Gastrointestinal perforation medical therapy

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohammed Abdelwahed M.D[2]

Overview

• Initial management of the patient with gastrointestinal perforation includes:
• Intravenous fluid therapy and broad-spectrum antibiotics.
• The administration of intravenous proton pump inhibitors is appropriate for those suspected to have an upper gastrointestinal perforation.
• Patients with intestinal perforation can have severe volume depletion.
• Electrolyte abnormalities correction especially metabolic alkalosis if fistula developed. The severity of any electrolyte abnormalities depends upon the nature and volume of material leaking from the gastrointestinal tract.

Antibiotics 

Broad-spectrum antibiotic therapy is initiated if the level of perforation is unknown. The following tabel shows the regimens of choice in these cases:

Regimen	Dose
First choice regimens
Ampicillin-sulbactam	3 g IV every six hours
Piperacillin-tazobactam	3.375 or 4.5 g IV every six hours
Ticarcillin-clavulanate	3.1 g IV every four hours
Ceftriaxone	1 g IV every 24 hours (or 2 g IV every 12 hours for CNS infections)
Metronidazole	500 mg IV every eight hours
Alternative regimens
Ciprofloxacin or	400 mg IV every 12 hours
Levofloxacin	500 or 750 mg IV once daily
Metronidazole	500 mg IV every eight hours
Imipenem-cilastatin	500 mg IV every six hours
Meropenem	1 g IV every eight hours
Doripenem	500 mg IV every eight hours
Ertapenem	1 g IV once daily

Intravenous fluid therapy

• Tissue perfusion is predominantly achieved by the aggressive administration of intravenous fluids, given at 30 mL/kg within the first three hours following presentation.[7-12].
• using the following targets to measure the response:
• central venous oxyhemoglobin saturation (ScvO₂) ≥70 percent
• central venous pressure (CVP) 8 to 12 mmHg, mean arterial pressure (MAP) ≥65 mmHg
• urine output ≥0.5 mL/kg/hour [8-10]
• A lack of benefit of resuscitation protocols has also been reported in low income settings. As an example, in a randomized trial of 212 patients with sepsis (defined as suspected infection plus two systemic inflammatory response syndrome criteria) and hypotension (systolic blood pressure ≤90 mmHg or mean arterial pressure <65 mmHg) in Zambia, a protocolized approach of aggressive fluid resuscitation, monitoring, blood, and vasopressor transfusion within the first six hours of presentation resulted in a higher rate of death (48 versus 33 percent) when compared with usual care [16]. However, several flaws including crude measurements of monitoring, lower than usual rates of lactate elevation, larger than typical volumes of fluid resuscitation, and use of dopamine (as opposed to norepinephrine) in a population with a high percentage of patients with human immune deficiency virus may have biased the results.
• The importance of timely treatment, particularly with antibiotics, was illustrated in a database study of nearly 50,000 patients with sepsis and septic shock who were treated with various types of protocolized treatment bundles (that included fluids and antibiotics, blood cultures, and serum lactate measurements) [17]. Compared with those in whom a three-hour bundle (blood cultures before broad spectrum antibiotics, serum lactate level) was completed within the three-hour time frame, a higher in-hospital mortality was reported when a three-hour bundle was completed later than three hours (odds ratio [OR] 1.04 per hour). Increased mortality was associated with the delayed administration of antibiotics but not with a longer time to completion of a fluid bolus (as part of a six hour bundle) (OR 1.04 per hour versus 1.10 per hour).

first three hours

In patients with sepsis, intravascular hypovolemia is typical and may be severe, requiring rapid fluid resuscitation. (See "Treatment of severe hypovolemia or hypovolemic shock in adults".)

Volume — Intravascular hypovolemia is typical and may be severe in sepsis. Rapid, large volume infusions of IVF (30 mL/kg)are indicated as initial therapy for severe sepsis or septic shock, unless there is convincing evidence of significant pulmonary edema. This approach is based upon several randomized trials that reported no difference in mortality when mean infusion volumes of 2 to 3 liters were administered in the first three hours [8-10] compared with larger volumes of three to five liters, which was considered standard therapy at the time [7]. However, some patients may require higher than recommended volumes, particularly those who demonstrate clinical and/or hemodynamic indicators of fluid-responsiveness. (See 'Monitor response' below.)

