 25/13). P < 0.001), tachycardia (>100 bpm), heart rate, hyponatremia (<136 mmol/L), sodium, markedly elevated CRP (>50 mg/L), leukocytosis (>10/nL), and leukocytes correlated with infectious colon perforation, while signs in ECG, pain score, systolic blood pressure, hematocrit, creatinine, and potassium did not. The prevalence or mean values and the corresponding P values of the assessed markers of infectious colon perforation are shown in P < 0.001, OR  =  1.006), body temperature , and sodium  correlated significantly with infectious colon perforation, while heart rate  and leukocytes  did not. The significant difference of prevalence of hyponatremia in the group with and in the group without colon perforation is shown in One hundred and three patients were classified into the group with infectious colon perforation and one hundred and seventy-nine patients into the group without (perforation rate 37%). The group with and the group without infectious colon perforation were comparable with regard to baseline data and to regular medicament intake . In univHyponatremia, tachycardia, and fever have a moderate-to-high specificity for colon perforation. Therefore, their presence should raise suspicion of perforation. However, as the sensitivity of these three markers is poor, their absence cannot predict the absence of colon perforation in appendicitis or in sigmoid diverticulitis. The sensitivity of markedly elevated CRP and leukocytosis is moderate, while the specificity is poor. Therefore, the absence of these markers can be used to exclude colon perforation in appendicitis or in sigmoid diverticulitis. However, if present, they are not strong predictors of colon perforation in appendicitis or in sigmoid diverticulitis.To our knowledge, no other study has found hyponatremia to be correlated significantly with colon perforation with consecutive peritonitis in appendicitis or sigmoid diverticulitis. This is of certain clinical importance as sodium measurement costs much less than measurement of CRP or other inflammation markers and sodium is often measured in the daily routine.Limitations such as possible patient selection, missing data, and confounding are possible due to the retrospective nature of this study. However, the results are strengthened by the fact that all consecutive patients older than fifty years with appendicitis or with acute sigmoid diverticulitis admitted between January 2008 and December 2010 to one hospital were included in this study and that pain score, heart rate, blood pressure, body temperature, and laboratory values were measured before any therapy began and later statistically assessed.As well as body temperature and CRP level, hyponatremia is a relevant and specific marker of infectious colon perforation in patients older than fifty years.


However about 60% of hypertensive patients in Germany treated with antihypertensives do not reach the recommended target blood pressure. The involvement of patients in medical decision making fulfils not only an ethical imperative but, furthermore, has the potential of higher treatment success. One concept to enhance the active role of patients is shared decision making. Until now there exists little information on the effects of shared decision making trainings for general practitioners on patient participation In a cluster-randomised controlled trial 1800 patients receiving antihypertensives will be screened with 24 h ambulatory blood pressure monitoring in their general practitioners’ practices. Only patients who have not reached their blood pressure target (approximately 1200) will remain in the study (T1 – T3). General practitioners of the intervention group will take part in a shared decision making-training after baseline assessment (T0). General practitioners of the control group will treat their patients as usual. Primary endpoints are change of systolic blood pressure and change of patients’ perceived participation. Secondary endpoints are changes of diastolic blood pressure, knowledge, medical adherence and cardiovascular risk. Data analysis will be performed with mixed effects models.The hypothesis underlying this study is that shared decision making, realised by a shared decision making training for general practitioners, activates patients, facilitates patients’ empowerment and contributes to a better hypertension control. This study is the first one that tests this hypothesis with a (cluster-) randomised trial and a large sample size.http://apps.who.int/trialsearch/Trial.aspx?TrialID=DRKS00000125WHO International Clinical Trials:  Hypertension is one of the key factors causing cardiovascular diseases  which maOne key concept to enhance patients’ active participation in medical decisions is shared decision making (SDM). It is characterised as an interactive process between physician and patient, acting according to the principle of equipoise. Both