الفهرس 
Sepsis and Septic ShockOnly 14 pages are availabe for public view
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Abstract
from the results obtained from this study, the following can be concluded:
• Midodrine use significantly reduced the duration of intravenous (IV) vasopressor infusion, total amount of IV vasopressor used and the weaning period during the recovery phase of septic shock patients.
• Midodrine use significantly reduced the intensive care unit (ICU) mortality rate but had no impact on ICU length of stay (LOS).
• Midodrine is a cost saving and dominant treatment in patients with septic shock
Limitations
1- The study design was single centered which limits the generalizability of the results
2- Dependence on the accuracy of medical and nursing records documentation.
3- The second arm of the study was non-blinded as norepinephrine patients did not receive placebo tablets.
4- The fixed midodrine drug dosing was selected to simplify the regimen.
5- Patients were not followed up after discharge from intensive care unit (ICU).
Recommendations
According to the results of the current study, it could be recommended that:
1- Further prospective randomized controlled clinical trials on larger number of patients with septic shock are needed to confirm the results of the present study.
2- The optimum midodrine dose in septic shock patients and its possible outcome on intensive care unit (ICU) length of stay (LOS) need to be assessed in the future studies.
3- Cost of illness module studies are required in future studies to measure the burden of the disease.
Summary
Sepsis and septic shock are the main causes of mortality of millions of intensive care unit patients worldwide. The patient ’s immune response to infection is the mainstay of pathophysiology of sepsis and septic shock. The systemic broad scale of that inflammatory response causes vasodilation, increase in the permeability of blood vessels and activates blood vessels’ thrombosis. Also, coagulation cascades leading to further endothelial and end-organ damage may occur. Accordingly, the majority of patients who die with septic shock have multiple organ dysfunction syndrome.
The International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3), the SSC, defines sepsis as the presence of infection plus life-threatening organ dysfunction caused by a dysregulated host response to infection. Organ dysfunction can be identified as an acute change in total score of ≥ 2 points as a consequence of the infection.
Also, the SSC defines septic shock as the sepsis subset in which significant underlying circulatory, cellular and metabolic abnormalities are associated with a high risk of mortality than with sepsis alone. Patients with septic shock can be clinically identified by a persistent fluid unresponsive hypotension with vasopressors requirement to maintain a mean arterial pressure of ≥ 65 mm Hg and having a serum lactate level of > 2mmol/L(>18mg/dl) despite adequate volume resuscitation.
The early treatment of sepsis and septic shock in the initial hours improves patients’ outcomes dramatically. The immediate fluid resuscitation and intravenous (IV) vasopressors use (norepinephrine as the first-choice vasopressor) are the cornerstones of the management of persistent severe hypotension and septic shock to keep mean arterial pressure (MAP) of ≥65 mm Hg and maintain tissue perfusion.
There are a lot of complications associated with the prolonged use of IV vasopressor in the intensive care unit (ICU) including; splanchnic and peripheral ischemia, increase risk of acquiring multidrug resistant infections and mortality.
A lot of patients with septic shock usually recover from their illness but still need low dose of IV vasopressor to maintain (MAP) ≥65 mm Hg. Inability to completely wean from IV vasopressor serve as hinder delaying discharge of septic shock patients who otherwise have met ICU discharge criteria thus increasing LOS and ICU related complications.
The use of oral medication with vasopressor effect as oral midodrine to replace IV vasopressor (norepinephrine) may be a good solution to reduce the duration of IV vasopressors infusions, length of stay (LOS) of the ICU and minimize the IV vasopressors’ adverse effects.
Based on the available limited published studies, Midodrine is considered an effective adjunct that can give hemodynamic support and hasten (IV) vasopressor weaning in critically ill patients (off-label use) .
The current study aimed to evaluate the impact of midodrine administration on the weaning of vasopressor infusions in critically ill septic patients and its impact on the hemodynamics of patients with septic shock, the effect of midodrine on the outcome of septic patients regarding LOS in the ICU and ICU mortality and assessment of the cost efficacy of using midodrine in critically ill septic patients.
