Generally, the treatment for SIRS is directed towards the underlying problem or inciting cause (i.e. adequate fluid replacement for hypovolemia, IVF/NPO for pancreatitis, epinephrine/steroids/diphenhydramine for anaphylaxis).

Selenium, glutamine, and eicosapentaenoic acid have shown effectiveness in improving symptoms in clinical trials. Other antioxidants such as vitamin E may be helpful as well.

Septic treatment protocol and diagnostic tools have been created due to the potentially severe outcome septic shock. For example, the SIRS criteria were created as mentioned above to be extremely sensitive in suggesting which patients may have sepsis. However, these rules lack specificity, i.e. not a true diagnosis of the condition, but rather a suggestion to take necessary precautions. The SIRS criteria are guidelines set in place to ensure septic patients receive care as early as possible.

In cases caused by an implanted mesh, removal (explantation) of the polypropylene surgical mesh implant may be indicated.

If the person has been sufficiently fluid resuscitated but the mean arterial pressure is not greater than 65 mmHg, vasopressors are recommended. Norepinephrine (noradrenaline) is recommended as the initial choice. If a single vasopressor is not enough to raise the blood pressure, epinephrine (adrenaline) or vasopressin may be added. Dopamine is typically not recommended. Dobutamine may be used if heart function is poor or blood flow is insufficient despite sufficient fluid volumes and blood pressure.

General anaesthesia is recommended for people with sepsis who require surgical procedures to remove the infective source. Inhalational and intravenous anaesthetics are used. Requirements for anaesthetics may be reduced. Inhalational anaesthetics can reduce the level of proinflammatory cytokines, altering leukocyte adhesion and proliferation, inducing apoptosis (cell death) of the lymphocytes, possibly with a toxic effect on mitochondrial function. Although etomidate has a minimal effect on the cardiovascular system, it is often not recommended as a medication to help with intubation in this situation due to concerns it may lead to poor adrenal function and an increased risk of death. The small amount of evidence there is, however, has not found a change in the risk of death with etomidate.

It is recommended that the head of the bed be raised if possible to improve ventilation. Paralytic agents should be avoided unless ARDS is suspected.

Among the choices for vasopressors, norepinephrine is superior to dopamine in septic shock. Norepinephrine is the preferred vasopressor, while epinephrine may be added to norepinephrine when needed. Low-dose vasopressin also may be used as an addition to norepinephrine, but is not recommended as a first-line treatment. Dopamine may cause rapid heart rate and arrhythmias, and is only recommended in combination with norepinephrine in those with slow heart rate and low risk of arrhythmia. In the initial treatment of low blood pressure in septic shock, the goal of vasopressor treatment is a mean arterial pressure (MAP) of 65 mm Hg. In 2017, the FDA approved angiotensin II injection for intravenous infusion to increase blood pressure in adults with septic or other distributive shock.

Treatment guidelines call for the administration of broad-spectrum antibiotics within the first hour following recognition of septic shock. Prompt antimicrobial therapy is important, as risk of dying increases by approximately 10% for every hour of delay in receiving antibiotics. Time constraints do not allow the culture, identification, and testing for antibiotic sensitivity of the specific microorganism responsible for the infection. Therefore, combination antimicrobial therapy, which covers a wide range of potential causative organisms, is tied to better outcomes.

The main goals of treatment in distributive shock are to reverse the underlying cause and achieve hemodynamic stabilization. Immediate treatment involves fluid resuscitation and the use of vasoactive drugs, both vasopressors and inotropes. Hydrocortisone is used for patients whose hypotension does not respond to fluid resuscitation and vasopressors. Opening and keeping open the microcirculation is a consideration in the treatment of distributive shock, as a result limiting the use of vasopressors has been suggested. Control of inflammation, vascular function and coagulation to correct pathological differences in blood flow and microvascular shunting has been pointed to as a potentially important adjunct goal in the treatment of distributive shock.

Patients with septic shock are treated with antimicrobial drugs to treat the causative infection. Some sources of infection require surgical intervention including necrotizing fasciitis, cholangitis, abscess, intestinal ischemia, or infected medical devices.

Anaphylactic shock is treated with epinephrine.

