Emergency Medicine

Case

A 24-year-old man in cardiac arrest was brought to the ED via emergency medical services (EMS). Unfortunately, resuscitation efforts were unsuccessful. Little was known about the patient, but the emergency physician was informed that the patient had ingested sodium azide (NaN₃), which he had ordered online. The patient collapsed shortly after ingesting the sodium azide, approximately the same time police officers arrived at the patient’s home.

No specific details were known about the patient’s ingestion. Upon learning of the exposure to sodium azide, a member of the ED staff contacted the local poison control center for information on the proper course of action to ensure staff safety and limit exposure. Shortly thereafter, several of emergency medical technicians and police officers, who had responded to the emergency assistance call for this patient, presented to the ED with concerns of exposure.

What is sodium azide?

Sodium azide is a colorless, odorless crystalline water-soluble solid that has a pK of 4.8.¹ When sodium azide is dissolved in an acid, it liberates hydrazoic acid (HN₃), which has a pungent odor, high vapor pressure (484 mm Hg), and a relatively low-boiling point of 37°C (98°F).²

The most common industrial use of sodium azide is as a propellant in air bags. In this capacity, sodium azide rapidly decomposes to nitrogen gas when it reaches a temperature of 300°C (572°F), causing rapid expansion of the air bag. In addition to air bags, sodium azide is used in research laboratories as a preservative and in agriculture as a pesticide. The main nontoxicological concern with all azide agents is the potential for explosion when they react with metals, such as lead, copper, silver, and mercury, to form metal azides that are sensitive to shock.³ An example of the explosive nature of these azides was demonstrated in a report wherein diluted sodium azide was poured down a drain, causing an explosion as a worker was fixing the pipe.⁴

In addition to industrial and commercial use, sodium azide is occasionally used in suicide attempts because it is rapidly fatal, has no specific antidote, and can be purchased online.³

What is the toxicity of sodium azide?

The lethal dose for both oral and dermal exposure to sodium azide is approximately 10 to 20 mg/kg.^3,5 Therefore, ingestion of 700 mg of sodium azide, a volume approximately the size of a penny, is likely to be fatal.³

Sodium azide is primarily a mitochondrial toxin, which binds the electron transport chain, inhibiting oxidative phosphorylation. The resulting reduction in adenosine triphosphate (ATP) production, even in the presence of oxygen, results in metabolic failure.⁶ This mechanism of action is similar to that of cyanide, although sodium azide causes more pronounced vasodilation due to the in vivo conversion of some azide to the vasodilator nitric oxide.⁷ Some reports suggest that azide lethality is due to enhanced excitatory transmission from nitric oxide in the central nervous system.⁸

What are the clinical manifestations of azide poisoning, and what is the treatment?

The early clinical findings of a patient with azide poisoning include hypotension, dizziness, headache, nausea, vomiting, palpitations, tachycardia, dyspnea, and restlessness. Inhalation of hydrazoic acid can also produce wheezing and coughing. The most common effect is hypotension, which can occur within 1 minute of exposure. Following depletion of cellular ATP, anaerobic glycolysis generates lactate and produces acidemia. More severe findings of azide poisoning include seizures, cardiac arrhythmia, loss of consciousness, pulmonary edema, and cardiopulmonary failure.³

Currently, there is no specific antidote for azide poisoning, and treatment mainly consists of supportive care. Cyanide antidote treatments are generally ineffective in reducing azide-related death in animal models.^3,8Early aggressive supportive care can improve survival rates.⁹ Some authors suggest that administration of oral activated charcoal, orogastric lavage, hemodialysis, and plasma exchange reduce azide concentrations, while others believe these treatments have little effect.^3,9 More research is needed to identify effective therapeutic measures and to control for dose, time, and patient population.

What are the safety concerns for emergency medical technicians and hospital staff following exposure to sodium azide?

The most probable routes of exposure for prehospital and hospital staff include dermal contact with sodium azide or inhalation of gaseous hydrazoic acid; inhalational exposure is most concerning.¹ In one case, hospital-staff members developed headaches, light-headedness, and nausea while treating a patient for azide poisoning; however, staff exposure was not confirmed and no sequelae were evident.¹⁰

More objectively, workers at an azide plant exposed to azide concentrations above the occupational exposure limit developed headaches, hypotension, and palpitations.¹¹ Another study found no evidence of kidney, heart, or liver damage after patients were given sodium azide for more than a year during a clinical trial.¹² Not unexpectedly, there is little risk of exposure when proper safety precautions are taken.

Emergency response personnel should carefully inspect the scene for the presence of any sodium azide powder, and should also question bystanders and family members to determine if anyone performed mouth-to-mouth resuscitation on the patient. Standard universal precautions, along with attentiveness to one’s surroundings, should be sufficient to prevent dermal exposure. If small amounts of sodium azide residue are found on the patient, his or her clothes should be cautiously removed and placed in a plastic bag to prevent dispersion of particles. If large quantities of sodium azide are present on a patient, the hazardous materials response team should be called, in accordance with institutional and regional protocols. To avoid explosion, every attempt should be made to prevent azide salt (eg, from emesis) from contact with any metal surfaces (eg, oxygen tanks, metal stretcher).¹³Vomit from patients who have ingested sodium azide can cause liberation of hydrazoic acid, which can escape through the esophagus. A pungent ambient odor may provide a warning, which is particularly concerning in a confined space such as an ambulance. As a precaution, EMS personnel should open windows and maximize ventilation. After the call, EMS and hospital personnel should thoroughly wash their hands with soap and water, and change their uniform if they believe it has been contaminated. There is no risk of delayed exposure following exposure to hydrazoic acid.

During autopsy, medical examiners must exercise caution due to the potential for liberation of hydrazoic acids from the stomach.¹⁴Unless it is absolutely necessary, the medical examiner should avoid opening the stomach. If this is unavoidable, the autopsy should occur in a well-ventilated setting with the examiner wearing a supplied air respirator to limit exposure in a high-risk scenario.

Case Conclusion

None of the exposed first responders experienced dizziness, light-headedness, or irritation, and after a period of observation in the ED, they were discharged home without further sequelae. All hospital staff involved in the patient’s care, including those who performed cardiopulmonary resuscitation on the patient and cleaned his room, were advised to use protective equipment when handling the patient and bodily secretions. None of the health care workers developed abnormal clinical findings. Given the hazard in conducting a full postmortem examination, the medical examiner opted to send blood, bile, urine, and vitreous humor out for analysis, but did not conduct a full postmortem examination. Notably, the stomach was not opened, and its contents were not exposed.

Case

A 24-year-old man in cardiac arrest was brought to the ED via emergency medical services (EMS). Unfortunately, resuscitation efforts were unsuccessful. Little was known about the patient, but the emergency physician was informed that the patient had ingested sodium azide (NaN₃), which he had ordered online. The patient collapsed shortly after ingesting the sodium azide, approximately the same time police officers arrived at the patient’s home.

No specific details were known about the patient’s ingestion. Upon learning of the exposure to sodium azide, a member of the ED staff contacted the local poison control center for information on the proper course of action to ensure staff safety and limit exposure. Shortly thereafter, several of emergency medical technicians and police officers, who had responded to the emergency assistance call for this patient, presented to the ED with concerns of exposure.

What is sodium azide?

Sodium azide is a colorless, odorless crystalline water-soluble solid that has a pK of 4.8.¹ When sodium azide is dissolved in an acid, it liberates hydrazoic acid (HN₃), which has a pungent odor, high vapor pressure (484 mm Hg), and a relatively low-boiling point of 37°C (98°F).²

The most common industrial use of sodium azide is as a propellant in air bags. In this capacity, sodium azide rapidly decomposes to nitrogen gas when it reaches a temperature of 300°C (572°F), causing rapid expansion of the air bag. In addition to air bags, sodium azide is used in research laboratories as a preservative and in agriculture as a pesticide. The main nontoxicological concern with all azide agents is the potential for explosion when they react with metals, such as lead, copper, silver, and mercury, to form metal azides that are sensitive to shock.³ An example of the explosive nature of these azides was demonstrated in a report wherein diluted sodium azide was poured down a drain, causing an explosion as a worker was fixing the pipe.⁴

In addition to industrial and commercial use, sodium azide is occasionally used in suicide attempts because it is rapidly fatal, has no specific antidote, and can be purchased online.³

What is the toxicity of sodium azide?

The lethal dose for both oral and dermal exposure to sodium azide is approximately 10 to 20 mg/kg.^3,5 Therefore, ingestion of 700 mg of sodium azide, a volume approximately the size of a penny, is likely to be fatal.³

Sodium azide is primarily a mitochondrial toxin, which binds the electron transport chain, inhibiting oxidative phosphorylation. The resulting reduction in adenosine triphosphate (ATP) production, even in the presence of oxygen, results in metabolic failure.⁶ This mechanism of action is similar to that of cyanide, although sodium azide causes more pronounced vasodilation due to the in vivo conversion of some azide to the vasodilator nitric oxide.⁷ Some reports suggest that azide lethality is due to enhanced excitatory transmission from nitric oxide in the central nervous system.⁸

What are the clinical manifestations of azide poisoning, and what is the treatment?

The early clinical findings of a patient with azide poisoning include hypotension, dizziness, headache, nausea, vomiting, palpitations, tachycardia, dyspnea, and restlessness. Inhalation of hydrazoic acid can also produce wheezing and coughing. The most common effect is hypotension, which can occur within 1 minute of exposure. Following depletion of cellular ATP, anaerobic glycolysis generates lactate and produces acidemia. More severe findings of azide poisoning include seizures, cardiac arrhythmia, loss of consciousness, pulmonary edema, and cardiopulmonary failure.³

Currently, there is no specific antidote for azide poisoning, and treatment mainly consists of supportive care. Cyanide antidote treatments are generally ineffective in reducing azide-related death in animal models.^3,8Early aggressive supportive care can improve survival rates.⁹ Some authors suggest that administration of oral activated charcoal, orogastric lavage, hemodialysis, and plasma exchange reduce azide concentrations, while others believe these treatments have little effect.^3,9 More research is needed to identify effective therapeutic measures and to control for dose, time, and patient population.

What are the safety concerns for emergency medical technicians and hospital staff following exposure to sodium azide?

The most probable routes of exposure for prehospital and hospital staff include dermal contact with sodium azide or inhalation of gaseous hydrazoic acid; inhalational exposure is most concerning.¹ In one case, hospital-staff members developed headaches, light-headedness, and nausea while treating a patient for azide poisoning; however, staff exposure was not confirmed and no sequelae were evident.¹⁰

More objectively, workers at an azide plant exposed to azide concentrations above the occupational exposure limit developed headaches, hypotension, and palpitations.¹¹ Another study found no evidence of kidney, heart, or liver damage after patients were given sodium azide for more than a year during a clinical trial.¹² Not unexpectedly, there is little risk of exposure when proper safety precautions are taken.

Emergency response personnel should carefully inspect the scene for the presence of any sodium azide powder, and should also question bystanders and family members to determine if anyone performed mouth-to-mouth resuscitation on the patient. Standard universal precautions, along with attentiveness to one’s surroundings, should be sufficient to prevent dermal exposure. If small amounts of sodium azide residue are found on the patient, his or her clothes should be cautiously removed and placed in a plastic bag to prevent dispersion of particles. If large quantities of sodium azide are present on a patient, the hazardous materials response team should be called, in accordance with institutional and regional protocols. To avoid explosion, every attempt should be made to prevent azide salt (eg, from emesis) from contact with any metal surfaces (eg, oxygen tanks, metal stretcher).¹³Vomit from patients who have ingested sodium azide can cause liberation of hydrazoic acid, which can escape through the esophagus. A pungent ambient odor may provide a warning, which is particularly concerning in a confined space such as an ambulance. As a precaution, EMS personnel should open windows and maximize ventilation. After the call, EMS and hospital personnel should thoroughly wash their hands with soap and water, and change their uniform if they believe it has been contaminated. There is no risk of delayed exposure following exposure to hydrazoic acid.

During autopsy, medical examiners must exercise caution due to the potential for liberation of hydrazoic acids from the stomach.¹⁴Unless it is absolutely necessary, the medical examiner should avoid opening the stomach. If this is unavoidable, the autopsy should occur in a well-ventilated setting with the examiner wearing a supplied air respirator to limit exposure in a high-risk scenario.

Case Conclusion

None of the exposed first responders experienced dizziness, light-headedness, or irritation, and after a period of observation in the ED, they were discharged home without further sequelae. All hospital staff involved in the patient’s care, including those who performed cardiopulmonary resuscitation on the patient and cleaned his room, were advised to use protective equipment when handling the patient and bodily secretions. None of the health care workers developed abnormal clinical findings. Given the hazard in conducting a full postmortem examination, the medical examiner opted to send blood, bile, urine, and vitreous humor out for analysis, but did not conduct a full postmortem examination. Notably, the stomach was not opened, and its contents were not exposed.

Case

A 24-year-old man in cardiac arrest was brought to the ED via emergency medical services (EMS). Unfortunately, resuscitation efforts were unsuccessful. Little was known about the patient, but the emergency physician was informed that the patient had ingested sodium azide (NaN₃), which he had ordered online. The patient collapsed shortly after ingesting the sodium azide, approximately the same time police officers arrived at the patient’s home.

No specific details were known about the patient’s ingestion. Upon learning of the exposure to sodium azide, a member of the ED staff contacted the local poison control center for information on the proper course of action to ensure staff safety and limit exposure. Shortly thereafter, several of emergency medical technicians and police officers, who had responded to the emergency assistance call for this patient, presented to the ED with concerns of exposure.

What is sodium azide?

Sodium azide is a colorless, odorless crystalline water-soluble solid that has a pK of 4.8.¹ When sodium azide is dissolved in an acid, it liberates hydrazoic acid (HN₃), which has a pungent odor, high vapor pressure (484 mm Hg), and a relatively low-boiling point of 37°C (98°F).²

The most common industrial use of sodium azide is as a propellant in air bags. In this capacity, sodium azide rapidly decomposes to nitrogen gas when it reaches a temperature of 300°C (572°F), causing rapid expansion of the air bag. In addition to air bags, sodium azide is used in research laboratories as a preservative and in agriculture as a pesticide. The main nontoxicological concern with all azide agents is the potential for explosion when they react with metals, such as lead, copper, silver, and mercury, to form metal azides that are sensitive to shock.³ An example of the explosive nature of these azides was demonstrated in a report wherein diluted sodium azide was poured down a drain, causing an explosion as a worker was fixing the pipe.⁴

In addition to industrial and commercial use, sodium azide is occasionally used in suicide attempts because it is rapidly fatal, has no specific antidote, and can be purchased online.³

What is the toxicity of sodium azide?

The lethal dose for both oral and dermal exposure to sodium azide is approximately 10 to 20 mg/kg.^3,5 Therefore, ingestion of 700 mg of sodium azide, a volume approximately the size of a penny, is likely to be fatal.³

Sodium azide is primarily a mitochondrial toxin, which binds the electron transport chain, inhibiting oxidative phosphorylation. The resulting reduction in adenosine triphosphate (ATP) production, even in the presence of oxygen, results in metabolic failure.⁶ This mechanism of action is similar to that of cyanide, although sodium azide causes more pronounced vasodilation due to the in vivo conversion of some azide to the vasodilator nitric oxide.⁷ Some reports suggest that azide lethality is due to enhanced excitatory transmission from nitric oxide in the central nervous system.⁸

What are the clinical manifestations of azide poisoning, and what is the treatment?

The early clinical findings of a patient with azide poisoning include hypotension, dizziness, headache, nausea, vomiting, palpitations, tachycardia, dyspnea, and restlessness. Inhalation of hydrazoic acid can also produce wheezing and coughing. The most common effect is hypotension, which can occur within 1 minute of exposure. Following depletion of cellular ATP, anaerobic glycolysis generates lactate and produces acidemia. More severe findings of azide poisoning include seizures, cardiac arrhythmia, loss of consciousness, pulmonary edema, and cardiopulmonary failure.³

Currently, there is no specific antidote for azide poisoning, and treatment mainly consists of supportive care. Cyanide antidote treatments are generally ineffective in reducing azide-related death in animal models.^3,8Early aggressive supportive care can improve survival rates.⁹ Some authors suggest that administration of oral activated charcoal, orogastric lavage, hemodialysis, and plasma exchange reduce azide concentrations, while others believe these treatments have little effect.^3,9 More research is needed to identify effective therapeutic measures and to control for dose, time, and patient population.

What are the safety concerns for emergency medical technicians and hospital staff following exposure to sodium azide?