All patients with septic shock presenting to the department were assessed for eligibility according to the inclusion and exclusion criteria
Inclusion criteria included: Adult patients who are (18-80) years, septic shock diagnosis on admission (sepsis with persistent hypotension with systolic blood pressure <90 mmHg, MAP <65mmHg despite adequate volume resuscitation) requiring one or more IV vasopressors for more than 24 hrs to maintain their target arterial blood pressure goals and have a stable blood pressure on (IV) vasopressor infusion at a rate of <8 µg/min but unable to wean for >24 hrs.
Exclusion criteria included: Severe organic heart disease (ejection fraction less than 30%), bradycardia (HR<50 b/min), chronic kidney disease (serum creatinine >2mg/dl), thyrotoxicosis, pheochromocytoma, patients with hypovolemic shock and known allergy to midodrine.
Sixty eligible participants fulfilled the inclusion and exclusion criteria and completed the study and were randomized into one of 2 groups in a 1:1 ratio:
Norepinephrine group: thirty patients received IV vasopressor infusion (norepinephrine) only.
Midodrine group: thirty patients received oral vasopressor (midodrine 10 mg daily three times daily) in addition to IV vasopressor infusion (norepinephrine).
Intervention: When patients were well perfused and hemodynamically stable (no signs of tissue hypoperfusion),
(IV) vasopressor infusion at rate of < 8 µg/min but unable to wean for >24 h and no need to increase the dose of IV vasopressor during the past 24 h), the IV vasopressor weaning was commenced and patients of midodrine group received midodrine 10mg three times daily.
Results of the current study regarding the clinical evaluation showed no statistically significant differences in baseline demographics (sex, age and weight) and clinical characteristics between both groups. Hemodynamic parameters (heart rate, systolic blood pressure, diastolic blood pressure, mean arterial pressure, respiratory rate, temperature, central venous pressure, urine output) and comorbidities (hypertension, type 2 diabetes mellitus, coronary artery disease, asthma, peripheral artery disease, renal failure, cancer and psychiatric disease) were comparable in both groups at IV vasopressor start and all through the whole study. Also, there was no significant differences between both groups regarding Acute Physiologic Assessment and chronic Health Evaluation (APACHE II) score and Sequential Organ Failure Assessment (SOFA) score.
The primary outcomes: The duration of IV vasopressor infusion (h), the total amount of IV vasopressors (mg), and the weaning period till IV vasopressor discontinuation/patient death (hrs) were all significantly less in the midodrine group versus the norepinephrine group. In contrast, there were no significant differences between midodrine and norepinephrine groups regarding; the average IV vasopressor dose (µg /h), IV vasopressor start dose (µg/kg/min), min IV vasopressor dose (µg/kg/min), IV vasopressor at weaning initiation (µg/kg/min) or baseline IV vasopressor dose (µg/kg/min) used.
The secondary outcomes: The LOS was comparable in both groups, The mortality rate in the midodrine group was significantly less than that in the norepinephrine group. No side effects were associated with the use of midodrine. An equal percentage of patients (10%) in both groups were reinstituted on IV vasopressors after successful discontinuation.
Regarding the economic evaluation: Direct medical costs (medical care, ICU stay, service fees, medications, midodrine, supplies, radiograph, labs, blood gases, medical surveillance, medical consultation, blood transfusion, physical therapy and other investigation) were comparable in both groups. Regarding the relationship between the primary clinical outcomes and total costs in both groups, midodrine was a dominant treatment owing to the significantly higher percentage of survival, the less weaning time until discharge or patient death, the lower duration of vasopressors and lower cost. The total midodrine cost saving was 152, 413 EGP (equivalent to 9, 675.4 USD) and 5, 080.4 EGP per patient (equivalent to 322.5 USD). The estimated total cost saving in Egypt would be 2, 661, 941, 685 EGP (Equivalent to 168, 984, 275 USD).
from the results of the current study, it can be concluded that midodrine use reduced the duration of intravenous (IV) vasopressor infusion, total amount of IV vasopressor used and the weaning period during the recovery phase of septic shock patients. Also, Midodrine use reduced the intensive care unit (ICU) mortality rate but had no impact on ICU length of stay (LOS).