SIRS is frequently complicated by failure of one or more organs or organ systems. The complications of SIRS include:

- Acute lung injury

- Acute kidney injury

- Shock

- Multiple organ dysfunction syndrome

Although frequently employed to treat patients experiencing the cytokine storm associated with ARDS, corticosteroids and NSAIDs have been evaluated in clinical trials and have shown no effect on lung mechanics, gas exchange, or beneficial outcome in early established ARDS.

Abdominal pain is often the predominant symptom in patients with acute pancreatitis and should be treated with analgesics.

Opioids are safe and effective at providing pain control in patients with acute pancreatitis. Adequate pain control requires the use of intravenous opiates, usually in the form of a patient-controlled analgesia pump. Hydromorphone or fentanyl (intravenous) may be used for pain relief in acute pancreatitis. Fentanyl is being increasingly used due to its better safety profile, especially in renal impairment. As with other opiates, fentanyl can depress respiratory function. It can be given both as a bolus as well as constant infusion.

Meperidine has been historically favored over morphine because of the belief that morphine caused an increase in sphincter of Oddi pressure. However, no clinical studies suggest that morphine can aggravate or cause pancreatitis or cholecystitis. In addition, meperidine has a short half-life and repeated doses can lead to accumulation of the metabolite normeperidine, which causes neuromuscular side effects and, rarely, seizures.

Some types of arthritis medications are designed to reduce inflammation by inhibiting the tumor necrosis factor-alpha pathway to immune cell activation; these drugs are known as TNF-alpha blockers. One study found that three different TNF-alpha blockers afforded a slight reduction in antibody presentation after vaccination against influenza in a group of immunocompromised patients, however it did not significantly affect patients' protective factor gained from inoculation. More research is necessary before any conclusions may be made regarding the efficacy of TNF-alpha blockers at reducing the effects of a cytokine storm in hospitalized flu patients.

Septic shock is associated with significant mortality and is the leading non cardiac cause of death in intensive care units (ICUs).

Initial management of a patient with acute pancreatitis consists of supportive care with fluid resuscitation, pain control, and nutritional support.

Vasopressors may be used if blood pressure does not improve with fluids. There is no evidence of substantial superiority of one vasopressor over another; however, using dopamine leads to an increased risk of arrythmia when compared with norepinephrine. Vasopressors have not been found to improve outcomes when used for hemorrhagic shock from trauma but may be of use in neurogenic shock. Activated protein C (Xigris) while once aggressively promoted for the management of septic shock has been found not to improve survival and is associated with a number of complications. Xigris was withdrawn from the market in 2011, and clinical trials were discontinued. The use of sodium bicarbonate is controversial as it has not been shown to improve outcomes. If used at all it should only be considered if the pH is less than 7.0.

Aggressive intravenous fluids are recommended in most types of shock (e.g. 1–2 liter normal saline bolus over 10 minutes or 20 ml/kg in a child) which is usually instituted as the person is being further evaluated. Which intravenous fluid is superior, colloids or crystalloids, remains undetermined. Thus as crystalloids are less expensive they are recommended. If the person remains in shock after initial resuscitation packed red blood cells should be administered to keep the hemoglobin greater than 100 g/l.

For those with haemorrhagic shock the current evidence supports limiting the use of fluids for penetrating thorax and abdominal injuries allowing mild hypotension to persist (known as permissive hypotension). Targets include a mean arterial pressure of 60 mmHg, a systolic blood pressure of 70–90 mmHg, or until their adequate mentation and peripheral pulses.

Acute respiratory distress syndrome is usually treated with mechanical ventilation in the intensive care unit (ICU). Mechanical ventilation is usually delivered through a rigid tube which enters the oral cavity and is secured in the airway (endotracheal intubation), or by tracheostomy when prolonged ventilation (≥2 weeks) is necessary. The role of non-invasive ventilation is limited to the very early period of the disease or to prevent worsening respiratory distress in individuals with atypical pneumonias, lung bruising, or major surgery patients, who are at risk of developing ARDS. Treatment of the underlying cause is crucial. Appropriate antibiotic therapy must be administered as soon as microbiological culture results are available, or clinical infection is suspected (whichever is earlier). Empirical therapy may be appropriate if local microbiological surveillance is efficient. The origin of infection, when surgically treatable, must be removed. When sepsis is diagnosed, appropriate local protocols should be enacted.