The most probable routes of exposure for prehospital and hospital staff include dermal contact with sodium azide or inhalation of gaseous hydrazoic acid; inhalational exposure is most concerning.¹ In one case, hospital-staff members developed headaches, light-headedness, and nausea while treating a patient for azide poisoning; however, staff exposure was not confirmed and no sequelae were evident.¹⁰

More objectively, workers at an azide plant exposed to azide concentrations above the occupational exposure limit developed headaches, hypotension, and palpitations.¹¹ Another study found no evidence of kidney, heart, or liver damage after patients were given sodium azide for more than a year during a clinical trial.¹² Not unexpectedly, there is little risk of exposure when proper safety precautions are taken.

Emergency response personnel should carefully inspect the scene for the presence of any sodium azide powder, and should also question bystanders and family members to determine if anyone performed mouth-to-mouth resuscitation on the patient. Standard universal precautions, along with attentiveness to one’s surroundings, should be sufficient to prevent dermal exposure. If small amounts of sodium azide residue are found on the patient, his or her clothes should be cautiously removed and placed in a plastic bag to prevent dispersion of particles. If large quantities of sodium azide are present on a patient, the hazardous materials response team should be called, in accordance with institutional and regional protocols. To avoid explosion, every attempt should be made to prevent azide salt (eg, from emesis) from contact with any metal surfaces (eg, oxygen tanks, metal stretcher).¹³Vomit from patients who have ingested sodium azide can cause liberation of hydrazoic acid, which can escape through the esophagus. A pungent ambient odor may provide a warning, which is particularly concerning in a confined space such as an ambulance. As a precaution, EMS personnel should open windows and maximize ventilation. After the call, EMS and hospital personnel should thoroughly wash their hands with soap and water, and change their uniform if they believe it has been contaminated. There is no risk of delayed exposure following exposure to hydrazoic acid.

During autopsy, medical examiners must exercise caution due to the potential for liberation of hydrazoic acids from the stomach.¹⁴Unless it is absolutely necessary, the medical examiner should avoid opening the stomach. If this is unavoidable, the autopsy should occur in a well-ventilated setting with the examiner wearing a supplied air respirator to limit exposure in a high-risk scenario.

Case Conclusion

None of the exposed first responders experienced dizziness, light-headedness, or irritation, and after a period of observation in the ED, they were discharged home without further sequelae. All hospital staff involved in the patient’s care, including those who performed cardiopulmonary resuscitation on the patient and cleaned his room, were advised to use protective equipment when handling the patient and bodily secretions. None of the health care workers developed abnormal clinical findings. Given the hazard in conducting a full postmortem examination, the medical examiner opted to send blood, bile, urine, and vitreous humor out for analysis, but did not conduct a full postmortem examination. Notably, the stomach was not opened, and its contents were not exposed.

ANSWER

The image reveals a hypodense extra-axial fluid collection in the right frontoparietal region, measuring 8 to 10 mm in diameter. There is some mass effect and evidence of right-to-left shift. These findings are consistent with a subacute subdural hematoma, possibly secondary to the patient’s anticoagulant use. (The patient later recalled bumping his head a couple of months prior—but that may have been incidental.)

Arrangements were made for him at a local hospital where neurosurgical services were available. He underwent successful evacuation and was subsequently symptom free.

ANSWER

The image reveals a hypodense extra-axial fluid collection in the right frontoparietal region, measuring 8 to 10 mm in diameter. There is some mass effect and evidence of right-to-left shift. These findings are consistent with a subacute subdural hematoma, possibly secondary to the patient’s anticoagulant use. (The patient later recalled bumping his head a couple of months prior—but that may have been incidental.)

Arrangements were made for him at a local hospital where neurosurgical services were available. He underwent successful evacuation and was subsequently symptom free.

ANSWER

The image reveals a hypodense extra-axial fluid collection in the right frontoparietal region, measuring 8 to 10 mm in diameter. There is some mass effect and evidence of right-to-left shift. These findings are consistent with a subacute subdural hematoma, possibly secondary to the patient’s anticoagulant use. (The patient later recalled bumping his head a couple of months prior—but that may have been incidental.)

Arrangements were made for him at a local hospital where neurosurgical services were available. He underwent successful evacuation and was subsequently symptom free.

Case

An 86-year-old woman, who recently had been seen in the same facility after a ground level fall, presented to the ED with to a 2- to 3-day history of vague abdominal pain, increasing weakness, nausea, and dry heaves.

Upon examination, the patient was unable to stand due to generalized weakness She arrived at the ED via emergency medical services. Her vital signs at presentation were significant for a systolic blood pressure (BP) of 90 mm Hg with a wide complex tachycardia concerning for ventricular tachycardia. The patient’s other vital signers were: heart rate, 136 beats/min; respiratory rate 20 breaths/min; and pulse oximetry was 94% on 4 liters/min of oxygen via nasal cannula.

The patient’s medical history was significant for atrial fibrillation and an indwelling pacemaker, for which she was chronically on flecainide and anticoagulation therapy with apixaban.

The initial electrocardiogram (ECG) revealed a wide complex rhythm with pacemaker spikes (Figure 1). Based on these findings, electrodes were placed on the patient in the event she required cardioversion. The patient was started on an amiodarone intravenous (IV) drip for presumptive ventricular tachycardia.

Discussion

Flecainide acetate was approved by the Food and Drug Administration in 1984.¹It is a Vaughan-Williams class IC antiarrhythmic with a sodium channel blocker action used to treat supra ventricular arrhythmias. The CAST trial in 1989 investigated the efficacy of this class of antiarrhythmics, which resulted in a revision of its role.² Based on this study, flecainide is not recommended for patients with structural heart disease or coronary artery disease.^2,3 However, it is recommended as a first-line therapy for pharmacologic cardioversion and maintenance of normal sinus rhythm in patients with atrial fibrillation and supraventricular tachycardia^4,5 without the above caveats.

Class IC agents produce a selective block at the sodium (Na+) channels, resulting in the slowing of cardiac conduction.^6,7 This high affinity for Na+ channels combined with slow unbinding kinetics during diastole explain the slowing of recovery time and prolongation of the refractory period.^6,8,9 These electrophysiologic properties all can increase the PR, QRS, and QT interval duration. The QT interval is not significantly affected, as most of the QT prolongation is due to the QRS widening.^6,10,11 Widening of the QRS by greater than 25% as compared to the baseline value is used as the threshold to decrease dosing or discontinue the use of flecainide.³The toxic effects of flecainide on cardiac conduction can produce prolonged QRS duration of up to 50%, and PR interval up to 30%, especially in rapid heart rates. Signs of intoxication are difficult to discern owing to its nonspecific presentation. A well-documented, but under-recognized, presentation of flecainide toxicity is the transformation of atrial fibrillation to atrial flutter.^5,7,9,11-13 The reported rate of this pro arrhythmic effect can be as high as 3.5% to 5%.^14,15Flecainide toxicity can occur secondary to chronic ingestion and may be precipitated in mild renal failure. The majority of flecainide is renally excreted and the half-life is 20 hours. Maximum therapeutic effect is seen between levels of 0.2 to 1 mcg/mL with levels greater than 0.7 to 1 mcg/mL associated with adverse effects.⁹ Systemic effects include dizziness and visual disturbances. A high degree of suspicion for flecainide toxicity is required when the patient’s initial presentation is nonspecific. In this circumstance, real-time bedside interrogation of the pacemaker is invaluable. Early diagnosis and treatment minimizes the risk for adverse sequelae, including death. Treatment includes increasing the excretion of flecainide, symptomatic support (including pacemaker placement, intravenous fat emulsion, or extracorporeal circulatory support) and administration of sodium bicarbonate, to transiently reverse the effect of the sodium channel blockade, in severe cases.^15-17

Case

An 86-year-old woman, who recently had been seen in the same facility after a ground level fall, presented to the ED with to a 2- to 3-day history of vague abdominal pain, increasing weakness, nausea, and dry heaves.

Upon examination, the patient was unable to stand due to generalized weakness She arrived at the ED via emergency medical services. Her vital signs at presentation were significant for a systolic blood pressure (BP) of 90 mm Hg with a wide complex tachycardia concerning for ventricular tachycardia. The patient’s other vital signers were: heart rate, 136 beats/min; respiratory rate 20 breaths/min; and pulse oximetry was 94% on 4 liters/min of oxygen via nasal cannula.

The patient’s medical history was significant for atrial fibrillation and an indwelling pacemaker, for which she was chronically on flecainide and anticoagulation therapy with apixaban.

The initial electrocardiogram (ECG) revealed a wide complex rhythm with pacemaker spikes (Figure 1). Based on these findings, electrodes were placed on the patient in the event she required cardioversion. The patient was started on an amiodarone intravenous (IV) drip for presumptive ventricular tachycardia.

Discussion

Flecainide acetate was approved by the Food and Drug Administration in 1984.¹It is a Vaughan-Williams class IC antiarrhythmic with a sodium channel blocker action used to treat supra ventricular arrhythmias. The CAST trial in 1989 investigated the efficacy of this class of antiarrhythmics, which resulted in a revision of its role.² Based on this study, flecainide is not recommended for patients with structural heart disease or coronary artery disease.^2,3 However, it is recommended as a first-line therapy for pharmacologic cardioversion and maintenance of normal sinus rhythm in patients with atrial fibrillation and supraventricular tachycardia^4,5 without the above caveats.

Class IC agents produce a selective block at the sodium (Na+) channels, resulting in the slowing of cardiac conduction.^6,7 This high affinity for Na+ channels combined with slow unbinding kinetics during diastole explain the slowing of recovery time and prolongation of the refractory period.^6,8,9 These electrophysiologic properties all can increase the PR, QRS, and QT interval duration. The QT interval is not significantly affected, as most of the QT prolongation is due to the QRS widening.^6,10,11 Widening of the QRS by greater than 25% as compared to the baseline value is used as the threshold to decrease dosing or discontinue the use of flecainide.³The toxic effects of flecainide on cardiac conduction can produce prolonged QRS duration of up to 50%, and PR interval up to 30%, especially in rapid heart rates. Signs of intoxication are difficult to discern owing to its nonspecific presentation. A well-documented, but under-recognized, presentation of flecainide toxicity is the transformation of atrial fibrillation to atrial flutter.^5,7,9,11-13 The reported rate of this pro arrhythmic effect can be as high as 3.5% to 5%.^14,15Flecainide toxicity can occur secondary to chronic ingestion and may be precipitated in mild renal failure. The majority of flecainide is renally excreted and the half-life is 20 hours. Maximum therapeutic effect is seen between levels of 0.2 to 1 mcg/mL with levels greater than 0.7 to 1 mcg/mL associated with adverse effects.⁹ Systemic effects include dizziness and visual disturbances. A high degree of suspicion for flecainide toxicity is required when the patient’s initial presentation is nonspecific. In this circumstance, real-time bedside interrogation of the pacemaker is invaluable. Early diagnosis and treatment minimizes the risk for adverse sequelae, including death. Treatment includes increasing the excretion of flecainide, symptomatic support (including pacemaker placement, intravenous fat emulsion, or extracorporeal circulatory support) and administration of sodium bicarbonate, to transiently reverse the effect of the sodium channel blockade, in severe cases.^15-17

Case

An 86-year-old woman, who recently had been seen in the same facility after a ground level fall, presented to the ED with to a 2- to 3-day history of vague abdominal pain, increasing weakness, nausea, and dry heaves.

Upon examination, the patient was unable to stand due to generalized weakness She arrived at the ED via emergency medical services. Her vital signs at presentation were significant for a systolic blood pressure (BP) of 90 mm Hg with a wide complex tachycardia concerning for ventricular tachycardia. The patient’s other vital signers were: heart rate, 136 beats/min; respiratory rate 20 breaths/min; and pulse oximetry was 94% on 4 liters/min of oxygen via nasal cannula.

The patient’s medical history was significant for atrial fibrillation and an indwelling pacemaker, for which she was chronically on flecainide and anticoagulation therapy with apixaban.

The initial electrocardiogram (ECG) revealed a wide complex rhythm with pacemaker spikes (Figure 1). Based on these findings, electrodes were placed on the patient in the event she required cardioversion. The patient was started on an amiodarone intravenous (IV) drip for presumptive ventricular tachycardia.

Discussion

Flecainide acetate was approved by the Food and Drug Administration in 1984.¹It is a Vaughan-Williams class IC antiarrhythmic with a sodium channel blocker action used to treat supra ventricular arrhythmias. The CAST trial in 1989 investigated the efficacy of this class of antiarrhythmics, which resulted in a revision of its role.² Based on this study, flecainide is not recommended for patients with structural heart disease or coronary artery disease.^2,3 However, it is recommended as a first-line therapy for pharmacologic cardioversion and maintenance of normal sinus rhythm in patients with atrial fibrillation and supraventricular tachycardia^4,5 without the above caveats.

Class IC agents produce a selective block at the sodium (Na+) channels, resulting in the slowing of cardiac conduction.^6,7 This high affinity for Na+ channels combined with slow unbinding kinetics during diastole explain the slowing of recovery time and prolongation of the refractory period.^6,8,9 These electrophysiologic properties all can increase the PR, QRS, and QT interval duration. The QT interval is not significantly affected, as most of the QT prolongation is due to the QRS widening.^6,10,11 Widening of the QRS by greater than 25% as compared to the baseline value is used as the threshold to decrease dosing or discontinue the use of flecainide.³The toxic effects of flecainide on cardiac conduction can produce prolonged QRS duration of up to 50%, and PR interval up to 30%, especially in rapid heart rates. Signs of intoxication are difficult to discern owing to its nonspecific presentation. A well-documented, but under-recognized, presentation of flecainide toxicity is the transformation of atrial fibrillation to atrial flutter.^5,7,9,11-13 The reported rate of this pro arrhythmic effect can be as high as 3.5% to 5%.^14,15Flecainide toxicity can occur secondary to chronic ingestion and may be precipitated in mild renal failure. The majority of flecainide is renally excreted and the half-life is 20 hours. Maximum therapeutic effect is seen between levels of 0.2 to 1 mcg/mL with levels greater than 0.7 to 1 mcg/mL associated with adverse effects.⁹ Systemic effects include dizziness and visual disturbances. A high degree of suspicion for flecainide toxicity is required when the patient’s initial presentation is nonspecific. In this circumstance, real-time bedside interrogation of the pacemaker is invaluable. Early diagnosis and treatment minimizes the risk for adverse sequelae, including death. Treatment includes increasing the excretion of flecainide, symptomatic support (including pacemaker placement, intravenous fat emulsion, or extracorporeal circulatory support) and administration of sodium bicarbonate, to transiently reverse the effect of the sodium channel blockade, in severe cases.^15-17

A 40-year-old man with a history of hypertension and alcohol abuse presented with acute onset of mild chest tightness, left leg pain, and increasing agitation, which prevented us from obtaining additional meaningful information from him.

On admission, his heart rate was 120 beats per minute, blood pressure 211/122 mm Hg, respiratory rate 18 per minute, and oxygen saturation 92% on room air. Given his history of alcohol abuse, we checked his blood ethanol level, which was less than 0.01%, well below the legal limit for intoxication.

We gave the patient intravenous lorazepam for possible alcohol withdrawal and started labetalol by intravenous infusion to lower his blood pressure.

On physical examination, his left lower extremity was cold and without pulses, including the femoral pulse. Suspecting acute arterial thrombosis, we ordered immediate computed tomographic (CT) angiography of the abdomen and pelvis with left lower extremity runoff. The images showed dissection of the abdominal aorta with extension to both the left and right common iliac arteries and the origin of the right external iliac artery. There was resultant occlusion of the left external iliac artery (Figure 1).

Immediate CT angiography of the chest was then performed, which revealed dissection of the thoracic aorta as well, starting superior to the aortic valve annulus and involving the ascending aorta, aortic arch, and the entire descending thoracic aorta (Figure 2).

The patient underwent emergency surgical repair of the aortic root, ascending aorta, and aortic arch. Residual dissection of the descending aorta was managed conservatively with blood pressure control using intravenous labetalol initially, which was then switched to oral carvedilol, and the pulses returned in his left lower extremity. He had an unremarkable postoperative recovery and was discharged after 1 week.

AORTIC DISSECTION AND MALPERFUSION SYNDROME

Aortic dissection is most often associated with acute onset of sharp chest pain and upper back pain. On rare occasions, it can have an atypical presentation such as stroke, paraplegia, mesenteric ischemia, or lower limb malperfusion.¹

Extension of aortic dissection into the iliac and femoral arteries can cause impaired or absent blood flow to the lower extremity. These pulse deficits are a part of limb mal­perfusion syndrome. Symptoms of malperfusion syndrome vary greatly and depend on the vessels involved. Malperfusion of the branches of the aortic arch can result in stroke or altered sensorium. Compromise of intra-abdominal vessels due to dissection can involve the mesenteric bed, the renal arteries, or both, resulting in laboratory derangements such as lactic acidosis and renal failure.