parties share information with the aim to build a consensus about the preferred treatment and its realisation. One precondition to realise SDM is the existence of equivalent treatment options ,7.It must be assumed that patients with hypertension who do not reach target blood pressure despite antihypertensive medication are – at least in their majority – not able to put behaviour change and / or medical adherence into practice. In these cases, first of all, general practitioners (GP) should support patients to improve their health behaviour -10.Evidence on SDM interventions showed positive effects of SDM on patients’ participation, satisfaction with their treatment, decisional conflict, knowledge about the disease, adherence, and partly clinical outcomes -17. NeveWithin the research programme “The patient as partner in medical decision making”, funded from 2001 by the German Ministry of Health, an SDM training programme for clinicians has been developed  and evaland clinical outcomes [Until now there exists little information on the effects of SDM trainings for GPs on patient participation outcomes . This hooutcomes . The aimOur study attempts to answer the following research questions: Does the SDM training programme for GPs1) enhance patients’ perceived participation?2) optimise the blood pressure values of patients?3) enhance patients’ knowledge about hypertension?4) improve patient adherence?The Ethical Committee of the University Medical Centre Freiburg approved this study on 26 February 2009. A non-substantial protocol amendment was approved on 7 March 2012 by the Ethical Committee of the University Medical Centre Freiburg.The study will be conducted as a cluster-RCT with 40 GP practices in the Suedbaden region, Germany. Patients who receive an antihypertensive medication will be invited to take part in the study. After a baseline data assessment (T0), GPs will be randomised into intervention group (SDM training and dissemination of printed patient information on hypertension and antihypertensive treatment) and into control group . After the intervention, three follow-up data assessments are scheduled  will be informed about the study.Each participating GP is asked to include 30 patients in the study who are currently treated for hypertension. These patients have to fulfil the following criteria.Inclusion criteria: (1) Repeated prescription of antihypertensive medication, (2) at least 18 years old, (3) insured by a statutory health fund, (4) understanding of the German language.Exclusion criteria: Dementia, mental handicap, or short life expectancyTo assure a random sample of the patients in each GP practice, medical assistants of the practices (MA) will be instructed to invite every third consecutive patient fulfilling the inclusion criteria to take part in the study. For all patients fulfilling the inclusion criteria and willing to take part in the study, a baseline assessment is performed. This includes ambulatory blood pressure measurement (ABPM) to screen blood pressure control in all recruited patients, further clinical data and a patient questionnaire. Recruiting takes place over half a year.After baseline ABPM, patients will be classified as ‘controlled’ treated if their blood pressure values are below the thresholds for hypertension measured by ABPM: mean values for 24 h ≤ 130/80 mmHg, ≤ 135/85 mmHg during the day, and ≤ 120/70 mmHg at night [As soon as the baseline assessment has been completed, GP practices will be randomised into intervention and control group. The randomisation will be performed by lot procedure. Thus, about half of the GPs will be assigned to the intervention and half of the GPs to the control group.GPs of the intervention group will take part in an evaluated SDM training . The traAfter the SDM training, GP practices will receive printed patient information developed by the German College of General Practitioners and Family Physicians (DEGAM) regarding blood pressure and the role of physical activity, healthy nutrition, and smoking cessation. GPs will be appealed to deliver patient information to the patients with hypertension.GPs of the control group treat their patients as usual. They are invited to take part in the SDM training after the study.arriba (http://www.arriba-hausarzt.de/arriba/index.html).