Inhaled nitric oxide (NO) selectively widens the lung's arteries which allows for more blood flow to open alveoli for gas exchange. Despite evidence of increased oxygenation status, there is no evidence that inhaled nitric oxide decreases morbidity and mortality in people with ARDS. Furthermore, nitric oxide may cause kidney damage and is not recommended as therapy for ARDS regardless of severity.

Surgical decompression can be achieved by opening the abdominal wall and abdominal fascia anterior in order to physically create more space for the abdominal viscera. Once opened, the fascia can be bridged for support and to prevent loss of domain by a variety of medical devices (Bogota bag, artificial bur, and vacuum devices using negative pressure wound therapy ).

Cholangitis requires admission to hospital. Intravenous fluids are administered, especially if the blood pressure is low, and antibiotics are commenced. Empirical treatment with broad-spectrum antibiotics is usually necessary until it is known for certain which pathogen is causing the infection, and to which antibiotics it is sensitive. Combinations of penicillins and aminoglycosides are widely used, although ciprofloxacin has been shown to be effective in most cases, and may be preferred to aminoglycosides because of fewer side effects. Metronidazole is often added to specifically treat the anaerobic pathogens, especially in those who are very ill or at risk of anaerobic infections. Antibiotics are continued for 7–10 days. Drugs that increase the blood pressure (vasopressors) may also be required to counter the low blood pressure.

In cases where a person is too ill to tolerate endoscopy or when a retrograde endoscopic approach fails to access the obstruction, a percutaneous transhepatic cholangiogram (PTC) may be performed to evaluate the biliary system for placement of a percutaneous biliary drain (PBD). This is often necessary in the case of a proximal stricture or a bilioenteric anastomosis (a surgical connection between the bile duct and small bowel, such as the duodenum or jejunum). Once access across the stricture is obtained, balloon dilation can be performed and stones can be swept forward into the duodenum. Due to potential complications of percutaneous biliary drain placement and the necessity of regular drain maintenance, a retrograde approach via ERCP remains first-line therapy.

CIP/CIM can lead to difficulty weaning a person from a mechanical ventilator, and is associated with increased length of stay in the ICU and increased mortality (death). It can lead to impaired rehabilitation. Since CIP/CIM can lead to decreased mobility (movement), it increases the risk of pneumonia, deep vein thrombosis, and pulmonary embolism.

Critically ill people that are in a coma can become completely paralyzed from CIP/CIM. Improvement usually occurs in weeks to months, as the innervation to the muscles are restored. About half of patients recover fully.

While the exact incidence is unknown, estimates range from 33 - 57 percent of patients staying in the ICU for longer than 7 days. More exact data is difficult to obtain, since variation exists in defining the condition.

The three main risk factors for CIP and CIM are sepsis and systemic inflammatory response syndrome (SIRS), and multi-organ failure. Reported rates of CIP/CIM in people with sepsis and SIRS range from 68 to 100 percent. Additional risk factors for developing CIP/CIM include: female gender, high blood sugar (hyperglycemia), low serum albumin, and immobility. A greater severity of illness increases the risk of CIP/CIM. Such risk factors include: multi-organ dysfunction, renal failure, renal replacement therapy, duration of organ dysfunction, duration of ICU stay, low albumin, and central neurologic failure.

Certain medications are associated with CIP/CIM, such as corticosteroids, neuromuscular blocking agents, vasopressors, catecholamines, and intravenous nutrition (parenteral nutrition). Research has produced inconsistent results for the impact of hypoxia, hypotension, hyperpyrexia, and increased age on the risk of CIP/CIM. The use of aminoglycosides is "not" an independent risk for the development of CIP/CIM.

Abdominal compartment syndrome occurs when the abdomen becomes subject to increased pressure. Specific cause of abdominal compartment syndrome is not known, although some causes can be sepsis and severe abdominal trauma. Increasing pressure reduces blood flow to abdominal organs and impairs pulmonary, cardiovascular, renal, and gastro-intestinal (GI) function, causing multiple organ dysfunction syndrome and death.