How aortic dissection and malperfusion syndrome occur

Over time, shear forces on the aortic wall result in degeneration of the tunica intima and media. Dissection occurs when deterioration of the intima causes propagation of blood through a cleavage plane into the outer portion of the diseased media, forming a false lumen.

Anterograde or retrograde progression of dissection depends on the balance of the pressure gradient between true and false lumens.² With every systolic ventricular contraction, a fluid and pressure wave travels down both lumens (true and false). However, the pressure gradient between the false and true lumens allows the more pliable intimal flap to bulge into the true lumen and ostia of branch vessels, resulting in static or dynamic obstruction.

Static obstruction occurs when the false lumen projects completely into the branch vessel and there is resultant thrombosis. As the name implies, dynamic obstruction is intermittent and is responsible for 80% of the cases of malperfusion syndrome.³ Dynamic obstruction has 2 distinct mechanisms: hypoperfusion through the true lumen due to impaired flow, and prolapse of the false lumen into a branch vessel.

Factors that exacerbate hypoperfusion through the true lumen and make obliteration by the false lumen more likely include large circumference of the dissected aorta, rapid heart rate, and high systolic pressure.⁴ Therefore, it is important to control the heart rate and blood pressure using beta-blockers in cases of aortic dissection with malperfusion syndrome. This treatment may resolve the dynamic obstruction through expansion and resumption of perfusion through the true lumen.⁵

MANAGEMENT OF MALPERFUSION SYNDROME

Aortic dissection can be classified as either Stanford type A (involving the ascending aorta) or type B (involving the descending aorta). Type B dissection associated with malperfusion syndrome is termed “complicated” type B aortic dissection. Our patient had both Stanford type A and complicated type B aortic dissection.

Unlike type A aortic dissection, which requires definitive open surgical repair, complicated type B aortic dissection occasionally responds to medical management alone. A plausible explanation for resolution of limb malperfusion with optimal blood pressure control is expansion of the true lumen and obliteration of the false lumen, as was likely the case in our patient.

In most cases, however, limb malperfusion persists despite optimal medical management. In such patients, endovascular graft stenting or open surgical repair may be needed. Open surgical repair procedures like bypass grafting or surgical fenestration are associated with significant rates of mortality and morbidity.⁵ Therefore, an endovascular approach rather than conventional surgical repair for complicated type B aortic dissection is advocated after optimal medical management.⁶ Endovascular repair also promotes favorable aortic remodeling without the morbidity associated with open surgical repair.

A 40-year-old man with a history of hypertension and alcohol abuse presented with acute onset of mild chest tightness, left leg pain, and increasing agitation, which prevented us from obtaining additional meaningful information from him.

On admission, his heart rate was 120 beats per minute, blood pressure 211/122 mm Hg, respiratory rate 18 per minute, and oxygen saturation 92% on room air. Given his history of alcohol abuse, we checked his blood ethanol level, which was less than 0.01%, well below the legal limit for intoxication.

We gave the patient intravenous lorazepam for possible alcohol withdrawal and started labetalol by intravenous infusion to lower his blood pressure.

On physical examination, his left lower extremity was cold and without pulses, including the femoral pulse. Suspecting acute arterial thrombosis, we ordered immediate computed tomographic (CT) angiography of the abdomen and pelvis with left lower extremity runoff. The images showed dissection of the abdominal aorta with extension to both the left and right common iliac arteries and the origin of the right external iliac artery. There was resultant occlusion of the left external iliac artery (Figure 1).

Immediate CT angiography of the chest was then performed, which revealed dissection of the thoracic aorta as well, starting superior to the aortic valve annulus and involving the ascending aorta, aortic arch, and the entire descending thoracic aorta (Figure 2).

The patient underwent emergency surgical repair of the aortic root, ascending aorta, and aortic arch. Residual dissection of the descending aorta was managed conservatively with blood pressure control using intravenous labetalol initially, which was then switched to oral carvedilol, and the pulses returned in his left lower extremity. He had an unremarkable postoperative recovery and was discharged after 1 week.

AORTIC DISSECTION AND MALPERFUSION SYNDROME

Aortic dissection is most often associated with acute onset of sharp chest pain and upper back pain. On rare occasions, it can have an atypical presentation such as stroke, paraplegia, mesenteric ischemia, or lower limb malperfusion.¹

Extension of aortic dissection into the iliac and femoral arteries can cause impaired or absent blood flow to the lower extremity. These pulse deficits are a part of limb mal­perfusion syndrome. Symptoms of malperfusion syndrome vary greatly and depend on the vessels involved. Malperfusion of the branches of the aortic arch can result in stroke or altered sensorium. Compromise of intra-abdominal vessels due to dissection can involve the mesenteric bed, the renal arteries, or both, resulting in laboratory derangements such as lactic acidosis and renal failure.

How aortic dissection and malperfusion syndrome occur

Over time, shear forces on the aortic wall result in degeneration of the tunica intima and media. Dissection occurs when deterioration of the intima causes propagation of blood through a cleavage plane into the outer portion of the diseased media, forming a false lumen.

Anterograde or retrograde progression of dissection depends on the balance of the pressure gradient between true and false lumens.² With every systolic ventricular contraction, a fluid and pressure wave travels down both lumens (true and false). However, the pressure gradient between the false and true lumens allows the more pliable intimal flap to bulge into the true lumen and ostia of branch vessels, resulting in static or dynamic obstruction.

Static obstruction occurs when the false lumen projects completely into the branch vessel and there is resultant thrombosis. As the name implies, dynamic obstruction is intermittent and is responsible for 80% of the cases of malperfusion syndrome.³ Dynamic obstruction has 2 distinct mechanisms: hypoperfusion through the true lumen due to impaired flow, and prolapse of the false lumen into a branch vessel.

Factors that exacerbate hypoperfusion through the true lumen and make obliteration by the false lumen more likely include large circumference of the dissected aorta, rapid heart rate, and high systolic pressure.⁴ Therefore, it is important to control the heart rate and blood pressure using beta-blockers in cases of aortic dissection with malperfusion syndrome. This treatment may resolve the dynamic obstruction through expansion and resumption of perfusion through the true lumen.⁵

MANAGEMENT OF MALPERFUSION SYNDROME

Aortic dissection can be classified as either Stanford type A (involving the ascending aorta) or type B (involving the descending aorta). Type B dissection associated with malperfusion syndrome is termed “complicated” type B aortic dissection. Our patient had both Stanford type A and complicated type B aortic dissection.

Unlike type A aortic dissection, which requires definitive open surgical repair, complicated type B aortic dissection occasionally responds to medical management alone. A plausible explanation for resolution of limb malperfusion with optimal blood pressure control is expansion of the true lumen and obliteration of the false lumen, as was likely the case in our patient.

In most cases, however, limb malperfusion persists despite optimal medical management. In such patients, endovascular graft stenting or open surgical repair may be needed. Open surgical repair procedures like bypass grafting or surgical fenestration are associated with significant rates of mortality and morbidity.⁵ Therefore, an endovascular approach rather than conventional surgical repair for complicated type B aortic dissection is advocated after optimal medical management.⁶ Endovascular repair also promotes favorable aortic remodeling without the morbidity associated with open surgical repair.

A 40-year-old man with a history of hypertension and alcohol abuse presented with acute onset of mild chest tightness, left leg pain, and increasing agitation, which prevented us from obtaining additional meaningful information from him.

On admission, his heart rate was 120 beats per minute, blood pressure 211/122 mm Hg, respiratory rate 18 per minute, and oxygen saturation 92% on room air. Given his history of alcohol abuse, we checked his blood ethanol level, which was less than 0.01%, well below the legal limit for intoxication.

We gave the patient intravenous lorazepam for possible alcohol withdrawal and started labetalol by intravenous infusion to lower his blood pressure.

On physical examination, his left lower extremity was cold and without pulses, including the femoral pulse. Suspecting acute arterial thrombosis, we ordered immediate computed tomographic (CT) angiography of the abdomen and pelvis with left lower extremity runoff. The images showed dissection of the abdominal aorta with extension to both the left and right common iliac arteries and the origin of the right external iliac artery. There was resultant occlusion of the left external iliac artery (Figure 1).

Immediate CT angiography of the chest was then performed, which revealed dissection of the thoracic aorta as well, starting superior to the aortic valve annulus and involving the ascending aorta, aortic arch, and the entire descending thoracic aorta (Figure 2).

The patient underwent emergency surgical repair of the aortic root, ascending aorta, and aortic arch. Residual dissection of the descending aorta was managed conservatively with blood pressure control using intravenous labetalol initially, which was then switched to oral carvedilol, and the pulses returned in his left lower extremity. He had an unremarkable postoperative recovery and was discharged after 1 week.

AORTIC DISSECTION AND MALPERFUSION SYNDROME

Aortic dissection is most often associated with acute onset of sharp chest pain and upper back pain. On rare occasions, it can have an atypical presentation such as stroke, paraplegia, mesenteric ischemia, or lower limb malperfusion.¹

Extension of aortic dissection into the iliac and femoral arteries can cause impaired or absent blood flow to the lower extremity. These pulse deficits are a part of limb mal­perfusion syndrome. Symptoms of malperfusion syndrome vary greatly and depend on the vessels involved. Malperfusion of the branches of the aortic arch can result in stroke or altered sensorium. Compromise of intra-abdominal vessels due to dissection can involve the mesenteric bed, the renal arteries, or both, resulting in laboratory derangements such as lactic acidosis and renal failure.

How aortic dissection and malperfusion syndrome occur

Over time, shear forces on the aortic wall result in degeneration of the tunica intima and media. Dissection occurs when deterioration of the intima causes propagation of blood through a cleavage plane into the outer portion of the diseased media, forming a false lumen.

Anterograde or retrograde progression of dissection depends on the balance of the pressure gradient between true and false lumens.² With every systolic ventricular contraction, a fluid and pressure wave travels down both lumens (true and false). However, the pressure gradient between the false and true lumens allows the more pliable intimal flap to bulge into the true lumen and ostia of branch vessels, resulting in static or dynamic obstruction.

Static obstruction occurs when the false lumen projects completely into the branch vessel and there is resultant thrombosis. As the name implies, dynamic obstruction is intermittent and is responsible for 80% of the cases of malperfusion syndrome.³ Dynamic obstruction has 2 distinct mechanisms: hypoperfusion through the true lumen due to impaired flow, and prolapse of the false lumen into a branch vessel.

Factors that exacerbate hypoperfusion through the true lumen and make obliteration by the false lumen more likely include large circumference of the dissected aorta, rapid heart rate, and high systolic pressure.⁴ Therefore, it is important to control the heart rate and blood pressure using beta-blockers in cases of aortic dissection with malperfusion syndrome. This treatment may resolve the dynamic obstruction through expansion and resumption of perfusion through the true lumen.⁵

MANAGEMENT OF MALPERFUSION SYNDROME

Aortic dissection can be classified as either Stanford type A (involving the ascending aorta) or type B (involving the descending aorta). Type B dissection associated with malperfusion syndrome is termed “complicated” type B aortic dissection. Our patient had both Stanford type A and complicated type B aortic dissection.

Unlike type A aortic dissection, which requires definitive open surgical repair, complicated type B aortic dissection occasionally responds to medical management alone. A plausible explanation for resolution of limb malperfusion with optimal blood pressure control is expansion of the true lumen and obliteration of the false lumen, as was likely the case in our patient.

In most cases, however, limb malperfusion persists despite optimal medical management. In such patients, endovascular graft stenting or open surgical repair may be needed. Open surgical repair procedures like bypass grafting or surgical fenestration are associated with significant rates of mortality and morbidity.⁵ Therefore, an endovascular approach rather than conventional surgical repair for complicated type B aortic dissection is advocated after optimal medical management.⁶ Endovascular repair also promotes favorable aortic remodeling without the morbidity associated with open surgical repair.

ANSWER

The image shows a large, convex hyperdensity within the left parietal region. This is a textbook image of an acute epidural hematoma. There is considerable mass effect and evidence of left-to-right shift. Windowing shows an underlying fracture, which is typically associated with these types of hemorrhages.

There is also evidence of a right-side concave hyperdensity, consistent with an acute subdural hematoma. Typically, this is referred to as a contrecoup injury.

The patient was transported to the operating room for an emergent left craniotomy for epidural evacuation; he recovered uneventfully.

ANSWER

The image shows a large, convex hyperdensity within the left parietal region. This is a textbook image of an acute epidural hematoma. There is considerable mass effect and evidence of left-to-right shift. Windowing shows an underlying fracture, which is typically associated with these types of hemorrhages.

There is also evidence of a right-side concave hyperdensity, consistent with an acute subdural hematoma. Typically, this is referred to as a contrecoup injury.

The patient was transported to the operating room for an emergent left craniotomy for epidural evacuation; he recovered uneventfully.

ANSWER

The image shows a large, convex hyperdensity within the left parietal region. This is a textbook image of an acute epidural hematoma. There is considerable mass effect and evidence of left-to-right shift. Windowing shows an underlying fracture, which is typically associated with these types of hemorrhages.

There is also evidence of a right-side concave hyperdensity, consistent with an acute subdural hematoma. Typically, this is referred to as a contrecoup injury.

The patient was transported to the operating room for an emergent left craniotomy for epidural evacuation; he recovered uneventfully.

Resuscitation of critically ill patients in shock from cardiogenic, hypovolemic, obstructive, distributive, or neurogenic etiology is a cornerstone of the care delivered by emergency physicians (EPs).¹ Regardless of the etiology, it is essential that the treating EP initiate resuscitative measures in a timely manner and closely trend the patient’s response to these interventions.

The early goal-directed therapy (EGDT) initially proposed by Rivers et al² in 2001 demonstrated a bundled approach to fluid resuscitation by targeting end points for volume resuscitation, mean arterial blood pressure (MAP), oxygen (O₂) delivery/extraction (mixed venous O₂ saturation, [S_vO₂]), hemoglobin (Hgb) concentration, and cardiac contractility. Since then, advancements in laboratory testing and hemodynamic monitoring (HDM) devices further aid and guide resuscitative efforts, and are applicable to any etiology of shock.

In addition to these advancements, the growing evidence of the potential harm from improper fluid resuscitation, such as the administration of excessive intravascular fluid (IVF),³ underscores the importance of a precise, targeted, and individualized approach to care. This article reviews the background, benefits, and limitations of some of the common and readily available tools in the ED that the EP can employ to guide fluid resuscitation in critically ill patients.

Physical Examination

Background

The rapid recognition and treatment of septic shock in the ED is associated with lower rates of in-hospital morbidity and mortality.⁴ The physical examination by the EP begins immediately upon examining the patient. The acquisition of vital signs and recognition of physical examination findings suggestive of intravascular volume depletion allows the EP to initiate treatment immediately.

In this discussion, hypotension is defined as systolic blood pressure (SBP) of less than 95 mm Hg, MAP of less than 65 mm Hg, or a decrease in SBP of more than 40 mm Hg from baseline measurements. Subsequently, shock is defined as hypotension with evidence of tissue hypoperfusion-induced dysfunction.^5,6 Although the use of findings from the physical examination to guide resuscitation allows for rapid patient assessment and treatment, the predictive value of the physical examination to assess hemodynamic status is limited.

Benefits

The major benefit of the physical examination as a tool to evaluate hemodynamic status is its ease and rapid acquisition. The patient’s vital signs and physical examination can be obtained in the matter of moments upon presentation, without the need to wait on results of laboratory evaluation or additional equipment. Additionally, serial examinations by the same physician can be helpful to monitor a patient’s response to resuscitative efforts. The negative predictive value (NPV) of the physical examination in evaluating for hypovolemia may be helpful, but only when it is taken in the appropriate clinical context and is used in conjunction with other diagnostic tools. The physical examination can exclude hypovolemic volume status with an NPV of approximately 70%.⁷

A constellation of findings from the physical examination may include altered mentation, hypotension, tachycardia, and decreased urinary output by 30% to 40% intravascular volume loss.^8,9Findings from the physical examination to assess fluid status should be used with caution as interobserver reliability has proven to be poor and the prognostic value is limited.

Limitations

The literature shows the limited prognostic value of the physical examination in determining a patient’s volume status and whether fluid resuscitation is indicated. For example, in one meta-analysis,¹⁰ supine hypotension and tachycardia were frequently absent on examination—even in patients who underwent large volume phlebotomy.⁸ This study also showed postural dizziness to be of no prognostic value.

Another study by Saugel et al⁷ that compared the physical examination (skin assessment, lung auscultation, and percussion) to transpulmonary thermodilution measurements of the cardiac index, global end-diastolic volume index, and extravascular lung water index, found poor interobserver correlation and agreement among physicians.