(1) Systolic and diastolic office blood pressure measurement in mmHg, (2) comorbidity: diabetes mellitus (and HbA1c), coronary heart disease / heart attack, ischaemic stroke / transient ischaemic attack or peripheral arterial occlusive disease, (3) cholesterol: total, HDL and LDL cholesterol, (4) 24 h ambulatory blood pressure monitoring (ABPM), (5) cardiovascular 10-year-risk score calculated according to the algorithm of the cardiovascular risk calculator (1) Index reflecting patients’ intention to treat hypertension , (2) Med(1) Current medication prescription plans of the GP practices (before each ABPM) including data on medication to lower blood pressure and cholesterol (ATC codes C02-C04 and C07–C10), dose and number of each entity, and time of day when a medication is taken. (2) Data of filled prescriptions (ATC codes C02-C04 and C07–C10). The prescription data will be used to define a medication possession ratio (MPR)  for eachAll used scales – except knowledge questions and utilisation of further health care services – have been validated by other authors and translated into German by a consensus procedure. Retranslations (from German into English) were authorised by the original author. Besides age, gender, degree of education, employment status and family history of cardiovascular events we ask whether patients are living with a partner. Furthermore height and weight as well as tobacco consumption will be assessed.Co-primary endpoints are (1) change of patients’ perceived participation (measured by SDM-Q-9) from T0 to T1, T2 and T3, evaluated by the mean effect over the three time points, and (2) change of systolic blood pressure (mean of 24 h), measured by ABPM , from T1Secondary endpoints are (1) change of diastolic blood pressure (24 h mean), (2) change of knowledge score, (3) change of adherence, measured by MARS-D and the MPR, and (4) change of cardiovascular risk score (CVR), all evaluated by the mean effect over the two and three follow-up time points, respectively. While the intervention may affect knowledge directly after T0, the other secondary endpoints will be affected at T2 at the earliest.The study should also be used to investigate whether patient characteristics like API, CVR, MARS-D, Intention-To-Treat-Hypertension-Index, helping relationship in taking medication and high knowledge score may predict treatment effects.In all participating GP practices identical ABPM instruments will be installed by supervised personnel. Medical assistants (MAs) of GPs will be instructed about utilisation of the ABPM, recruitment procedure and data collection.Patients who agree to take part in the study sign an informed consent form. Blood pressure, gender, age and comorbidity of patients who do not agree to take part in the study will be anonymously assessed to account for a possible selection bias due to the study enrolment.The baseline assessment includes all clinical data, socio-demographic data and prescription data. Before the ABPM will be performed, patients complete a first questionnaire including socio-demographic data, intention-to-treat-hypertension index , medicatIf the average blood pressure in the ABPM protocol exceeds 130/80 mmHg (24 h mean) or 135/85 mmHg (daytime mean) or 120/70 mmHg (night mean), previous blood pressure treatment is considered as ‘uncontrolled’ . These pThe follow-up assessments take place every 6 (+ − 2) months. In each follow-up, all clinical data and prescription plans will be assessed. After ABPM and the following consultation focusing blood pressure protocol, patients are asked to complete a follow-up questionnaire which includes MARS, TPS, knowledge about hypertension, treatment decision made to control hypertension, SDM-Q-9, tobacco consumption, height and weight, and utilisation of further health services.The GP practices or medical assistants, respectively receive a case payment of 10 € per complete dataset of each patient in each assessment. The ABPM equipment will be offered to the GPs after the end of the study.All pseudonymised data of the patient questionnaires, forms, prescription plans, ABPM protocols and filled prescriptions will be merged into an SPSS data file. The quality of the data entry of each assessment will be proved by a 10% random sample check. Additionally, extensive plausibility checks are performed.Major analyses will be conducted by the Clinical Trials Unit at the University Medical Centre Freiburg. Statistical programming will be performed with the Statistical Analysis System (SAS) Version 9.2 or higher.The sample size calculation resulted in about 40 practices (20 per intervention group) with a total of 1200 patients (600 per treatment group), including about 20% drop outs on patient as well as practice level. Hence, data on 788 patients are expected to be available for analysis (i.e. about 33 practices with 24 patients each). Studies regarding hypertension prevalence  assume tDue to changes in the statistical analysis plan, a power calculation for the new analysis strategy has been performed .The analysis of the primary endpoints ‘change of perceived participation’ and ‘change of systolic blood pressure will be done according to the intention-to-treat (ITT) principle. As we have no means to define protocol violations on the patient level and there were made no attempts to assess compliance at the practice level, no per-protocol analyses are planned.Prior to the analysis, the missing patterns will be explored. Depending on the