Fluid therapy should be administered in well-defined (eg, 500 mL), rapidly infused boluses. The clinical and hemodynamic response and the presence or absence of pulmonary edema must be assessed before and after each bolus. Intravenous fluid challenges can be repeated until blood pressure and tissue perfusion are acceptable, pulmonary edema ensues, or fluid fails to augment perfusion.

Choice of fluid — Evidence from randomized trials and meta-analyses have found no convincing difference between using albumin solutions and crystalloid solutions (eg, normal saline, Ringer's lactate) in the treatment of sepsis or septic shock, but they have identified potential harm from using pentastarch or hydroxyethyl starch [18-27]. There is no role for hypertonic saline [28].

In our practice, we generally use a crystalloid solution instead of albumin solution because of the lack of clear benefit and higher cost of albumin. However, some experts administer albumin as an additive or maintenance fluid if there is a perceived need to avoid or treat the hyperchloremia that occurs when large volumes of crystalloid are administered, although the data to support this practice are weak.

Data discussing IVF choice among patients with sepsis include the following:

●Crystalloid versus albumin – Among patients with sepsis, several randomized trials and meta-analyses have reported no difference in mortality when albumin was compared with crystalloids, although one meta-analysis suggested benefit in those with septic shock [19,26,27]. In the Saline versus Albumin Fluid Evaluation (SAFE) trial performed in critically ill patients, there was no benefit to albumin compared with saline even in the subgroup with severe sepsis, who comprised 18 percent of the total group [18]. Among the crystalloids, there are no guidelines to suggest that one form is more beneficial than the other.

●Crystalloid versus hydroxyethyl starch (HES) – In the Scandinavian Starch for Severe Sepsis and Septic Shock (6S) trial, compared with Ringer’s acetate, use of HES resulted in increased mortality (51 versus 43 percent) and renal replacement therapy (22 versus 16 percent) [20]. Similar results were found in additional trials of patients without sepsis.

●Crystalloid versus pentastarch – The Efficacy of Volume Substitution and Insulin Therapy in Severe Sepsis (VISEP) trial compared pentastarch to modified Ringer's lactate in patients with severe sepsis and found no difference in 28-day mortality [21]. The trial was stopped early because there was a trend toward increased 90-day mortality among patients who received pentastarch.

Data discussing IVF choice in non-septic patients are provided separately. (See "Treatment of severe hypovolemia or hypovolemic shock in adults", section on 'Choice of replacement fluid'.)

MONITOR RESPONSE — After fluids and empiric antibiotics have been administered, the therapeutic response should be assessed frequently. We suggest that clinical, hemodynamic, and laboratory parameters be followed as outlined in the sections below. In our experience, most patients respond within the first 6 to 24 hours to initial fluid therapy, however, resolution can be protracted and take days or weeks. The response mostly influences further fluid management but can also affect antimicrobial therapy and source control.

Monitoring catheters — For many patients, a central venous catheter (CVC) and an arterial catheter are placed, although they are not always necessary. For example, an arterial catheter may be inserted if blood pressure is labile, sphygmomanometer readings are unreliable, restoration of perfusion is expected to be protracted (especially when vasopressors are administered), or dynamic measures of fluid responsiveness are selected to follow the hemodynamic response. A CVC may be placed if the infusion of large volumes of fluids or vasopressors are anticipated, peripheral access is poor, or the central venous pressure (CVP) or the central venous oxyhemoglobin saturation (ScvO₂) are chosen as methods of monitoring the hemodynamic response. (See "Arterial catheterization techniques for invasive monitoring" and "Novel tools for hemodynamic monitoring in critically ill patients with shock"and "Overview of central venous access".)