The physical examination is also associated with weak predictive capabilities for the estimation of volume status compared to the device measurements. Another contemporary study by Saugel et al⁹ evaluated the predictive value of the physical examination to accurately identify volume responsiveness replicated these results, and reported poor interobserver correlation (κ coefficient 0.01; 95% caval index [CI] -0.39-0.42) among physical examination findings, with a sensitivity of only 71%, specificity of 23.5%, positive predictive value of 27.8%, and negative predictive value of 66.7%.⁹

Serum Lactate Levels

Background

In the 1843 book titled, Investigations of Pathological Substances Obtained During the Epidemic of Puerperal Fever, Johann Joseph Scherer described the cases of seven young peripartum female patients who died from a clinical picture of what is now understood to be septic shock.¹¹ In his study of these cases, Scherer demonstrated the presence of lactic acid in patients with pathological conditions. Prior to this discovery, lactic acid had never been isolated in a healthy individual. These results were recreated in 1851 by Scherer and Virchow,¹¹ who demonstrated the presence of lactic acid in the blood of a patient who died from leukemia. The inference based on Scherer and Virchow’s work correlated the presence of excessive lactic acid with bodily deterioration and severe disease. Since this finding, there has been a great deal of interest in measuring serum lactic acid as a means to identify and manage critical illness.

In a 2001 groundbreaking study of EGDT for severe sepsis and septic shock, Rivers et al² studied lactic acid levels as a marker for severe disease. Likewise, years later, the 2014 Protocol-Based Care for Early Septic Shock (PROCESS), Prospective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE), and Australasian Resuscitation in Sepsis Evaluation (ARISE) trials used lactate levels in a similar manner to identify patients appropriate for randomization.^12-14 While the purpose of measuring lactic acid was only employed in these studies to identify patients at risk for critical illness, the 2012 Surviving Sepsis Campaign Guidelines recommended serial measurement of lactate, based on the assumption that improved lactate levels signified better tissue perfusion.¹⁵

Although much of the studies on lactate levels appear to be based on the treatment and management of septic patients, findings can be applied to any etiology of shock. For example, a serum lactate level greater than 2 mmol/L is considered abnormal, and a serum lactate greater than 4 mmol/L indicates a significantly increased risk for in-hospital mortality.¹⁶

Benefits

It is now a widely accepted belief that the rapid identification, triage, and treatment of critically ill patients has a dramatic effect on morbidity and mortality.⁴ As previously noted, lactate has been extensively studied and identified as a marker of severe illness.^17,18 A serum lactate level, which can be rapidly processed in the ED, can be easily obtained from a minimally invasive venous, arterial, or capillary blood draw.¹⁸ The only risk associated with serum lactate testing is that of any routine venipuncture; the test causes minimal, if any, patient discomfort.

Thanks to advances in point-of-care (POC) technology, the result of serum lactate assessment can be available within 10 minutes from blood draw. This technology is inexpensive and can be easily deployed in the prehospital setting or during the initial triage assessment of patients arriving at the ED.¹⁹ These POC instruments have been well correlated with whole blood measurements and permit for the rapid identification and treatment of at risk patients.

Limitations

The presence of elevated serum lactate levels is believed to represent the presence of cellular anaerobic metabolism due to impaired O₂ delivery in the shock state. Abnormal measurements therefore prompt aggressive interventions aimed at maximizing O₂ delivery to the tissues, such as intravenous fluid boluses, vasopressor therapy, or even blood product administration.

A return to a normalized serum lactate level is assumed to represent a transition back to aerobic metabolism. Lactate elevations, however, are not solely an indication of anaerobic metabolism and may only represent a small degree of lactate production.²⁰ While the specific cellular mechanics are out of the scope of this article, it has been postulated that the increase in plasma lactate concentration is primarily driven by β-2 receptor stimulation from increased circulating catecholamines leading to increased aerobic glycolysis. Increased lactate levels could therefore be an adaptive mechanism of energy production—aggressive treatment and rapid clearance may, in fact, be harmful. Type A lactic acidosis is categorized as elevated serum levels due to tissue hypoperfusion.²¹

However, lactate elevations do not exclusively occur in severe illness. The use of β-2 receptor agonists such as continuous albuterol treatments or epinephrine may cause abnormal lactate levels.²² Other medications have also been associated with elevated serum lactate levels, including, but not limited to linezolid, metformin, and propofol.^23-25 Additionally, lactate levels may be elevated after strenuous exercise, seizure activity, or in liver and kidney disease.²⁶ These “secondary” causes of lactic acidosis that are not due to tissue hypoperfusion are referred to as type B lactic acidosis. Given these multiple etiologies and lack of specificity for this serum measurement, a failure to understand these limitations may result in over aggressive or unnecessary medical treatments.

Central Venous Pressure

Background

Central venous pressure (CVP) measurements can be obtained through a catheter, the distal tip of which transduces pressure of the superior vena cava at the entrance of the right atrium (RA). Thus, CVP is often used as a representation of RA pressure (RAP) and therefore an estimate of right ventricular (RV) preload. While CVP is used to diagnose and determine the etiology of shock, evidence and controversy regarding the use of CVP as a marker for resuscitation comes largely from sepsis-focused literature.⁵ Central venous pressure is meant to represent preload, which is essential for stroke volume as described by the Frank-Starling mechanism; however, its use as a target in distributive shock, a state in which it is difficult to determine a patient’s volume status, has been popularized by EGDT since 2001.²

Since the publication of the 2004 Surviving Sepsis Guidelines, CVP monitoring has been in the spotlight of sepsis resuscitation, albeit with some controversy.²⁷ Included as the result of two studies, this recommendation has been removed in the most recent guidelines after 12 years of further study and scrutiny.^2,27,28

Hypovolemic and hemorrhagic shock are usually diagnosed clinically and while a low CVP can be helpful in the diagnosis, the guidelines do not support CVP as a resuscitation endpoint. Obstructive and cardiogenic shock will both result in elevated CVP; however, treatment of obstructive shock is generally targeted at the underlying cause. While cardiogenic shock can be preload responsive, the mainstay of therapy in the ED is identification of patients for revascularization and inotropic support.²⁹

Benefits

The CVP has been used as a surrogate for RV preload volume. If a patient’s preload volume is low, the treating physician can administer fluids to improve stroke volume and cardiac output (CO). Clinically, CVP measurements are easy to obtain provided a central venous line has been placed with the distal tip at the entrance to the RA. Central venous pressure is measured by transducing the pressure via manometry and connecting it to the patient’s bedside monitor. This provides an advantage of being able to provide serial or even continuous measurements. The “normal” RAP should be a low value (1-5 mm Hg, mean of 3 mm Hg), as this aids in the pressure gradient to drive blood from the higher pressures of the left ventricle (LV) and aorta through the circulation back to the low-pressure of the RA.³⁰ The value of the CVP is meant to correspond to the physical examination findings of jugular venous distension.^31,32 Thus, a low CVP may be “normal” and seen in patients with hypovolemic shock, whereas an elevated CVP can suggest volume overload or obstructive shock. However, this is of questionable value in distributive shock cases.

Aside from the two early studies on CVP monitoring during treatment of septic patients, there are few data to support the use of CVP measurement in the early resuscitation of patients with shock.^2,28 More recent trials (PROMISE, ARISE, PROCESS) that compared protocolized sepsis care to standard care showed no benefit to bundles including CVP measurements.^12-14 However, a subsequent, large observational trial spanning 7.5 years demonstrated improvements in sepsis-related mortality in patients who received a central venous catheter (CVC) and CVP-targeted therapy.³³ Thus, it is possible that protocols including CVP are still beneficial in combination with other therapies even though CVP in isolation is not.

Limitations

The traditional two assumptions in CVP monitoring are CVP value represents the overall volume status of the patient, and the LV is able to utilize additional preload volume. The latter assumption, however, may be hampered by the presence of sepsis-induced myocardial dysfunction, which may be present in up to 40% of critically ill patients.³⁴ The former assumption does not always hold true due to processes that change filling pressures independent of intravascular volume—eg, acute or chronic pulmonary hypertension, cardiac tamponade, intra-abdominal hypertension, or LV failure. Even before the landmark EGDT study, available data suggested that CVP was not a reliable marker for resuscitation management.³⁵ A recent systematic review by Gottlieb and Hunter³⁶ showed that the area under the receiver-operator curve for low, mid-range, or high CVPs was equivocal at best. In addition to its unreliability and lack of specificity, another significant drawback to using CVP to guide resuscitation therapy in the ED is that it necessitates placement of a CVC, which can be time-consuming and, if not otherwise indicated, lead to complications of infection, pneumothorax, and/or thrombosis.³⁷

Mixed Venous Oxygen

Background

Most EPs are familiar with the use of S_cvO₂ in EGDT protocols to guide volume resuscitation of septic patients.² A patient’s S_cvO₂ represents the O₂ saturation of venous blood obtained via a CVC at the confluence of the superior vena cava and the RA, and thus it reflects tissue O₂ consumption as a surrogate for tissue perfusion. The measurement parallels the S_vO₂ obtained from the pulmonary artery. In a healthy patient, S_vO₂ is around 65% to 70% and includes blood returning from both the superior and inferior vena cava (IVC). As such, S_cvO₂ values are typically 3% to 5% lower than S_vO₂ owing to the lower O₂ extracted by tissues draining into the IVC compared to the mixed venous blood sampled from the pulmonary artery.³⁸

Though a debate over the benefit of EGDT in treating sepsis continues, understanding the physiology of S_cvO₂ measurements is another potential tool the EP can use to guide the resuscitation of critically ill patients.³⁹ A patient’s S_vO₂ and, by extension, S_cvO₂ represents the residual O₂ saturation after the tissues have extracted the amount of O₂ necessary to meet metabolic demands (Figure 2).

Benefits

A critically ill patient’s S_cvO₂ can potentially provide EPs with insight into the patient’s global tissue perfusion and the source of any mismatch between O₂ delivery and consumption. Using additional tools and measurements (physical examination, serum Hgb levels, and pulse oximetry) in conjunction with an S_cvO₂ measurement, assists EPs in identifying targets for therapeutic intervention. The effectiveness of this intervention can then be assessed using serial S_cvO₂ measurements, as described in Rivers et al² EGDT protocol. Importantly, EPs should take care to measure serial S_cvO₂ values to maximize its utility.³⁸ Similar to a CVP measurement, S_cvO₂is easily obtained from blood samples for serial laboratory measurements, assuming the patient already has a CVC with the distal tip at the entrance to the RA (S_cvO₂) or a pulmonary artery catheter (PAC) (S_vO₂).

Limitations

Serial measurements provide the most reliable information, which may be more useful in patients who spend extended periods of their resuscitation in the ED. In comparison to other measures of global tissue hypoxia, work by Jones et al⁴¹ suggests non-inferiority of peripherally sampled, serial lactate measurements as an alternative to S_cvO₂. This, in conjunction with the requirement for an internal jugular CVC, subclavian CVC, or PAC with their associated risks, may make S_cvO₂ a less attractive guide for the resuscitation of critically ill patients in the ED.

Monitoring Devices

Background

As noted throughout this review, it is important not only to identify and rapidly treat shock, but to also correctly identify the type of shock, such that treatment can be appropriately directed at its underlying cause. However, prior work suggests that EPs are unable to grossly estimate CO or systemic vascular resistance when compared to objective measurements of these parameters.⁴² This is in agreement with the overall poor performance of physical examination and clinical evaluation as a means of predicting volume responsiveness or guiding resuscitation, as discussed previously. Fortunately, a wide variety of devices to objectively monitor hemodynamics are now available to the EP.

In 1970, Swan et al⁴³ published their initial experience with pulmonary artery catheterization at the bedside, using a balloon-tipped, flow-guided PAC in lieu of fluoroscopy, which had been mandated by earlier techniques. The ability to measure CO, right heart pressures, pulmonary arterial pressures, and estimate LV end diastolic pressure ushered in an era of widespread PAC use, despite an absence of evidence for causation of improved patient outcomes. The utilization of PACs has fallen, as the literature suggests that the empiric placement of PACs in critically ill patients does not improve mortality, length of stay, or cost, and significant complication rates have been reported in large trials.^44,45Subsequently, a number of non-invasive or less-invasive HDM devices have been developed. Amongst the more commonly encountered modern devices, the techniques utilized for providing hemodynamic assessments include thermodilution and pulse contour analysis (PiCCO^TM), pulse contour analysis (FloTrac/Vigileo^TM), and lithium chemodilution with pulse power analysis (LiDCOplus^TM).⁴⁶ The primary utility of these devices for the EP lies in the ability to quantify CO, stroke volume, and stroke volume or pulse pressure variation (PPV) to predict or assess response to resuscitative interventions (volume administration, vasopressors, inotropes, etc).

Benefits

Many of these devices require placement of an arterial catheter. Some require the addition of a CVC. Both of these procedures are well within the clinical scope of the EP, and are performed with fair frequency on critically ill patients. This is a distinct advantage when compared to pulmonary artery catheterization, a higher risk procedure that is rarely performed outside of the intensive care unit or cardiac catheterization laboratory. In addition, all of the devices below present hemodynamic data in a graphical, easy-to-read format, in real time. All of the devices discussed report stroke volume variation (SVV) or PPV continuously.

Limitations

Though these measures have validated threshold values that predict volume responsiveness, they require the patient to be intubated with a set tidal volume of greater than or equal to 8 mL/kg without spontaneous respirations and cardiac arrhythmias, in order to accurately do so. All of the HDM devices that rely on pulse contour analysis as the primary means of CO measurement cannot be used in the presence of significant cardiac arrhythmias (ie, atrial fibrillation), or mechanical circulatory assistance devices (ie, intra-aortic balloon counterpulsation). None of these devices are capable of monitoring microcirculatory changes, felt to be of increasing clinical importance in the critically ill.

The use of HDM devices to monitor CO with a reasonable degree of accuracy, trend CO, and assess for volume responsiveness using a number of previously validated parameters such as SVV is now in little doubt. However, these devices are still invasive, if less so than a pulmonary artery. The crux of the discussion of HDM devices for use in ED resuscitation revolves around whether or not the use of such devices to drive previously validated, protocolized care results in better outcomes for patients. The EP can now have continuous knowledge of a large number of hemodynamic parameters at their fingertips with relatively minimal additional efforts. At the time of this writing, though, this is both untested and unproven, with respect to the ED population.

Point-of-Care Ultrasound

Background

Over the past two decades, ultrasound (US) has become an integral part of the practice of emergency medicine (EM), and is now included in all United States Accreditation Council for Graduate Medical Education Emergency Medicine Residency Programs.^47,48 It has emerged as a very important bedside tool performed by the clinician to identify type of shock and guide resuscitation, and has been endorsed by both EM and critical care societies.^49-51 This section reviews the utility of US as a modality in identifying shock and guiding resuscitation, in addition to the pitfalls and limitations of this important tool.

In 2010, Perera et al⁴⁷ described in their landmark article the Rapid Ultrasound in SHock (RUSH) examination, which describes a stepwise (the pump, tank, pipes) approach to identify the type of shock (cardiogenic, hypovolemic, obstructive, or distributive) in the crashing, hypotensive ED patient. We do not describe the full RUSH examination in this review, but discuss key elements of it as examples of how POCUS can assist the EP to make a rapid diagnosis and aid in the management of patients in shock. The “pump” is the heart, which is assessed in four different views to identify a pericardial effusion and possible tamponade, assess contractility or ejection fraction of the LV (severely decreased, decreased, normal, or hyperdynamic), and right heart strain which is identified by an RV that is larger than the LV, indicative of a potential pulmonary embolus.

The “tank” is then assessed by visualizing the IVC in the subxiphoid plane, and is evaluated for respiratory collapsibility (CI) and maximum size. This has been quite the debated topic over the last two decades. In 1988, Simonson and Schiller⁵² were the first to describe a correlation in spontaneously breathing patients between IVC caliber (measured 2 cm from the cavoatrial junction) and variation and RAP, where a larger IVC diameter and less respiratory variation correlated with a high RAP. Kircher et al⁵³ later went on to describe that a CI greater than 50% correlated with an RAP of less than 10 mm Hg and vice versa in spontaneously breathing patients. Since then there have been more studies attempting to verify these findings in both spontaneously breathing and mechanically ventilated patients.^54-56 The purpose of performing these measurements is not to estimate CVP, but to assess fluid responsiveness (ie, a blood pressure response to a fluid challenge). It can be assumed in states of shock that a small IVC, or one with a high CI, in the presence of a hyperdynamic heart is indicative of an underfilled ventricle and fluid responsiveness, especially if the IVC size increases with fluid.^55,57 However, there are several caveats to this. First, in mechanically ventilated patients, the IVC is already plethoric due to positive pressure ventilation, and increases in diameter with inspiration and decreases with expiration as compared to spontaneously breathing patients. Second, the CI value to predict volume responsiveness in ventilated patients is set at 15% instead of 50%.⁵⁵ Third, it is important to always take the clinical scenario in context; a dilated IVC with small CI is not necessarily only due to volume overload and congestive heart failure, but can be due to elevated RAP from obstructive shock due to cardiac tamponade or massive pulmonary embolus, which is why it is important to assess the “pump” first.^47,58 It is also crucial to not forget to assess the abdominal and thoracic cavities, as intraperitoneal or pleural fluid with a collapsed IVC can potentially make a diagnosis of hemorrhagic or hypovolemic shock depending on the clinical scenario.⁴⁷ The final part of the RUSH protocol is to evaluate the “pipes,” inclusive of the lower extremity deep venous system for evaluation of potential thrombosis that could increase suspicion for a pulmonary embolism causing obstructive shock, and the aorta with the common iliac arteries if there is concern for aortic dissection or aneurysmal rupture.