findings, strategies will be worked out to reduce missing values. Possible strategies are, for example, imputation or exclusion of single items with many missing values in questionnaires.In addition, we will analyse the missing patterns with respect to frequency and association with patient characteristics, with outcome measurements at other time points and with treatment status. The overall aim is to provide arguments to justify the use of a mixed model analysis, which formally relies on the missing at random (MAR) assumption.For illustration of the main trends, boxplots will be used to visualise the distribution of primary and secondary outcome measurements at baseline and follow-up measurements as well as changes from baseline. In addition, the changes in the primary outcomes SDM and systolic blood pressure are plotted for each patient separately to explore the individual course of measurements.The analysis of effectiveness of the intervention on the primary endpoints ‘change of perceived participation’ and change of systolic blood pressure will be performed with a mixed effects model of typei specifies the practice, j the patients  and k the time point . In addition, μ is the intercept, αi the random practice effect, βk the fixed effect of intervention at time point Tk, γij the random patient effect, δk the fixed effect for time point Tk, λ the fixed effect of baseline measurement Yijb (with b = 0 for perceived participation and b = 1 for systolic blood pressure) and ϵijk the error term.where index This model accounts for the variation within and between the clusters . The effect of intervention (β) will be tested based on the mean of estimated effects over the different follow-up time points, i.e. According to the EMA points to consider adjustment for baseline covariates  in ‘chanThe secondary endpoints will be analysed analogously with significance level 5%. No adjustment for multiple testing will be used.For the endpoints systolic and diastolic blood pressure, medication adherence report scale (MARS) and cardiovascular risk score (CVR) with baseline T1, a model with baseline T0 is also considered as a sensitivity analysis.For the primary endpoints, an additional sensitivity analysis based on a model adjusted for the prognostic factors practice, age, gender, baseline values of cardiovascular risk and comorbidity, MARS, API, intention to treat hypertension, helping relationship in taking medication, knowledge about hypertension, TPS and an indicator for treatment outside medical practice (aggregated over the complete study period) is conducted.As an exploratory analysis, the influence of the prognostic factors mentioned above on the primary endpoints at baseline will be investigated.No interim analysis will be performed during the course of the study.The hypotheses on the predictiveness of the factors API, CVR, intention to treat hypertension, helping relationship in taking medication, adherence, and knowledge will be addressed visually by depicting the mean values of the change in the two primary outcomes stratified by the factors in three (API) and two groups  based on the terciles and median, respectively. In addition, regression models will be fitted in analogy to the primary analyses that are assuming identical effects at each time point, but allowing an interaction with the factor of interest, i.e. intervention. Since the influence of API on the change in perceived participation is expected to be strongest for medium sized API and less pronounced for small and large values ,31, a quFurther analyses will be performed: (1) Association of practice characteristics with practice specific treatment effects, (2) predictiveness of change in a) perceived participation and b) TPS on change in systolic blood pressure, (3) association between a) change in perceived participation and change in TPS and b) change in adherence and change in perceived participation and systolic blood pressure, (4) comparison of the MPR with patients’ self-assessed adherence (MARS).For the power calculation we assume that 788 patients are available for analysis with 24 patients per practice (i.e. about 33 practices) according to the original sample size calculation . Since Kerry and Bland  state thSince knowledge on the expected effects for systolic blood pressure and perceived participation is rare, we base the calculation on the standardised effect size . AccordiThese calculations are based on the assumption of only one measurement per patient during follow-up. They can be considered as conservative for the situation of repeated measurements at T1, T2, and T3, since this gives additional information  randomised trial and a large sample size.ABPM:Ambulatory blood pressure monitoring / measurement; API:Autonomy Preference Index; ATC:Anatomical Therapeutic Chemical Classification System; BP:Blood pressure; CVR:Cardiovascular risk; DEGAM:German