We believe that pulmonary artery catheters (PACs) should not be used in the routine management of patients with sepsis or septic shock since they have not been shown to improve outcome [66-68]. PACs can measure the pulmonary artery occlusion pressure (PAOP) and mixed venous oxyhemoglobin saturation (SvO₂). However, the PAOP has proven to be a poor predictor of fluid responsiveness in sepsis and the SvO₂ is similar to the ScvO₂, which can be obtained from a CVC [69,70]. (See "Pulmonary artery catheterization: Indications, contraindications, and complications in adults".)

Clinical — All patients should be followed clinically for improved mean arterial pressure (MAP), urine output, heart rate, respiratory rate, skin color, temperature, pulse oximetry, and mental status. Among these, a MAP ≥65 mmHg (MAP = [(2 x diastolic) + systolic]/3) (calculator 1), and urine output ≥0.5 mL/kg per hour are common targets used in clinical practice. They have not been compared to each other nor have they been proven to be superior to any other target or to clinical assessment. Data supporting their use are discussed above. (See 'Initial resuscitative therapy' above.)

The ideal target for MAP, is unknown. One trial that randomized patients to a target MAP of 65 to 70 mmHg (low target MAP) or 80 to 85 mmHg (high target MAP) reported no mortality benefit to targeting a higher MAP [71,72]. Patients with a higher MAP had a greater incidence of atrial fibrillation (7 versus 3 percent), suggesting that targeting a MAP >80 mmHg is potentially harmful. Another pilot randomized trial that compared a lower MAP target (60-65 mmHg) to a higher target (75-80 mmHg) reported that among patients aged 75 years or older, a higher MAP target was associated with increased hospital mortality (60 versus 13 percent) [72]. An analysis of data from both trials reported that targeting a higher MAP had no effect on mortality but was associated with a greater risk of supraventricular cardiac arrhythmias [73].

Hemodynamic — Static or dynamic predictors of fluid responsiveness should be employed in order to determine further fluid management. Guidelines state a preference for dynamic measures [3] since they are more accurate than static measures (eg, CVP) at predicting fluid responsiveness. However whether their use improved clinically impactful outcomes such as mortality remains unproven.

●Static – Traditionally, in addition to MAP, the following static CVC measurements were used to determine adequate fluid management:

•CVP at a target of 8 to 12 mmHg

•ScvO₂ ≥70 percent (≥65 percent if sample is drawn off a PAC)

While one early trial of patients with septic shock reported a mortality benefit to these parameters in a protocol-based therapy, trials published since then (ProCESS, ARISE, ProMISe) have reported no mortality benefit in association with their use [7-10]. (See 'Initial resuscitative therapy' above.)

●Dynamic – Respiratory changes in the vena caval diameter, radial artery pulse pressure, aortic blood flow peak velocity, left ventricular outflow tract velocity-time integral, and brachial artery blood flow velocity are considered dynamic measures of fluid responsiveness. There is increasing evidence that dynamic measures are more accurate predictors of fluid responsiveness than static measures, as long as the patients are in sinus rhythm and passively ventilated with a sufficient tidal volume. For actively breathing patients or those with irregular cardiac rhythms, an increase in the cardiac output in response to a passive leg-raising maneuver (measured by echocardiography, arterial pulse waveform analysis, or pulmonary artery catheterization) also predicts fluid responsiveness. Choosing among these is dependent upon availability and technical expertise, but a passive leg raising maneuver may be the most accurate and broadly available. Future studies that report improved outcomes (eg, mortality, ventilator free days) in association with their use are needed. Further details are provided separately. (See "Novel tools for hemodynamic monitoring in critically ill patients with shock".)

Laboratory

●Lactate clearance – Although the optimal frequency is unknown, we follow serum lactate (eg, every six hours) in patients with sepsis until the lactate value has clearly fallen. While guidelines promote normalization of lactate [3], only lactate-guided resuscitation has not been convincingly associated with improved outcomes.