Benefits

Some of the most significant advantages to the use of POCUS to guide resuscitation is that it is quick, non-invasive, does not use ionizing radiation, and can be easily repeated. As noted above, it is a requirement for EM residencies to teach its use, so that contemporary graduates are entering the specialty competent in applying it to the care of their patients. Furthermore, POCUS is done at the bedside, limiting the need to potentially transport unstable patients.

In the most basic applications, POCUS provides direct visualization of a patient’s cardiac function, presence or absence of lung sliding to suggest a pneumothorax, presence of pulmonary edema, assessment of CVP pressures or potential for fluid responsiveness, as well as identification of potential thoracic, peritoneal, or pelvic cavity fluid accumulation that may suggest hemorrhage. There is literature to support that these assessments performed by the EP have been shown to be comparable to those of cardiologists.^59,60 With continued practice and additional training, it is possible for EPs to even perform more “advanced” hemodynamic assessments to both diagnose and guide therapy to patients in shock (Figures 3 and 4).⁶¹

Limitations

Although POCUS has been shown as a remarkable tool to help assist the EP in making rapid decisions regarding resuscitation, it is always important to remember its limitations. Most of the studies regarding its use are of very small sample sizes, and further prospective studies have to be performed in order for this modality to be fully relied on.⁶²Compared to some of the previously mentioned HDM devices that may provide continuous data, POCUS needs to be performed by the treating physician, thereby occurring intermittently. Emergency physicians need to be aware of their own experience and limitations with this modality, as errors in misdiagnosis can lead to unnecessary procedures, with resulting significant morbidity and mortality. Blanco and Volpicelli⁶³ describe several common errors that include misdiagnosing the stomach as a peritoneal effusion, assuming adequate volume resuscitation when the IVC is seen to be plethoric in the setting of cardiac tamponade, or mistaking IVC movement as indicative of collapsibility, amongst other described misinterpretations. Several other studies have shown that, despite adequate performance of EPs in POCUS, diagnostic sensitivities remained higher when performed by radiologists.^64-67 Thus it remains important for the EPs to be vigilant and not anchor on a diagnosis when in doubt, and to consult early with radiology, particularly if there is any question, to avoid potential adverse patient outcomes.

Summary

There are several ways to diagnose and track resuscitation in the ED, which include physical examination, assessment of serum laboratory values, monitoring of hemodynamic status, and use of POCUS. Unfortunately, none of these methods provides a perfect assessment, and no method has been proven superior and effective over the others. Therefore, it is important for EPs treating patients in shock to be aware of the strengths and limitations of each assessment method (Table).

Resuscitation of critically ill patients in shock from cardiogenic, hypovolemic, obstructive, distributive, or neurogenic etiology is a cornerstone of the care delivered by emergency physicians (EPs).¹ Regardless of the etiology, it is essential that the treating EP initiate resuscitative measures in a timely manner and closely trend the patient’s response to these interventions.

The early goal-directed therapy (EGDT) initially proposed by Rivers et al² in 2001 demonstrated a bundled approach to fluid resuscitation by targeting end points for volume resuscitation, mean arterial blood pressure (MAP), oxygen (O₂) delivery/extraction (mixed venous O₂ saturation, [S_vO₂]), hemoglobin (Hgb) concentration, and cardiac contractility. Since then, advancements in laboratory testing and hemodynamic monitoring (HDM) devices further aid and guide resuscitative efforts, and are applicable to any etiology of shock.

In addition to these advancements, the growing evidence of the potential harm from improper fluid resuscitation, such as the administration of excessive intravascular fluid (IVF),³ underscores the importance of a precise, targeted, and individualized approach to care. This article reviews the background, benefits, and limitations of some of the common and readily available tools in the ED that the EP can employ to guide fluid resuscitation in critically ill patients.

Physical Examination

Background

The rapid recognition and treatment of septic shock in the ED is associated with lower rates of in-hospital morbidity and mortality.⁴ The physical examination by the EP begins immediately upon examining the patient. The acquisition of vital signs and recognition of physical examination findings suggestive of intravascular volume depletion allows the EP to initiate treatment immediately.

In this discussion, hypotension is defined as systolic blood pressure (SBP) of less than 95 mm Hg, MAP of less than 65 mm Hg, or a decrease in SBP of more than 40 mm Hg from baseline measurements. Subsequently, shock is defined as hypotension with evidence of tissue hypoperfusion-induced dysfunction.^5,6 Although the use of findings from the physical examination to guide resuscitation allows for rapid patient assessment and treatment, the predictive value of the physical examination to assess hemodynamic status is limited.

Benefits

The major benefit of the physical examination as a tool to evaluate hemodynamic status is its ease and rapid acquisition. The patient’s vital signs and physical examination can be obtained in the matter of moments upon presentation, without the need to wait on results of laboratory evaluation or additional equipment. Additionally, serial examinations by the same physician can be helpful to monitor a patient’s response to resuscitative efforts. The negative predictive value (NPV) of the physical examination in evaluating for hypovolemia may be helpful, but only when it is taken in the appropriate clinical context and is used in conjunction with other diagnostic tools. The physical examination can exclude hypovolemic volume status with an NPV of approximately 70%.⁷

A constellation of findings from the physical examination may include altered mentation, hypotension, tachycardia, and decreased urinary output by 30% to 40% intravascular volume loss.^8,9Findings from the physical examination to assess fluid status should be used with caution as interobserver reliability has proven to be poor and the prognostic value is limited.

Limitations

The literature shows the limited prognostic value of the physical examination in determining a patient’s volume status and whether fluid resuscitation is indicated. For example, in one meta-analysis,¹⁰ supine hypotension and tachycardia were frequently absent on examination—even in patients who underwent large volume phlebotomy.⁸ This study also showed postural dizziness to be of no prognostic value.

Another study by Saugel et al⁷ that compared the physical examination (skin assessment, lung auscultation, and percussion) to transpulmonary thermodilution measurements of the cardiac index, global end-diastolic volume index, and extravascular lung water index, found poor interobserver correlation and agreement among physicians.

The physical examination is also associated with weak predictive capabilities for the estimation of volume status compared to the device measurements. Another contemporary study by Saugel et al⁹ evaluated the predictive value of the physical examination to accurately identify volume responsiveness replicated these results, and reported poor interobserver correlation (κ coefficient 0.01; 95% caval index [CI] -0.39-0.42) among physical examination findings, with a sensitivity of only 71%, specificity of 23.5%, positive predictive value of 27.8%, and negative predictive value of 66.7%.⁹

Serum Lactate Levels

Background

In the 1843 book titled, Investigations of Pathological Substances Obtained During the Epidemic of Puerperal Fever, Johann Joseph Scherer described the cases of seven young peripartum female patients who died from a clinical picture of what is now understood to be septic shock.¹¹ In his study of these cases, Scherer demonstrated the presence of lactic acid in patients with pathological conditions. Prior to this discovery, lactic acid had never been isolated in a healthy individual. These results were recreated in 1851 by Scherer and Virchow,¹¹ who demonstrated the presence of lactic acid in the blood of a patient who died from leukemia. The inference based on Scherer and Virchow’s work correlated the presence of excessive lactic acid with bodily deterioration and severe disease. Since this finding, there has been a great deal of interest in measuring serum lactic acid as a means to identify and manage critical illness.

In a 2001 groundbreaking study of EGDT for severe sepsis and septic shock, Rivers et al² studied lactic acid levels as a marker for severe disease. Likewise, years later, the 2014 Protocol-Based Care for Early Septic Shock (PROCESS), Prospective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE), and Australasian Resuscitation in Sepsis Evaluation (ARISE) trials used lactate levels in a similar manner to identify patients appropriate for randomization.^12-14 While the purpose of measuring lactic acid was only employed in these studies to identify patients at risk for critical illness, the 2012 Surviving Sepsis Campaign Guidelines recommended serial measurement of lactate, based on the assumption that improved lactate levels signified better tissue perfusion.¹⁵

Although much of the studies on lactate levels appear to be based on the treatment and management of septic patients, findings can be applied to any etiology of shock. For example, a serum lactate level greater than 2 mmol/L is considered abnormal, and a serum lactate greater than 4 mmol/L indicates a significantly increased risk for in-hospital mortality.¹⁶

Benefits

It is now a widely accepted belief that the rapid identification, triage, and treatment of critically ill patients has a dramatic effect on morbidity and mortality.⁴ As previously noted, lactate has been extensively studied and identified as a marker of severe illness.^17,18 A serum lactate level, which can be rapidly processed in the ED, can be easily obtained from a minimally invasive venous, arterial, or capillary blood draw.¹⁸ The only risk associated with serum lactate testing is that of any routine venipuncture; the test causes minimal, if any, patient discomfort.

Thanks to advances in point-of-care (POC) technology, the result of serum lactate assessment can be available within 10 minutes from blood draw. This technology is inexpensive and can be easily deployed in the prehospital setting or during the initial triage assessment of patients arriving at the ED.¹⁹ These POC instruments have been well correlated with whole blood measurements and permit for the rapid identification and treatment of at risk patients.

Limitations

The presence of elevated serum lactate levels is believed to represent the presence of cellular anaerobic metabolism due to impaired O₂ delivery in the shock state. Abnormal measurements therefore prompt aggressive interventions aimed at maximizing O₂ delivery to the tissues, such as intravenous fluid boluses, vasopressor therapy, or even blood product administration.

A return to a normalized serum lactate level is assumed to represent a transition back to aerobic metabolism. Lactate elevations, however, are not solely an indication of anaerobic metabolism and may only represent a small degree of lactate production.²⁰ While the specific cellular mechanics are out of the scope of this article, it has been postulated that the increase in plasma lactate concentration is primarily driven by β-2 receptor stimulation from increased circulating catecholamines leading to increased aerobic glycolysis. Increased lactate levels could therefore be an adaptive mechanism of energy production—aggressive treatment and rapid clearance may, in fact, be harmful. Type A lactic acidosis is categorized as elevated serum levels due to tissue hypoperfusion.²¹

However, lactate elevations do not exclusively occur in severe illness. The use of β-2 receptor agonists such as continuous albuterol treatments or epinephrine may cause abnormal lactate levels.²² Other medications have also been associated with elevated serum lactate levels, including, but not limited to linezolid, metformin, and propofol.^23-25 Additionally, lactate levels may be elevated after strenuous exercise, seizure activity, or in liver and kidney disease.²⁶ These “secondary” causes of lactic acidosis that are not due to tissue hypoperfusion are referred to as type B lactic acidosis. Given these multiple etiologies and lack of specificity for this serum measurement, a failure to understand these limitations may result in over aggressive or unnecessary medical treatments.

Central Venous Pressure

Background

Central venous pressure (CVP) measurements can be obtained through a catheter, the distal tip of which transduces pressure of the superior vena cava at the entrance of the right atrium (RA). Thus, CVP is often used as a representation of RA pressure (RAP) and therefore an estimate of right ventricular (RV) preload. While CVP is used to diagnose and determine the etiology of shock, evidence and controversy regarding the use of CVP as a marker for resuscitation comes largely from sepsis-focused literature.⁵ Central venous pressure is meant to represent preload, which is essential for stroke volume as described by the Frank-Starling mechanism; however, its use as a target in distributive shock, a state in which it is difficult to determine a patient’s volume status, has been popularized by EGDT since 2001.²

Since the publication of the 2004 Surviving Sepsis Guidelines, CVP monitoring has been in the spotlight of sepsis resuscitation, albeit with some controversy.²⁷ Included as the result of two studies, this recommendation has been removed in the most recent guidelines after 12 years of further study and scrutiny.^2,27,28

Hypovolemic and hemorrhagic shock are usually diagnosed clinically and while a low CVP can be helpful in the diagnosis, the guidelines do not support CVP as a resuscitation endpoint. Obstructive and cardiogenic shock will both result in elevated CVP; however, treatment of obstructive shock is generally targeted at the underlying cause. While cardiogenic shock can be preload responsive, the mainstay of therapy in the ED is identification of patients for revascularization and inotropic support.²⁹

Benefits

The CVP has been used as a surrogate for RV preload volume. If a patient’s preload volume is low, the treating physician can administer fluids to improve stroke volume and cardiac output (CO). Clinically, CVP measurements are easy to obtain provided a central venous line has been placed with the distal tip at the entrance to the RA. Central venous pressure is measured by transducing the pressure via manometry and connecting it to the patient’s bedside monitor. This provides an advantage of being able to provide serial or even continuous measurements. The “normal” RAP should be a low value (1-5 mm Hg, mean of 3 mm Hg), as this aids in the pressure gradient to drive blood from the higher pressures of the left ventricle (LV) and aorta through the circulation back to the low-pressure of the RA.³⁰ The value of the CVP is meant to correspond to the physical examination findings of jugular venous distension.^31,32 Thus, a low CVP may be “normal” and seen in patients with hypovolemic shock, whereas an elevated CVP can suggest volume overload or obstructive shock. However, this is of questionable value in distributive shock cases.

Aside from the two early studies on CVP monitoring during treatment of septic patients, there are few data to support the use of CVP measurement in the early resuscitation of patients with shock.^2,28 More recent trials (PROMISE, ARISE, PROCESS) that compared protocolized sepsis care to standard care showed no benefit to bundles including CVP measurements.^12-14 However, a subsequent, large observational trial spanning 7.5 years demonstrated improvements in sepsis-related mortality in patients who received a central venous catheter (CVC) and CVP-targeted therapy.³³ Thus, it is possible that protocols including CVP are still beneficial in combination with other therapies even though CVP in isolation is not.

Limitations

The traditional two assumptions in CVP monitoring are CVP value represents the overall volume status of the patient, and the LV is able to utilize additional preload volume. The latter assumption, however, may be hampered by the presence of sepsis-induced myocardial dysfunction, which may be present in up to 40% of critically ill patients.³⁴ The former assumption does not always hold true due to processes that change filling pressures independent of intravascular volume—eg, acute or chronic pulmonary hypertension, cardiac tamponade, intra-abdominal hypertension, or LV failure. Even before the landmark EGDT study, available data suggested that CVP was not a reliable marker for resuscitation management.³⁵ A recent systematic review by Gottlieb and Hunter³⁶ showed that the area under the receiver-operator curve for low, mid-range, or high CVPs was equivocal at best. In addition to its unreliability and lack of specificity, another significant drawback to using CVP to guide resuscitation therapy in the ED is that it necessitates placement of a CVC, which can be time-consuming and, if not otherwise indicated, lead to complications of infection, pneumothorax, and/or thrombosis.³⁷

Mixed Venous Oxygen

Background

Most EPs are familiar with the use of S_cvO₂ in EGDT protocols to guide volume resuscitation of septic patients.² A patient’s S_cvO₂ represents the O₂ saturation of venous blood obtained via a CVC at the confluence of the superior vena cava and the RA, and thus it reflects tissue O₂ consumption as a surrogate for tissue perfusion. The measurement parallels the S_vO₂ obtained from the pulmonary artery. In a healthy patient, S_vO₂ is around 65% to 70% and includes blood returning from both the superior and inferior vena cava (IVC). As such, S_cvO₂ values are typically 3% to 5% lower than S_vO₂ owing to the lower O₂ extracted by tissues draining into the IVC compared to the mixed venous blood sampled from the pulmonary artery.³⁸

Though a debate over the benefit of EGDT in treating sepsis continues, understanding the physiology of S_cvO₂ measurements is another potential tool the EP can use to guide the resuscitation of critically ill patients.³⁹ A patient’s S_vO₂ and, by extension, S_cvO₂ represents the residual O₂ saturation after the tissues have extracted the amount of O₂ necessary to meet metabolic demands (Figure 2).

Benefits

A critically ill patient’s S_cvO₂ can potentially provide EPs with insight into the patient’s global tissue perfusion and the source of any mismatch between O₂ delivery and consumption. Using additional tools and measurements (physical examination, serum Hgb levels, and pulse oximetry) in conjunction with an S_cvO₂ measurement, assists EPs in identifying targets for therapeutic intervention. The effectiveness of this intervention can then be assessed using serial S_cvO₂ measurements, as described in Rivers et al² EGDT protocol. Importantly, EPs should take care to measure serial S_cvO₂ values to maximize its utility.³⁸ Similar to a CVP measurement, S_cvO₂is easily obtained from blood samples for serial laboratory measurements, assuming the patient already has a CVC with the distal tip at the entrance to the RA (S_cvO₂) or a pulmonary artery catheter (PAC) (S_vO₂).