College of General Practitioners and Family Physicians; DFG:German Research Foundation; GP:General Practitioners; ICC:Intra-cluster correlation; ITT:Intention-to-treat; MAR:Missing at random; MARS-D:Medication Adherence Report Scale; MA:Medical assistants of the practices; MPR:Medication possession ratio; PAOD:Peripheral arterial occlusive disease; RCT:Randomised Controlled Trial; SDM:Shared decision making; SDM-Q-9:9-item-questionnaire measuring patients’ perceived participation in medical decision making; TIA:Transient ischaemic attack; TPS:Trust in Physician Scale.The authors declare that they have no competing interests.KGF, WN, AL, TD, IT conceived the study. AB, WV, IT and AB planned the statistical analysis. AS and all other authors have been involved in drafting the manuscript and they revised it critically. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2261/12/73/prepub


CXCL5 gene, which encodes the neutrophilic chemokine ENA-78, are associated with blood pressure in cardiovascular disease (CVD)-free adults and that these polymorphisms are functional.Leukocyte count has been associated with blood pressure, hypertension, and hypertensive complications. We hypothesized that polymorphisms in the CXCL5 polymorphisms (−156 G > C (rs352046) and 398 G > A (rs425535)) were tested for associations with blood pressure. Allele-specific mRNA expression in leukocytes was also measured to determine whether heterozygosity was associated with allelic expression imbalance. In −156 C variant carriers, systolic blood pressure (SBP) was 7 mmHg higher than in −156 G/G wild-type homozygotes . Similarly, diastolic blood pressure (DBP) was 4 mmHg higher in −156 C variant carriers . In multivariate analysis of SBP, age, sex, body mass index, and the −156 G > C polymorphism were identified as significant variables. Age, sex, and the −156 G > C SNP were further associated with DBP, along with white blood cells. Allelic expression imbalance and significantly higher circulating ENA-78 concentrations were noted for variant carriers.A total of 192 community-dwelling participants without CVD or risk equivalents were enrolled. Two CXCL5 gene polymorphisms are functional and associated with variable blood pressure in CVD-free individuals. The role of CXCL5 as a hypertension- and CVD-susceptibility gene should be further explored. The relationship between inflammation and elevated blood pressure is increasingly being evaluated,2. It haAlthough the exact mechanistic relationship between leukocytosis and elevated blood pressure is unknown, it is plausible that low-grade inflammation may be a contributing factor. In this regard, WBC count may be a surrogate marker for increased activation of inflammatory pathways that cause leukocyte recruitment and activation. As such, increased activity of leukocytic chemokines could be related to increased blood pressure.CXCL5) occur in sites important for transcription and exon splicing[CXCL5 -156 G > C polymorphism and worse outcomes in patients with acute coronary syndromes[CXCL5 variant alleles would exhibit higher systolic blood pressure (SBP), diastolic blood pressure (DBP), or pulse pressure (PP) than wild-type homozygotes. Furthermore, to assess whether there was a functional role for these polymorphisms, we measured allele-specific mRNA expression of CXCL5 in leukocytes obtained from CVD-free individuals who were heterozygous for the SNPs at both loci.Epithelial neutrophil activator-78 (ENA-78), a key leukocytic chemokine that is both a neutrophil attractor and activator, has been implicated in many diseases with an inflammatory component -32. We hsplicing. In our splicing. We thenyndromes. In the The study population has been previously described. BrieflyCXCL5 genotypes were determined by polymerase chain reaction (PCR) and pyrosequencing  as we have previously described[Genomic DNA was isolated from whole blood or buccal cells using previously described methods. CXCL5 gescribed. Circulaescribed. SamplesCXCL5, while −156 G > C is a promoter polymorphism and as such cannot be quantified at the mRNA level. Because of the near complete linkage of the studied SNPs, we chose individuals who were heterozygotes at both loci so that 398 G > A genotype might serve as a functional surrogate for the upstream promoter locus.To determine whether variant carrier status results in functional changes at the transcriptional level, we quantified allele-specific mRNA transcripts from leukocytes using pyrosequencing-based methodology,39. Spec6 cells from each individual using the RNeasy mini kit . Cells were rinsed, lysed, and homogenized in buffered solutions and subsequently passed through the RNeasy mini column . Following a series of washes at room temperature and 15-min incubation with DNase, concentrations were determined by spectrophotometry . cDNA was synthesized using approximately 450 ng of cellular RNA from