The lactate clearance is defined by the equation [(initial lactate – lactate >2 hours later)/initial lactate] x 100. The lactate clearance and interval change in lactate over

the first 12 hours of resuscitation has been evaluated as a potential marker for effective resuscitation [13,74-78]. One meta-analysis of five low quality trials reported that lactate–guided resuscitation resulted in a reduction in mortality compared with resuscitation without lactate [3]. Other meta-analyses reported modest mortality benefit when lactate clearance strategies were used compared with usual care or ScvO₂ normalization [77,78]. However, many of the included trials contain heterogeneous populations and varying definitions of lactate clearance as well as additional variables that potentially affected the outcome.

In addition, after the restoration of perfusion, lactate is a poor marker of tissue perfusion [79]. As a result, lactate values are generally unhelpful following restoration of perfusion, with one exception that a rising lactate level should prompt reevaluation of perfusion. (See "Venous blood gases and other alternatives to arterial blood gases".)

Newer point of care analyzers are commercially available that may allow clinicians to follow lactate levels at the bedside more readily [80-82].

●Arterial blood gases – It is prudent to follow arterial blood gas parameters including the arterial partial pressure of oxygen:fraction of inspired oxygen ratio as well as severity and type of acidosis (resolution of metabolic acidosis and avoidance of hyperchloremic acidosis). Worsening gas exchange may indicate pulmonary edema from fluid resuscitation or other complications including pneumothorax from central catheter placement, acute respiratory distress syndrome, or venous thromboembolism.

●Routine laboratories – Follow up laboratory studies, in particular platelet count, serum chemistries, and liver function tests are often performed (eg, every six hours) until values have reached normal or baseline. Hyperchloremia should be avoided, but if detected, switching to low chloride-containing (ie, buffered) solutions may be indicated. (See "Treatment of severe hypovolemia or hypovolemic shock in adults", section on 'Buffered crystalloid'.)

●Microbiology – Follow up indices of infection are also indicated, including complete blood count and additional cultures. Results may prompt alteration of antibiotic choice and/or investigations directed toward source control. (See 'Septic focus identification and source control' below.)

SEPTIC FOCUS IDENTIFICATION AND SOURCE CONTROL — In our experience, a focused history and examination is the most valuable method for source detection. Following initial investigations and empiric antimicrobial therapy, further efforts aimed at identifying and controlling the source(s) of infection should be performed in all patients with sepsis. In addition, for those who fail despite therapy or those who fail having initially responded to therapy, further investigations aimed at adequacy of the antimicrobial regimen or nosocomial super infection should be considered.

●Identification – Additional investigations targeted at the suspected source(s) should be considered in patients with sepsis, within the first 12 hours. This may include imaging (eg, computed tomography, ultrasonography) and sample acquisition (eg, bronchoalveolar lavage, aspirating fluid collections or joints), and may incur risk if an intervention is involved and the patient remains unstable. If invasive Candida or Aspergillus infection is suspected, serologic assays for 1,3 beta-D-glucan, galactomannan, and anti-mannan antibodies, if available, may provide early evidence of these fungal infections. These assays are discussed separately. (See "Clinical manifestations and diagnosis of candidemia and invasive candidiasis in adults", section on 'Non-culture methods' and "Diagnosis of invasive aspergillosis", section on 'Galactomannan antigen detection' and "Diagnosis of invasive aspergillosis", section on 'Beta-D-glucan assay'.)

●Source control – Source control (ie, physical measures to eradicate a focus of infection and eliminate or treat microbial proliferation and infection) should be undertaken since undrained foci of infection may not respond to antibiotics alone (table 2). As examples, potentially infected vascular access devices should be removed (after other vascular access has been established). Other examples include removing other infected implantable devices/hardware, when feasible, abscess drainage (including thoracic empyema and joint), percutaneous nephrostomy, soft tissue debridement or amputation, colectomy (eg, for fulminant Clostridium difficile-associated colitis), and cholecystostomy.

The optimal timing of source control is unknown but guidelines suggest no more than 6 to 12 hours after diagnosis since survival is negatively impacted by inadequate source control [3]. Although the general rule of thumb is that source control should occur as soon as possible [83-85], this is not always practical or feasible. In addition, the decision should take into consideration the risk of the intervention and its complications (eg, death, fistula formation) and the likelihood of success, particularly when there is diagnostic uncertainty regarding the source.