Limitations

Serial measurements provide the most reliable information, which may be more useful in patients who spend extended periods of their resuscitation in the ED. In comparison to other measures of global tissue hypoxia, work by Jones et al⁴¹ suggests non-inferiority of peripherally sampled, serial lactate measurements as an alternative to S_cvO₂. This, in conjunction with the requirement for an internal jugular CVC, subclavian CVC, or PAC with their associated risks, may make S_cvO₂ a less attractive guide for the resuscitation of critically ill patients in the ED.

Monitoring Devices

Background

As noted throughout this review, it is important not only to identify and rapidly treat shock, but to also correctly identify the type of shock, such that treatment can be appropriately directed at its underlying cause. However, prior work suggests that EPs are unable to grossly estimate CO or systemic vascular resistance when compared to objective measurements of these parameters.⁴² This is in agreement with the overall poor performance of physical examination and clinical evaluation as a means of predicting volume responsiveness or guiding resuscitation, as discussed previously. Fortunately, a wide variety of devices to objectively monitor hemodynamics are now available to the EP.

In 1970, Swan et al⁴³ published their initial experience with pulmonary artery catheterization at the bedside, using a balloon-tipped, flow-guided PAC in lieu of fluoroscopy, which had been mandated by earlier techniques. The ability to measure CO, right heart pressures, pulmonary arterial pressures, and estimate LV end diastolic pressure ushered in an era of widespread PAC use, despite an absence of evidence for causation of improved patient outcomes. The utilization of PACs has fallen, as the literature suggests that the empiric placement of PACs in critically ill patients does not improve mortality, length of stay, or cost, and significant complication rates have been reported in large trials.^44,45Subsequently, a number of non-invasive or less-invasive HDM devices have been developed. Amongst the more commonly encountered modern devices, the techniques utilized for providing hemodynamic assessments include thermodilution and pulse contour analysis (PiCCO^TM), pulse contour analysis (FloTrac/Vigileo^TM), and lithium chemodilution with pulse power analysis (LiDCOplus^TM).⁴⁶ The primary utility of these devices for the EP lies in the ability to quantify CO, stroke volume, and stroke volume or pulse pressure variation (PPV) to predict or assess response to resuscitative interventions (volume administration, vasopressors, inotropes, etc).

Benefits

Many of these devices require placement of an arterial catheter. Some require the addition of a CVC. Both of these procedures are well within the clinical scope of the EP, and are performed with fair frequency on critically ill patients. This is a distinct advantage when compared to pulmonary artery catheterization, a higher risk procedure that is rarely performed outside of the intensive care unit or cardiac catheterization laboratory. In addition, all of the devices below present hemodynamic data in a graphical, easy-to-read format, in real time. All of the devices discussed report stroke volume variation (SVV) or PPV continuously.

Limitations

Though these measures have validated threshold values that predict volume responsiveness, they require the patient to be intubated with a set tidal volume of greater than or equal to 8 mL/kg without spontaneous respirations and cardiac arrhythmias, in order to accurately do so. All of the HDM devices that rely on pulse contour analysis as the primary means of CO measurement cannot be used in the presence of significant cardiac arrhythmias (ie, atrial fibrillation), or mechanical circulatory assistance devices (ie, intra-aortic balloon counterpulsation). None of these devices are capable of monitoring microcirculatory changes, felt to be of increasing clinical importance in the critically ill.

The use of HDM devices to monitor CO with a reasonable degree of accuracy, trend CO, and assess for volume responsiveness using a number of previously validated parameters such as SVV is now in little doubt. However, these devices are still invasive, if less so than a pulmonary artery. The crux of the discussion of HDM devices for use in ED resuscitation revolves around whether or not the use of such devices to drive previously validated, protocolized care results in better outcomes for patients. The EP can now have continuous knowledge of a large number of hemodynamic parameters at their fingertips with relatively minimal additional efforts. At the time of this writing, though, this is both untested and unproven, with respect to the ED population.

Point-of-Care Ultrasound

Background

Over the past two decades, ultrasound (US) has become an integral part of the practice of emergency medicine (EM), and is now included in all United States Accreditation Council for Graduate Medical Education Emergency Medicine Residency Programs.^47,48 It has emerged as a very important bedside tool performed by the clinician to identify type of shock and guide resuscitation, and has been endorsed by both EM and critical care societies.^49-51 This section reviews the utility of US as a modality in identifying shock and guiding resuscitation, in addition to the pitfalls and limitations of this important tool.

In 2010, Perera et al⁴⁷ described in their landmark article the Rapid Ultrasound in SHock (RUSH) examination, which describes a stepwise (the pump, tank, pipes) approach to identify the type of shock (cardiogenic, hypovolemic, obstructive, or distributive) in the crashing, hypotensive ED patient. We do not describe the full RUSH examination in this review, but discuss key elements of it as examples of how POCUS can assist the EP to make a rapid diagnosis and aid in the management of patients in shock. The “pump” is the heart, which is assessed in four different views to identify a pericardial effusion and possible tamponade, assess contractility or ejection fraction of the LV (severely decreased, decreased, normal, or hyperdynamic), and right heart strain which is identified by an RV that is larger than the LV, indicative of a potential pulmonary embolus.

The “tank” is then assessed by visualizing the IVC in the subxiphoid plane, and is evaluated for respiratory collapsibility (CI) and maximum size. This has been quite the debated topic over the last two decades. In 1988, Simonson and Schiller⁵² were the first to describe a correlation in spontaneously breathing patients between IVC caliber (measured 2 cm from the cavoatrial junction) and variation and RAP, where a larger IVC diameter and less respiratory variation correlated with a high RAP. Kircher et al⁵³ later went on to describe that a CI greater than 50% correlated with an RAP of less than 10 mm Hg and vice versa in spontaneously breathing patients. Since then there have been more studies attempting to verify these findings in both spontaneously breathing and mechanically ventilated patients.^54-56 The purpose of performing these measurements is not to estimate CVP, but to assess fluid responsiveness (ie, a blood pressure response to a fluid challenge). It can be assumed in states of shock that a small IVC, or one with a high CI, in the presence of a hyperdynamic heart is indicative of an underfilled ventricle and fluid responsiveness, especially if the IVC size increases with fluid.^55,57 However, there are several caveats to this. First, in mechanically ventilated patients, the IVC is already plethoric due to positive pressure ventilation, and increases in diameter with inspiration and decreases with expiration as compared to spontaneously breathing patients. Second, the CI value to predict volume responsiveness in ventilated patients is set at 15% instead of 50%.⁵⁵ Third, it is important to always take the clinical scenario in context; a dilated IVC with small CI is not necessarily only due to volume overload and congestive heart failure, but can be due to elevated RAP from obstructive shock due to cardiac tamponade or massive pulmonary embolus, which is why it is important to assess the “pump” first.^47,58 It is also crucial to not forget to assess the abdominal and thoracic cavities, as intraperitoneal or pleural fluid with a collapsed IVC can potentially make a diagnosis of hemorrhagic or hypovolemic shock depending on the clinical scenario.⁴⁷ The final part of the RUSH protocol is to evaluate the “pipes,” inclusive of the lower extremity deep venous system for evaluation of potential thrombosis that could increase suspicion for a pulmonary embolism causing obstructive shock, and the aorta with the common iliac arteries if there is concern for aortic dissection or aneurysmal rupture.

Benefits

Some of the most significant advantages to the use of POCUS to guide resuscitation is that it is quick, non-invasive, does not use ionizing radiation, and can be easily repeated. As noted above, it is a requirement for EM residencies to teach its use, so that contemporary graduates are entering the specialty competent in applying it to the care of their patients. Furthermore, POCUS is done at the bedside, limiting the need to potentially transport unstable patients.

In the most basic applications, POCUS provides direct visualization of a patient’s cardiac function, presence or absence of lung sliding to suggest a pneumothorax, presence of pulmonary edema, assessment of CVP pressures or potential for fluid responsiveness, as well as identification of potential thoracic, peritoneal, or pelvic cavity fluid accumulation that may suggest hemorrhage. There is literature to support that these assessments performed by the EP have been shown to be comparable to those of cardiologists.^59,60 With continued practice and additional training, it is possible for EPs to even perform more “advanced” hemodynamic assessments to both diagnose and guide therapy to patients in shock (Figures 3 and 4).⁶¹

Limitations

Although POCUS has been shown as a remarkable tool to help assist the EP in making rapid decisions regarding resuscitation, it is always important to remember its limitations. Most of the studies regarding its use are of very small sample sizes, and further prospective studies have to be performed in order for this modality to be fully relied on.⁶²Compared to some of the previously mentioned HDM devices that may provide continuous data, POCUS needs to be performed by the treating physician, thereby occurring intermittently. Emergency physicians need to be aware of their own experience and limitations with this modality, as errors in misdiagnosis can lead to unnecessary procedures, with resulting significant morbidity and mortality. Blanco and Volpicelli⁶³ describe several common errors that include misdiagnosing the stomach as a peritoneal effusion, assuming adequate volume resuscitation when the IVC is seen to be plethoric in the setting of cardiac tamponade, or mistaking IVC movement as indicative of collapsibility, amongst other described misinterpretations. Several other studies have shown that, despite adequate performance of EPs in POCUS, diagnostic sensitivities remained higher when performed by radiologists.^64-67 Thus it remains important for the EPs to be vigilant and not anchor on a diagnosis when in doubt, and to consult early with radiology, particularly if there is any question, to avoid potential adverse patient outcomes.

Summary

There are several ways to diagnose and track resuscitation in the ED, which include physical examination, assessment of serum laboratory values, monitoring of hemodynamic status, and use of POCUS. Unfortunately, none of these methods provides a perfect assessment, and no method has been proven superior and effective over the others. Therefore, it is important for EPs treating patients in shock to be aware of the strengths and limitations of each assessment method (Table).

Resuscitation of critically ill patients in shock from cardiogenic, hypovolemic, obstructive, distributive, or neurogenic etiology is a cornerstone of the care delivered by emergency physicians (EPs).¹ Regardless of the etiology, it is essential that the treating EP initiate resuscitative measures in a timely manner and closely trend the patient’s response to these interventions.

The early goal-directed therapy (EGDT) initially proposed by Rivers et al² in 2001 demonstrated a bundled approach to fluid resuscitation by targeting end points for volume resuscitation, mean arterial blood pressure (MAP), oxygen (O₂) delivery/extraction (mixed venous O₂ saturation, [S_vO₂]), hemoglobin (Hgb) concentration, and cardiac contractility. Since then, advancements in laboratory testing and hemodynamic monitoring (HDM) devices further aid and guide resuscitative efforts, and are applicable to any etiology of shock.

In addition to these advancements, the growing evidence of the potential harm from improper fluid resuscitation, such as the administration of excessive intravascular fluid (IVF),³ underscores the importance of a precise, targeted, and individualized approach to care. This article reviews the background, benefits, and limitations of some of the common and readily available tools in the ED that the EP can employ to guide fluid resuscitation in critically ill patients.

Physical Examination

Background

The rapid recognition and treatment of septic shock in the ED is associated with lower rates of in-hospital morbidity and mortality.⁴ The physical examination by the EP begins immediately upon examining the patient. The acquisition of vital signs and recognition of physical examination findings suggestive of intravascular volume depletion allows the EP to initiate treatment immediately.

In this discussion, hypotension is defined as systolic blood pressure (SBP) of less than 95 mm Hg, MAP of less than 65 mm Hg, or a decrease in SBP of more than 40 mm Hg from baseline measurements. Subsequently, shock is defined as hypotension with evidence of tissue hypoperfusion-induced dysfunction.^5,6 Although the use of findings from the physical examination to guide resuscitation allows for rapid patient assessment and treatment, the predictive value of the physical examination to assess hemodynamic status is limited.

Benefits

The major benefit of the physical examination as a tool to evaluate hemodynamic status is its ease and rapid acquisition. The patient’s vital signs and physical examination can be obtained in the matter of moments upon presentation, without the need to wait on results of laboratory evaluation or additional equipment. Additionally, serial examinations by the same physician can be helpful to monitor a patient’s response to resuscitative efforts. The negative predictive value (NPV) of the physical examination in evaluating for hypovolemia may be helpful, but only when it is taken in the appropriate clinical context and is used in conjunction with other diagnostic tools. The physical examination can exclude hypovolemic volume status with an NPV of approximately 70%.⁷

A constellation of findings from the physical examination may include altered mentation, hypotension, tachycardia, and decreased urinary output by 30% to 40% intravascular volume loss.^8,9Findings from the physical examination to assess fluid status should be used with caution as interobserver reliability has proven to be poor and the prognostic value is limited.

Limitations

The literature shows the limited prognostic value of the physical examination in determining a patient’s volume status and whether fluid resuscitation is indicated. For example, in one meta-analysis,¹⁰ supine hypotension and tachycardia were frequently absent on examination—even in patients who underwent large volume phlebotomy.⁸ This study also showed postural dizziness to be of no prognostic value.

Another study by Saugel et al⁷ that compared the physical examination (skin assessment, lung auscultation, and percussion) to transpulmonary thermodilution measurements of the cardiac index, global end-diastolic volume index, and extravascular lung water index, found poor interobserver correlation and agreement among physicians.

The physical examination is also associated with weak predictive capabilities for the estimation of volume status compared to the device measurements. Another contemporary study by Saugel et al⁹ evaluated the predictive value of the physical examination to accurately identify volume responsiveness replicated these results, and reported poor interobserver correlation (κ coefficient 0.01; 95% caval index [CI] -0.39-0.42) among physical examination findings, with a sensitivity of only 71%, specificity of 23.5%, positive predictive value of 27.8%, and negative predictive value of 66.7%.⁹

Serum Lactate Levels

Background

In the 1843 book titled, Investigations of Pathological Substances Obtained During the Epidemic of Puerperal Fever, Johann Joseph Scherer described the cases of seven young peripartum female patients who died from a clinical picture of what is now understood to be septic shock.¹¹ In his study of these cases, Scherer demonstrated the presence of lactic acid in patients with pathological conditions. Prior to this discovery, lactic acid had never been isolated in a healthy individual. These results were recreated in 1851 by Scherer and Virchow,¹¹ who demonstrated the presence of lactic acid in the blood of a patient who died from leukemia. The inference based on Scherer and Virchow’s work correlated the presence of excessive lactic acid with bodily deterioration and severe disease. Since this finding, there has been a great deal of interest in measuring serum lactic acid as a means to identify and manage critical illness.

In a 2001 groundbreaking study of EGDT for severe sepsis and septic shock, Rivers et al² studied lactic acid levels as a marker for severe disease. Likewise, years later, the 2014 Protocol-Based Care for Early Septic Shock (PROCESS), Prospective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE), and Australasian Resuscitation in Sepsis Evaluation (ARISE) trials used lactate levels in a similar manner to identify patients appropriate for randomization.^12-14 While the purpose of measuring lactic acid was only employed in these studies to identify patients at risk for critical illness, the 2012 Surviving Sepsis Campaign Guidelines recommended serial measurement of lactate, based on the assumption that improved lactate levels signified better tissue perfusion.¹⁵

Although much of the studies on lactate levels appear to be based on the treatment and management of septic patients, findings can be applied to any etiology of shock. For example, a serum lactate level greater than 2 mmol/L is considered abnormal, and a serum lactate greater than 4 mmol/L indicates a significantly increased risk for in-hospital mortality.¹⁶

Benefits

It is now a widely accepted belief that the rapid identification, triage, and treatment of critically ill patients has a dramatic effect on morbidity and mortality.⁴ As previously noted, lactate has been extensively studied and identified as a marker of severe illness.^17,18 A serum lactate level, which can be rapidly processed in the ED, can be easily obtained from a minimally invasive venous, arterial, or capillary blood draw.¹⁸ The only risk associated with serum lactate testing is that of any routine venipuncture; the test causes minimal, if any, patient discomfort.

Thanks to advances in point-of-care (POC) technology, the result of serum lactate assessment can be available within 10 minutes from blood draw. This technology is inexpensive and can be easily deployed in the prehospital setting or during the initial triage assessment of patients arriving at the ED.¹⁹ These POC instruments have been well correlated with whole blood measurements and permit for the rapid identification and treatment of at risk patients.

Limitations

The presence of elevated serum lactate levels is believed to represent the presence of cellular anaerobic metabolism due to impaired O₂ delivery in the shock state. Abnormal measurements therefore prompt aggressive interventions aimed at maximizing O₂ delivery to the tissues, such as intravenous fluid boluses, vasopressor therapy, or even blood product administration.