each individual using a High-Capacity cDNA Archive Kit  per protocol. Conditions for reverse transcription were 25°C for 10 min followed by 37°C for 2 h. cDNA quality was assessed by comparing cDNA and DNA PCR products generated using intron-spanning primers by gel electrophoresis. For allele-specific transcript quantification, subject DNA and cDNA underwent PCR simultaneously using previously described conditions[Leukocyte mRNA was prepared from approximately 6 × 10nditions. PCR proP ≤ 0.1 on univariate analysis was entered into the multivariable model. Because of small numbers of individuals within racial groups, analyses could not be performed within racial strata. However, race  was included in all multivariable analyses, and a race-by-genotype interaction term was considered in the regression models to avoid spurious associations secondary to racial differences in allele frequency. Multiple regression using step-type selection methods was performed to determine the joint effects of CXCL5 genotypes and clinical variables on SBP, DBP, or PP. All statistical analyses were performed using SPSS  or SAS . A P value < 0.05 was considered statistically significant.Genotype frequencies were determined by allele counting, and departures from Hardy-Weinberg equilibrium were assessed by chi-square analyses. Differences in blood pressure by genotype groups  were compared using one-way ANOVA. Based on the preexisting sample size and prevalence of variant alleles, we had 80% power with a two-sided α of 0.05 to detect a 6-mmHg difference in SBP, 4-mmHg difference in DBP, and 4-mmHg difference in PP between genotype groups. Multiple regression analysis was performed if blood pressure differences were seen across genotype groups. Covariates for multiple regression were chosen through univariate analyses of age, sex, smoking status , body mass index (BMI), CRP concentration, ENA-78 concentration, and WBC count. Any variable with a r2 for Caucasian, black, and Hispanic individuals of 0.82, 1.0, and 0.51, respectively, in our study population.Baseline demographic characteristics are shown in Table P = 0.008). Similarly, DBP was 4-mmHg higher in −156 C variant carriers . PP did not differ between −156 C variant carriers and wild-type homozygotes . Because of the high degree of linkage disequilibrium between the 398 G > A and −156 G > C SNPs, blood pressure differences were similar when compared by 398 G > A genotypes. For example, SBP was 130 ± 16 and 125 ± 14 mmHg in 398A variant carriers and 398 G/G homozygotes, respectively (P = 0.033); DBP was 78 ± 11 and 74 ± 11 mmHg, respectively (P = 0.038); and PP was not different between groups .In −156 C variant carriers, SBP was 7-mmHg higher than in −156 G/G wild-type homozygotes , sex (P ≤ 0.008), and BMI (P ≤ 0.002) were common univariate predictors of SBP, DBP, and PP. Furthermore, WBC count  and both CXCL5 polymorphisms (range P = 0.008 to 0.038) were additional predictors of SBP and DBP, while smoking status was associated with SBP alone (P = 0.038). In terms of circulating CRP and ENA-78 levels, both biomarkers were significant for SBP (P = 0.005 for CRP and P = 0.033 for ENA-78) and PP (P = 0.001 for CRP and P = 0.007 for ENA-78) in univariate analyses. Consistent with our previous report, CXCL5 genotype was associated with ENA-78 protein concentrations in the plasma whereby variant carriers at either SNP locus had higher protein concentrations than wild-type homozygotes . Consideration of the 398 G > A polymorphism rather than the −156 G > C promoter SNP resulted in a model in which only age, sex, and BMI were significantly associated with SBP .In multivariate analysis of SBP, age, sex, BMI, and the s Table . The oveR2 = 0.168; P < 0.0001) was slightly more informative than consideration of the 398 G > A SNP (P = 0.067) in which case age (P < 0.0001), sex (P = 0.001), and WBC (P = 0.02) still remained significant . In multivariable models of PP, only sex (P < 0.004) and BMI (P < 0.0001) were significant .Age, sex, and the −156 G > C SNP were further associated with DBP, along with WBC Table . ConsideCXCL5 genotypes . Importantly, there was consistently higher expression of CXCL5 mRNA from the 398A allele compared to the 398 G allele in heterozygous individuals .Allele-specific mRNA quantification was performed to determine whether there is a functional basis for the differences seen in blood pressure based on s FigureA. For exCXCL5 gene, which encodes the neutrophil attractor ENA-78, may be an important determinant of blood pressure. We demonstrated a significant, independent relationship between CXCL5 polymorphisms and SBP and DBP in the overall population of CVD-free individuals. Variant carriers of the −156 G > C promoter SNP had 7-mmHg and 4-mmHg higher SBP and DBP, respectively, than those with the wild-type −156 G/G genotype. Because of the epidemiologically significant difference