PATIENTS WHO FAIL INITIAL THERAPY — Patients having persistent hypoperfusion despite adequate fluid resuscitation and antimicrobial treatment should be reassessed for fluid responsiveness (see 'Hemodynamic' above) adequacy of the antimicrobial regimen and septic focus control (see 'Septic focus identification and source control' above) as well as the accuracy of the diagnosis and the possibility that unexpected complications or coexisting problems have occurred (eg, pneumothorax following CVC insertion) (see "Evaluation of and initial approach to the adult patient with undifferentiated hypotension and shock"). Other options including vasopressors, glucocorticoids, inotropic therapy, and blood transfusion are discussed in this section.

Vasopressors — Intravenous vasopressors are useful in patients who remain hypotensive despite adequate fluid resuscitation or who develop cardiogenic pulmonary edema. Based upon meta-analyses of small randomized trials and observational studies, a paradigm shift in practice has occurred such that most experts prefer to avoid dopamine in this population and favor norepinephrineas the first-choice agent (table 3 and table 4). Although guidelines suggest additional agents including vasopressin (up to 0.03 units/minute to reduce the dose of norepinephrine) or epinephrine (for refractory hypotension), practice varies considerably. Guidelines state a preference for central venous and arterial access especially when vasopressor administration is prolonged or high dose, or multiple vasopressors are administered through the same catheter [3]; while this is appropriate, waiting for placement should not delay their administration and the risks of catheter placement should also be taken into account.

●First agent – Data that support norepinephrine as the first-line single agent in septic shock are derived from numerous trials that have compared one vasopressor to another [86-92]. These trials included norepinephrine versus phenylephrine [93], norepinephrine versus vasopressin [94-97], norepinephrine versus terlipressin [98,99], norepinephrine versus epinephrine[100], and vasopressin versus terlipressin [101]. While some of the comparisons found no convincing difference in mortality, length of stay in the ICU or hospital, or incidence of kidney failure [97,102], two 2012 meta-analyses reported increased mortality among patients who received dopamine during septic shock compared with those who received norepinephrine (53 to 54 percent versus 48 to 49 percent) [89,103]. Although the causes of death in the two groups were not directly compared, both meta-analyses identified arrhythmic events about twice as often with dopamine than with norepinephrine.

However, we believe the initial choice of vasopressor in patients with sepsis is often individualized and determined by additional factors including the presence of coexistent conditions contributing shock (eg, heart failure), arrhythmias, organ ischemia, or agent availability. For example, in patients with significant tachycardia (eg, fast atrial fibrillation, sinus tachycardia >160/minute), agents that completely lack beta adrenergic effects (eg, vasopressin) may be preferred if it is believed that worsening tachycardia may prompt further decompensation. Similarly, dopamine (DA) may be acceptable in those with significant bradycardia; but low dose DA should not be used for the purposes of “renal protection.”

The impact of agent availability was highlighted by one study of nearly 28,000 patients from 26 hospitals, which reported that during periods of norepinephrine shortages, phenylephrine was the most frequent alternative agent chosen by intensivists (use rose from 36 to 54 percent) [104]. During the same period, mortality rates from septic shock rose from 36 to 40 percent. Whether this was directly related to phenylephrine use remains unknown.

●Additional agents – The addition of a second or third agent to norepinephrine may be required (eg, epinephrine, dobutamine, or vasopressin) with little data to support agent selection. For patients with refractory septic shock associated with a low cardiac output, an inotropic agent may be added. In a retrospective series of 234 patients with septic shock, among several vasopressor agents added to norepinephrine (dobutamine, dopamine, phenylephrine, vasopressin), inotropic support with dobutamine was associated with a survival advantage (epinephrine was not studied) [105]. (See "Use of vasopressors and inotropes", section on 'Epinephrine' and "Use of vasopressors and inotropes", section on 'Dobutamine'.)