A return to a normalized serum lactate level is assumed to represent a transition back to aerobic metabolism. Lactate elevations, however, are not solely an indication of anaerobic metabolism and may only represent a small degree of lactate production.²⁰ While the specific cellular mechanics are out of the scope of this article, it has been postulated that the increase in plasma lactate concentration is primarily driven by β-2 receptor stimulation from increased circulating catecholamines leading to increased aerobic glycolysis. Increased lactate levels could therefore be an adaptive mechanism of energy production—aggressive treatment and rapid clearance may, in fact, be harmful. Type A lactic acidosis is categorized as elevated serum levels due to tissue hypoperfusion.²¹

However, lactate elevations do not exclusively occur in severe illness. The use of β-2 receptor agonists such as continuous albuterol treatments or epinephrine may cause abnormal lactate levels.²² Other medications have also been associated with elevated serum lactate levels, including, but not limited to linezolid, metformin, and propofol.^23-25 Additionally, lactate levels may be elevated after strenuous exercise, seizure activity, or in liver and kidney disease.²⁶ These “secondary” causes of lactic acidosis that are not due to tissue hypoperfusion are referred to as type B lactic acidosis. Given these multiple etiologies and lack of specificity for this serum measurement, a failure to understand these limitations may result in over aggressive or unnecessary medical treatments.

Central Venous Pressure

Background

Central venous pressure (CVP) measurements can be obtained through a catheter, the distal tip of which transduces pressure of the superior vena cava at the entrance of the right atrium (RA). Thus, CVP is often used as a representation of RA pressure (RAP) and therefore an estimate of right ventricular (RV) preload. While CVP is used to diagnose and determine the etiology of shock, evidence and controversy regarding the use of CVP as a marker for resuscitation comes largely from sepsis-focused literature.⁵ Central venous pressure is meant to represent preload, which is essential for stroke volume as described by the Frank-Starling mechanism; however, its use as a target in distributive shock, a state in which it is difficult to determine a patient’s volume status, has been popularized by EGDT since 2001.²

Since the publication of the 2004 Surviving Sepsis Guidelines, CVP monitoring has been in the spotlight of sepsis resuscitation, albeit with some controversy.²⁷ Included as the result of two studies, this recommendation has been removed in the most recent guidelines after 12 years of further study and scrutiny.^2,27,28

Hypovolemic and hemorrhagic shock are usually diagnosed clinically and while a low CVP can be helpful in the diagnosis, the guidelines do not support CVP as a resuscitation endpoint. Obstructive and cardiogenic shock will both result in elevated CVP; however, treatment of obstructive shock is generally targeted at the underlying cause. While cardiogenic shock can be preload responsive, the mainstay of therapy in the ED is identification of patients for revascularization and inotropic support.²⁹

Benefits

The CVP has been used as a surrogate for RV preload volume. If a patient’s preload volume is low, the treating physician can administer fluids to improve stroke volume and cardiac output (CO). Clinically, CVP measurements are easy to obtain provided a central venous line has been placed with the distal tip at the entrance to the RA. Central venous pressure is measured by transducing the pressure via manometry and connecting it to the patient’s bedside monitor. This provides an advantage of being able to provide serial or even continuous measurements. The “normal” RAP should be a low value (1-5 mm Hg, mean of 3 mm Hg), as this aids in the pressure gradient to drive blood from the higher pressures of the left ventricle (LV) and aorta through the circulation back to the low-pressure of the RA.³⁰ The value of the CVP is meant to correspond to the physical examination findings of jugular venous distension.^31,32 Thus, a low CVP may be “normal” and seen in patients with hypovolemic shock, whereas an elevated CVP can suggest volume overload or obstructive shock. However, this is of questionable value in distributive shock cases.

Aside from the two early studies on CVP monitoring during treatment of septic patients, there are few data to support the use of CVP measurement in the early resuscitation of patients with shock.^2,28 More recent trials (PROMISE, ARISE, PROCESS) that compared protocolized sepsis care to standard care showed no benefit to bundles including CVP measurements.^12-14 However, a subsequent, large observational trial spanning 7.5 years demonstrated improvements in sepsis-related mortality in patients who received a central venous catheter (CVC) and CVP-targeted therapy.³³ Thus, it is possible that protocols including CVP are still beneficial in combination with other therapies even though CVP in isolation is not.

Limitations

The traditional two assumptions in CVP monitoring are CVP value represents the overall volume status of the patient, and the LV is able to utilize additional preload volume. The latter assumption, however, may be hampered by the presence of sepsis-induced myocardial dysfunction, which may be present in up to 40% of critically ill patients.³⁴ The former assumption does not always hold true due to processes that change filling pressures independent of intravascular volume—eg, acute or chronic pulmonary hypertension, cardiac tamponade, intra-abdominal hypertension, or LV failure. Even before the landmark EGDT study, available data suggested that CVP was not a reliable marker for resuscitation management.³⁵ A recent systematic review by Gottlieb and Hunter³⁶ showed that the area under the receiver-operator curve for low, mid-range, or high CVPs was equivocal at best. In addition to its unreliability and lack of specificity, another significant drawback to using CVP to guide resuscitation therapy in the ED is that it necessitates placement of a CVC, which can be time-consuming and, if not otherwise indicated, lead to complications of infection, pneumothorax, and/or thrombosis.³⁷

Mixed Venous Oxygen

Background

Most EPs are familiar with the use of S_cvO₂ in EGDT protocols to guide volume resuscitation of septic patients.² A patient’s S_cvO₂ represents the O₂ saturation of venous blood obtained via a CVC at the confluence of the superior vena cava and the RA, and thus it reflects tissue O₂ consumption as a surrogate for tissue perfusion. The measurement parallels the S_vO₂ obtained from the pulmonary artery. In a healthy patient, S_vO₂ is around 65% to 70% and includes blood returning from both the superior and inferior vena cava (IVC). As such, S_cvO₂ values are typically 3% to 5% lower than S_vO₂ owing to the lower O₂ extracted by tissues draining into the IVC compared to the mixed venous blood sampled from the pulmonary artery.³⁸

Though a debate over the benefit of EGDT in treating sepsis continues, understanding the physiology of S_cvO₂ measurements is another potential tool the EP can use to guide the resuscitation of critically ill patients.³⁹ A patient’s S_vO₂ and, by extension, S_cvO₂ represents the residual O₂ saturation after the tissues have extracted the amount of O₂ necessary to meet metabolic demands (Figure 2).

Benefits

A critically ill patient’s S_cvO₂ can potentially provide EPs with insight into the patient’s global tissue perfusion and the source of any mismatch between O₂ delivery and consumption. Using additional tools and measurements (physical examination, serum Hgb levels, and pulse oximetry) in conjunction with an S_cvO₂ measurement, assists EPs in identifying targets for therapeutic intervention. The effectiveness of this intervention can then be assessed using serial S_cvO₂ measurements, as described in Rivers et al² EGDT protocol. Importantly, EPs should take care to measure serial S_cvO₂ values to maximize its utility.³⁸ Similar to a CVP measurement, S_cvO₂is easily obtained from blood samples for serial laboratory measurements, assuming the patient already has a CVC with the distal tip at the entrance to the RA (S_cvO₂) or a pulmonary artery catheter (PAC) (S_vO₂).

Limitations

Serial measurements provide the most reliable information, which may be more useful in patients who spend extended periods of their resuscitation in the ED. In comparison to other measures of global tissue hypoxia, work by Jones et al⁴¹ suggests non-inferiority of peripherally sampled, serial lactate measurements as an alternative to S_cvO₂. This, in conjunction with the requirement for an internal jugular CVC, subclavian CVC, or PAC with their associated risks, may make S_cvO₂ a less attractive guide for the resuscitation of critically ill patients in the ED.

Monitoring Devices

Background

As noted throughout this review, it is important not only to identify and rapidly treat shock, but to also correctly identify the type of shock, such that treatment can be appropriately directed at its underlying cause. However, prior work suggests that EPs are unable to grossly estimate CO or systemic vascular resistance when compared to objective measurements of these parameters.⁴² This is in agreement with the overall poor performance of physical examination and clinical evaluation as a means of predicting volume responsiveness or guiding resuscitation, as discussed previously. Fortunately, a wide variety of devices to objectively monitor hemodynamics are now available to the EP.

In 1970, Swan et al⁴³ published their initial experience with pulmonary artery catheterization at the bedside, using a balloon-tipped, flow-guided PAC in lieu of fluoroscopy, which had been mandated by earlier techniques. The ability to measure CO, right heart pressures, pulmonary arterial pressures, and estimate LV end diastolic pressure ushered in an era of widespread PAC use, despite an absence of evidence for causation of improved patient outcomes. The utilization of PACs has fallen, as the literature suggests that the empiric placement of PACs in critically ill patients does not improve mortality, length of stay, or cost, and significant complication rates have been reported in large trials.^44,45Subsequently, a number of non-invasive or less-invasive HDM devices have been developed. Amongst the more commonly encountered modern devices, the techniques utilized for providing hemodynamic assessments include thermodilution and pulse contour analysis (PiCCO^TM), pulse contour analysis (FloTrac/Vigileo^TM), and lithium chemodilution with pulse power analysis (LiDCOplus^TM).⁴⁶ The primary utility of these devices for the EP lies in the ability to quantify CO, stroke volume, and stroke volume or pulse pressure variation (PPV) to predict or assess response to resuscitative interventions (volume administration, vasopressors, inotropes, etc).

Benefits

Many of these devices require placement of an arterial catheter. Some require the addition of a CVC. Both of these procedures are well within the clinical scope of the EP, and are performed with fair frequency on critically ill patients. This is a distinct advantage when compared to pulmonary artery catheterization, a higher risk procedure that is rarely performed outside of the intensive care unit or cardiac catheterization laboratory. In addition, all of the devices below present hemodynamic data in a graphical, easy-to-read format, in real time. All of the devices discussed report stroke volume variation (SVV) or PPV continuously.

Limitations

Though these measures have validated threshold values that predict volume responsiveness, they require the patient to be intubated with a set tidal volume of greater than or equal to 8 mL/kg without spontaneous respirations and cardiac arrhythmias, in order to accurately do so. All of the HDM devices that rely on pulse contour analysis as the primary means of CO measurement cannot be used in the presence of significant cardiac arrhythmias (ie, atrial fibrillation), or mechanical circulatory assistance devices (ie, intra-aortic balloon counterpulsation). None of these devices are capable of monitoring microcirculatory changes, felt to be of increasing clinical importance in the critically ill.

The use of HDM devices to monitor CO with a reasonable degree of accuracy, trend CO, and assess for volume responsiveness using a number of previously validated parameters such as SVV is now in little doubt. However, these devices are still invasive, if less so than a pulmonary artery. The crux of the discussion of HDM devices for use in ED resuscitation revolves around whether or not the use of such devices to drive previously validated, protocolized care results in better outcomes for patients. The EP can now have continuous knowledge of a large number of hemodynamic parameters at their fingertips with relatively minimal additional efforts. At the time of this writing, though, this is both untested and unproven, with respect to the ED population.

Point-of-Care Ultrasound

Background

Over the past two decades, ultrasound (US) has become an integral part of the practice of emergency medicine (EM), and is now included in all United States Accreditation Council for Graduate Medical Education Emergency Medicine Residency Programs.^47,48 It has emerged as a very important bedside tool performed by the clinician to identify type of shock and guide resuscitation, and has been endorsed by both EM and critical care societies.^49-51 This section reviews the utility of US as a modality in identifying shock and guiding resuscitation, in addition to the pitfalls and limitations of this important tool.

In 2010, Perera et al⁴⁷ described in their landmark article the Rapid Ultrasound in SHock (RUSH) examination, which describes a stepwise (the pump, tank, pipes) approach to identify the type of shock (cardiogenic, hypovolemic, obstructive, or distributive) in the crashing, hypotensive ED patient. We do not describe the full RUSH examination in this review, but discuss key elements of it as examples of how POCUS can assist the EP to make a rapid diagnosis and aid in the management of patients in shock. The “pump” is the heart, which is assessed in four different views to identify a pericardial effusion and possible tamponade, assess contractility or ejection fraction of the LV (severely decreased, decreased, normal, or hyperdynamic), and right heart strain which is identified by an RV that is larger than the LV, indicative of a potential pulmonary embolus.

The “tank” is then assessed by visualizing the IVC in the subxiphoid plane, and is evaluated for respiratory collapsibility (CI) and maximum size. This has been quite the debated topic over the last two decades. In 1988, Simonson and Schiller⁵² were the first to describe a correlation in spontaneously breathing patients between IVC caliber (measured 2 cm from the cavoatrial junction) and variation and RAP, where a larger IVC diameter and less respiratory variation correlated with a high RAP. Kircher et al⁵³ later went on to describe that a CI greater than 50% correlated with an RAP of less than 10 mm Hg and vice versa in spontaneously breathing patients. Since then there have been more studies attempting to verify these findings in both spontaneously breathing and mechanically ventilated patients.^54-56 The purpose of performing these measurements is not to estimate CVP, but to assess fluid responsiveness (ie, a blood pressure response to a fluid challenge). It can be assumed in states of shock that a small IVC, or one with a high CI, in the presence of a hyperdynamic heart is indicative of an underfilled ventricle and fluid responsiveness, especially if the IVC size increases with fluid.^55,57 However, there are several caveats to this. First, in mechanically ventilated patients, the IVC is already plethoric due to positive pressure ventilation, and increases in diameter with inspiration and decreases with expiration as compared to spontaneously breathing patients. Second, the CI value to predict volume responsiveness in ventilated patients is set at 15% instead of 50%.⁵⁵ Third, it is important to always take the clinical scenario in context; a dilated IVC with small CI is not necessarily only due to volume overload and congestive heart failure, but can be due to elevated RAP from obstructive shock due to cardiac tamponade or massive pulmonary embolus, which is why it is important to assess the “pump” first.^47,58 It is also crucial to not forget to assess the abdominal and thoracic cavities, as intraperitoneal or pleural fluid with a collapsed IVC can potentially make a diagnosis of hemorrhagic or hypovolemic shock depending on the clinical scenario.⁴⁷ The final part of the RUSH protocol is to evaluate the “pipes,” inclusive of the lower extremity deep venous system for evaluation of potential thrombosis that could increase suspicion for a pulmonary embolism causing obstructive shock, and the aorta with the common iliac arteries if there is concern for aortic dissection or aneurysmal rupture.

Benefits

Some of the most significant advantages to the use of POCUS to guide resuscitation is that it is quick, non-invasive, does not use ionizing radiation, and can be easily repeated. As noted above, it is a requirement for EM residencies to teach its use, so that contemporary graduates are entering the specialty competent in applying it to the care of their patients. Furthermore, POCUS is done at the bedside, limiting the need to potentially transport unstable patients.

In the most basic applications, POCUS provides direct visualization of a patient’s cardiac function, presence or absence of lung sliding to suggest a pneumothorax, presence of pulmonary edema, assessment of CVP pressures or potential for fluid responsiveness, as well as identification of potential thoracic, peritoneal, or pelvic cavity fluid accumulation that may suggest hemorrhage. There is literature to support that these assessments performed by the EP have been shown to be comparable to those of cardiologists.^59,60 With continued practice and additional training, it is possible for EPs to even perform more “advanced” hemodynamic assessments to both diagnose and guide therapy to patients in shock (Figures 3 and 4).⁶¹

Limitations

Although POCUS has been shown as a remarkable tool to help assist the EP in making rapid decisions regarding resuscitation, it is always important to remember its limitations. Most of the studies regarding its use are of very small sample sizes, and further prospective studies have to be performed in order for this modality to be fully relied on.⁶²Compared to some of the previously mentioned HDM devices that may provide continuous data, POCUS needs to be performed by the treating physician, thereby occurring intermittently. Emergency physicians need to be aware of their own experience and limitations with this modality, as errors in misdiagnosis can lead to unnecessary procedures, with resulting significant morbidity and mortality. Blanco and Volpicelli⁶³ describe several common errors that include misdiagnosing the stomach as a peritoneal effusion, assuming adequate volume resuscitation when the IVC is seen to be plethoric in the setting of cardiac tamponade, or mistaking IVC movement as indicative of collapsibility, amongst other described misinterpretations. Several other studies have shown that, despite adequate performance of EPs in POCUS, diagnostic sensitivities remained higher when performed by radiologists.^64-67 Thus it remains important for the EPs to be vigilant and not anchor on a diagnosis when in doubt, and to consult early with radiology, particularly if there is any question, to avoid potential adverse patient outcomes.

Summary

There are several ways to diagnose and track resuscitation in the ED, which include physical examination, assessment of serum laboratory values, monitoring of hemodynamic status, and use of POCUS. Unfortunately, none of these methods provides a perfect assessment, and no method has been proven superior and effective over the others. Therefore, it is important for EPs treating patients in shock to be aware of the strengths and limitations of each assessment method (Table).