in CVD risk conferred by blood pressure differences of this magnitude, and since variant carriers represent approximately 30% of the population studied, CXCL5 polymorphisms should be considered as a potential novel biomarker of pre-hypertension, hypertension, and CVD risk requiring future study. However, it is important to emphasize that genetic associations are preliminary and will require confirmation in additional populations.Accumulating evidence points to a relationship between inflammation and blood pressure. Data suggest that WBC counts are associated with incident hypertension and correlated with blood pressure concentrations. We hypothesized that WBC count is a surrogate for leukocytic chemokine activity and that the CXCL5 genotype was included in multivariable analysis, suggesting genotype may capture the contribution of inflammation to SBP more effectively than WBC count. WBC did, however, remain a significant predictor of DBP in multivariate analysis, along with age, sex, and CXCL5 -156 G > C genotype.Of particular interest, WBC count  was significantly associated with SBP and DBP in univariate analysis among CVD-free individuals. This finding supports the report by Orakzai et al. that demonstrated a relationship between WBC counts and SBP among nearly 3,500 white individuals without CVD and with SBP < 140 mmHg on entry. It alsoCXCL5 variant alleles and blood pressure, we performed allele expression imbalance experiments in a subset of participants. The exonic 398 G > A allele was chosen as the genetic marker given its location in the coding region of the mRNA. However, the 398 G/A heterozygous individuals (N = 18) were also heterozygous for the promoter polymorphism, which minimizes confounding of an association by differing genotypes at the upstream locus. It was noted that variant carriers displayed nearly threefold higher expression of variant CXCL5 mRNA transcripts from the 398A allele. This novel finding is consistent with our previous observation that variant carriers exhibited higher plasma and leukocyte-produced ENA-78 than wild-type homozygotes and that the promoter and exonic SNPs occur in transcription factor binding and splicing enhancer sites, respectively[To determine whether there is any functional basis for an observed association between ectively. Given tCXCL5 genotype was included. This suggests that in our analyses, genotype is more significantly associated with the blood pressure phenotype than systemically circulating concentrations of the non-specific inflammatory mediator CRP and the CXCL5 protein product ENA-78. While this observation may appear somewhat contradictory, it can be postulated that CXCL5 gene polymorphisms may be better indicators of chemokine activity at the target organ  level than a measurement in the circulation. Because of trans-acting influences on systemic biomarker expression, polymorphisms in CXCL5 may be more robustly associated with blood pressure. In fact, we have shown a similar finding in a different population for the endothelial nitric oxide synthase gene where NOS3 gene polymorphisms, but not measures of circulating NO activity, were associated with arterial stiffness in children with type 1 diabetes[In addition to genotype and traditional covariates, we included plasma CRP and ENA-78 protein concentrations in our analyses. While CRP and ENA-78 were significantly associated with SBP (and PP) in univariate analyses, they fell out of the models when diabetes,43. Furtdiabetes. Taken iCXCL5 in CVD. For example, the protein product of CXCL5, ENA-78, belongs to the same class of chemokines as IL-8, IP-10, and I-TAC, which have been previously implicated in atherosclerotic inflammation[CXCL5 polymorphisms to be associated with ENA-78 concentrations, blood pressure, and prognosis following acute coronary syndromes[CXCL5 in CVD should be further explored. As final hypothesis-generating evidence of a link between the CXCL5 pathway and blood pressure, statins have been hypothesized to have mild antihypertensive effects, and we have shown that atorvastatin reduces ENA-78 production from human endothelial cells in a dose-dependent fashion[CXCL5 as a hypertension- and CVD-susceptibility gene.In general, there is biological plausibility for the role of ammation,45. ENA-ammation,25. In aammation,44,46-51yndromes,33. Thus fashion,53. Our The authors declare that they have no competing interests.ALB performed statistical analyses and drafted the manuscript. CLA enrolled the study subjects and drafted the manuscript. HA assisted in the molecular genetic studies and provided critical revision of the manuscript. TYL assisted in the molecular genetic studies. GJW assisted in the molecular genetic studies. RSS assisted with the clinical study. IZ conceived the manuscript, enrolled the study subjects, and drafted the manuscript. All authors read and approved the final manuscript.