Lumbar puncture study revealed 34 nucleated cells/µL (94% lymphocytes), protein 58 mg/dL, and glucose 62 mg/dL. Cerebrospinal fluid Venereal Disease Research Laboratory and fluorescent treponemal antibody absorption tests were reactive, confirming a diagnosis of ocular syphilis.

The patient was admitted to the hospital for treatment with intravenous penicillin G. After 5 days, he was discharged with instructions to complete a 10-day course of intravenous ceftriaxone (chosen for its ease of administration), for a total of 14 days of antibiotic therapy. His vision improved with treatment.

He continued to follow up with ophthalmology and infectious disease. Subsequent dilated fundus examinations showed resolution of pathology in the left eye, resolution of Roth spots in the right eye, and resolution of the subhyaloid hemorrhage. Repeat cerebrospinal fluid study examination was planned if the serum rapid plasma reagin had not become nonreactive 24 months after treatment.

RECOGNIZING AND MANAGING OCULAR SYPHILIS AND NEUROSYPHILIS

In addition to ocular syphilis and neurosyphilis, the differential diagnosis for Roth spots and disc edema on dilated funduscopy includes endocarditis, viral retinitis, and autoimmune or inflammatory conditions such as sarcoidosis and vasculitis.

In our patient, infectious endocarditis was considered, given his history of intermittent fevers and rigors, but it was ultimately ruled out by negative blood cultures and the absence of valvular vegetations on echocardiography.

The large subhyaloid hemorrhage raised suspicion of leukemia, but this was ruled out by the normal total white blood cell count and differential. HIV, herpetic retinitis, and toxoplasmosis were also considered, but laboratory tests for these infections were negative.

Typically, retinal precipitates are more characteristic of syphilitic retinitis and distinguish it from other infectious causes such as herpetic retinitis and toxoplasmosis.¹ Additionally, ocular syphilis more commonly manifests as uveitis or panuveitis.^1,2 Our patient’s ocular syphilis presented with white-centered retinal hemorrhages, subhyaloid hemorrhage, and optic disc edema.

Who is at highest risk?

About 90% of syphilis cases occur in men, and 81% occur in men who have sex with men. The US Centers for Disease Control and Prevention (CDC) thus recommends annual syphilis testing for men who have sex with men.³

Classically, syphilis was called “the great imitator” because it mimicked manifestations of other diseases. Patients with ocular manifestations of syphilis may not have other neurologic symptoms.^4,5 Nevertheless, cerebrospinal fluid examination should be done in all instances of ocular syphilis, as many patients with ocular syphilis have evidence of neurosyphilis on testing.² The CDC also recommends follow-up cerebrospinal fluid analysis to assess treatment response.² This was planned in our patient.

Lumbar puncture study revealed 34 nucleated cells/µL (94% lymphocytes), protein 58 mg/dL, and glucose 62 mg/dL. Cerebrospinal fluid Venereal Disease Research Laboratory and fluorescent treponemal antibody absorption tests were reactive, confirming a diagnosis of ocular syphilis.

The patient was admitted to the hospital for treatment with intravenous penicillin G. After 5 days, he was discharged with instructions to complete a 10-day course of intravenous ceftriaxone (chosen for its ease of administration), for a total of 14 days of antibiotic therapy. His vision improved with treatment.

He continued to follow up with ophthalmology and infectious disease. Subsequent dilated fundus examinations showed resolution of pathology in the left eye, resolution of Roth spots in the right eye, and resolution of the subhyaloid hemorrhage. Repeat cerebrospinal fluid study examination was planned if the serum rapid plasma reagin had not become nonreactive 24 months after treatment.

RECOGNIZING AND MANAGING OCULAR SYPHILIS AND NEUROSYPHILIS

In addition to ocular syphilis and neurosyphilis, the differential diagnosis for Roth spots and disc edema on dilated funduscopy includes endocarditis, viral retinitis, and autoimmune or inflammatory conditions such as sarcoidosis and vasculitis.

In our patient, infectious endocarditis was considered, given his history of intermittent fevers and rigors, but it was ultimately ruled out by negative blood cultures and the absence of valvular vegetations on echocardiography.

The large subhyaloid hemorrhage raised suspicion of leukemia, but this was ruled out by the normal total white blood cell count and differential. HIV, herpetic retinitis, and toxoplasmosis were also considered, but laboratory tests for these infections were negative.

Typically, retinal precipitates are more characteristic of syphilitic retinitis and distinguish it from other infectious causes such as herpetic retinitis and toxoplasmosis.¹ Additionally, ocular syphilis more commonly manifests as uveitis or panuveitis.^1,2 Our patient’s ocular syphilis presented with white-centered retinal hemorrhages, subhyaloid hemorrhage, and optic disc edema.

Who is at highest risk?

About 90% of syphilis cases occur in men, and 81% occur in men who have sex with men. The US Centers for Disease Control and Prevention (CDC) thus recommends annual syphilis testing for men who have sex with men.³

Classically, syphilis was called “the great imitator” because it mimicked manifestations of other diseases. Patients with ocular manifestations of syphilis may not have other neurologic symptoms.^4,5 Nevertheless, cerebrospinal fluid examination should be done in all instances of ocular syphilis, as many patients with ocular syphilis have evidence of neurosyphilis on testing.² The CDC also recommends follow-up cerebrospinal fluid analysis to assess treatment response.² This was planned in our patient.

Lumbar puncture study revealed 34 nucleated cells/µL (94% lymphocytes), protein 58 mg/dL, and glucose 62 mg/dL. Cerebrospinal fluid Venereal Disease Research Laboratory and fluorescent treponemal antibody absorption tests were reactive, confirming a diagnosis of ocular syphilis.

The patient was admitted to the hospital for treatment with intravenous penicillin G. After 5 days, he was discharged with instructions to complete a 10-day course of intravenous ceftriaxone (chosen for its ease of administration), for a total of 14 days of antibiotic therapy. His vision improved with treatment.

He continued to follow up with ophthalmology and infectious disease. Subsequent dilated fundus examinations showed resolution of pathology in the left eye, resolution of Roth spots in the right eye, and resolution of the subhyaloid hemorrhage. Repeat cerebrospinal fluid study examination was planned if the serum rapid plasma reagin had not become nonreactive 24 months after treatment.

RECOGNIZING AND MANAGING OCULAR SYPHILIS AND NEUROSYPHILIS

In addition to ocular syphilis and neurosyphilis, the differential diagnosis for Roth spots and disc edema on dilated funduscopy includes endocarditis, viral retinitis, and autoimmune or inflammatory conditions such as sarcoidosis and vasculitis.

In our patient, infectious endocarditis was considered, given his history of intermittent fevers and rigors, but it was ultimately ruled out by negative blood cultures and the absence of valvular vegetations on echocardiography.

The large subhyaloid hemorrhage raised suspicion of leukemia, but this was ruled out by the normal total white blood cell count and differential. HIV, herpetic retinitis, and toxoplasmosis were also considered, but laboratory tests for these infections were negative.

Typically, retinal precipitates are more characteristic of syphilitic retinitis and distinguish it from other infectious causes such as herpetic retinitis and toxoplasmosis.¹ Additionally, ocular syphilis more commonly manifests as uveitis or panuveitis.^1,2 Our patient’s ocular syphilis presented with white-centered retinal hemorrhages, subhyaloid hemorrhage, and optic disc edema.

Who is at highest risk?

About 90% of syphilis cases occur in men, and 81% occur in men who have sex with men. The US Centers for Disease Control and Prevention (CDC) thus recommends annual syphilis testing for men who have sex with men.³

Classically, syphilis was called “the great imitator” because it mimicked manifestations of other diseases. Patients with ocular manifestations of syphilis may not have other neurologic symptoms.^4,5 Nevertheless, cerebrospinal fluid examination should be done in all instances of ocular syphilis, as many patients with ocular syphilis have evidence of neurosyphilis on testing.² The CDC also recommends follow-up cerebrospinal fluid analysis to assess treatment response.² This was planned in our patient.

To this day I remain impressed by the algorithmic nature of trauma management. A routine that to the internist could appear mindless and slavish was to the trauma physician a protocol designed to take no chances on missing a life-threatening complication in the heat of the moment. The trauma physician cannot afford to wait for a cognitively derived epiphany in a clinical setting that often rapidly unfolds as a series of “never-miss” scenarios. The appropriate algorithm, rigorously followed, offers the best chance of avoiding a catastrophe of omission. This was long before Atul Gawande published his Checklist Manifesto.

Reviewing the article by Sussman et al, “Eyes of the mimicker,” in this issue of the Journal got me thinking about the power of algorithmic thinking and practice in internal medicine, how the patient they describe specifically relates to my practice experiences over the years, and how important the context of where we practice and who we treat informs (and can misinform) our clinical reasoning. When I was a medical student at Bellevue Hospital in New York City (in the pre-HIV era), the rapid plasma reagin (RPR) was a routine blood test, as syphilis routinely earned its moniker as the “great imitator.” When I did my residency at the Hospital of the University of Pennsylvania, my ingrained habit of ordering this test was extinguished, along with my also previously learned habit of obtaining blood cultures in all patients who presented with new heart failure that was not explained by the electrocardiogram. These habits disappeared not because of arguments steeped in evidence-based medicine or an emphasis on Bayesian test-ordering, but because in Philadelphia at that time we were not seeing patients with occult syphilis and endocarditis with the same frequency as at Bellevue. Context can and should play a role in our diagnostic reasoning.

But I still remember the patient I saw in the Philadelphia emergency room, a second visit for a man in his 20s with a diffuse, mostly macular rash on his trunk, palms, and soles (visible when the light was turned up in his darkened room, as he felt uncomfortable with bright light), diffuse adenopathy, and enlarged doughy and minimally tender wrists and finger (metacarpophalangeal) joints. I recall wondering why no one had thought to obtain an RPR test on him the first time he had presented to the emergency room; if he had been at Bellevue, the test results would already have returned.

Without appropriate algorithms, things get missed. But using algorithms indiscriminately is cost-ineffective and can lead to cascades of inappropriate tests and interventions. Striking the appropriate balance is part of what comprises the writing of useful clinical care paths.

As I read the article by Sussman et al I wondered who first looked at the patient’s retinas and what initially prompted the testing that was ordered. The presentation was not typical of ocular syphilis, and I would guess that an ophthalmologist or infectious disease consultant evaluating the blurred vision observed the retinal findings, suspected the diagnosis, and ordered serologies, as well as other studies searching for infections and systemic autoimmune disorders that can also cause Roth spots. Gone are the days when internists (and residents) routinely examine the eyes as part of a full physical examination. I am certain an evidence-based study of this practice would find it time-ineffective and with inappropriately low sensitivity.

I don’t think the retinal examination will return to the internist’s checklist. Yet that is where the algorithm that led to this patient’s diagnosis likely began. One can “google” the causes of Roth spots, but as yet there is no app for demonstrating that they are present.

To this day I remain impressed by the algorithmic nature of trauma management. A routine that to the internist could appear mindless and slavish was to the trauma physician a protocol designed to take no chances on missing a life-threatening complication in the heat of the moment. The trauma physician cannot afford to wait for a cognitively derived epiphany in a clinical setting that often rapidly unfolds as a series of “never-miss” scenarios. The appropriate algorithm, rigorously followed, offers the best chance of avoiding a catastrophe of omission. This was long before Atul Gawande published his Checklist Manifesto.

Reviewing the article by Sussman et al, “Eyes of the mimicker,” in this issue of the Journal got me thinking about the power of algorithmic thinking and practice in internal medicine, how the patient they describe specifically relates to my practice experiences over the years, and how important the context of where we practice and who we treat informs (and can misinform) our clinical reasoning. When I was a medical student at Bellevue Hospital in New York City (in the pre-HIV era), the rapid plasma reagin (RPR) was a routine blood test, as syphilis routinely earned its moniker as the “great imitator.” When I did my residency at the Hospital of the University of Pennsylvania, my ingrained habit of ordering this test was extinguished, along with my also previously learned habit of obtaining blood cultures in all patients who presented with new heart failure that was not explained by the electrocardiogram. These habits disappeared not because of arguments steeped in evidence-based medicine or an emphasis on Bayesian test-ordering, but because in Philadelphia at that time we were not seeing patients with occult syphilis and endocarditis with the same frequency as at Bellevue. Context can and should play a role in our diagnostic reasoning.

But I still remember the patient I saw in the Philadelphia emergency room, a second visit for a man in his 20s with a diffuse, mostly macular rash on his trunk, palms, and soles (visible when the light was turned up in his darkened room, as he felt uncomfortable with bright light), diffuse adenopathy, and enlarged doughy and minimally tender wrists and finger (metacarpophalangeal) joints. I recall wondering why no one had thought to obtain an RPR test on him the first time he had presented to the emergency room; if he had been at Bellevue, the test results would already have returned.

Without appropriate algorithms, things get missed. But using algorithms indiscriminately is cost-ineffective and can lead to cascades of inappropriate tests and interventions. Striking the appropriate balance is part of what comprises the writing of useful clinical care paths.

As I read the article by Sussman et al I wondered who first looked at the patient’s retinas and what initially prompted the testing that was ordered. The presentation was not typical of ocular syphilis, and I would guess that an ophthalmologist or infectious disease consultant evaluating the blurred vision observed the retinal findings, suspected the diagnosis, and ordered serologies, as well as other studies searching for infections and systemic autoimmune disorders that can also cause Roth spots. Gone are the days when internists (and residents) routinely examine the eyes as part of a full physical examination. I am certain an evidence-based study of this practice would find it time-ineffective and with inappropriately low sensitivity.

I don’t think the retinal examination will return to the internist’s checklist. Yet that is where the algorithm that led to this patient’s diagnosis likely began. One can “google” the causes of Roth spots, but as yet there is no app for demonstrating that they are present.

To this day I remain impressed by the algorithmic nature of trauma management. A routine that to the internist could appear mindless and slavish was to the trauma physician a protocol designed to take no chances on missing a life-threatening complication in the heat of the moment. The trauma physician cannot afford to wait for a cognitively derived epiphany in a clinical setting that often rapidly unfolds as a series of “never-miss” scenarios. The appropriate algorithm, rigorously followed, offers the best chance of avoiding a catastrophe of omission. This was long before Atul Gawande published his Checklist Manifesto.

Reviewing the article by Sussman et al, “Eyes of the mimicker,” in this issue of the Journal got me thinking about the power of algorithmic thinking and practice in internal medicine, how the patient they describe specifically relates to my practice experiences over the years, and how important the context of where we practice and who we treat informs (and can misinform) our clinical reasoning. When I was a medical student at Bellevue Hospital in New York City (in the pre-HIV era), the rapid plasma reagin (RPR) was a routine blood test, as syphilis routinely earned its moniker as the “great imitator.” When I did my residency at the Hospital of the University of Pennsylvania, my ingrained habit of ordering this test was extinguished, along with my also previously learned habit of obtaining blood cultures in all patients who presented with new heart failure that was not explained by the electrocardiogram. These habits disappeared not because of arguments steeped in evidence-based medicine or an emphasis on Bayesian test-ordering, but because in Philadelphia at that time we were not seeing patients with occult syphilis and endocarditis with the same frequency as at Bellevue. Context can and should play a role in our diagnostic reasoning.

But I still remember the patient I saw in the Philadelphia emergency room, a second visit for a man in his 20s with a diffuse, mostly macular rash on his trunk, palms, and soles (visible when the light was turned up in his darkened room, as he felt uncomfortable with bright light), diffuse adenopathy, and enlarged doughy and minimally tender wrists and finger (metacarpophalangeal) joints. I recall wondering why no one had thought to obtain an RPR test on him the first time he had presented to the emergency room; if he had been at Bellevue, the test results would already have returned.

Without appropriate algorithms, things get missed. But using algorithms indiscriminately is cost-ineffective and can lead to cascades of inappropriate tests and interventions. Striking the appropriate balance is part of what comprises the writing of useful clinical care paths.

As I read the article by Sussman et al I wondered who first looked at the patient’s retinas and what initially prompted the testing that was ordered. The presentation was not typical of ocular syphilis, and I would guess that an ophthalmologist or infectious disease consultant evaluating the blurred vision observed the retinal findings, suspected the diagnosis, and ordered serologies, as well as other studies searching for infections and systemic autoimmune disorders that can also cause Roth spots. Gone are the days when internists (and residents) routinely examine the eyes as part of a full physical examination. I am certain an evidence-based study of this practice would find it time-ineffective and with inappropriately low sensitivity.

I don’t think the retinal examination will return to the internist’s checklist. Yet that is where the algorithm that led to this patient’s diagnosis likely began. One can “google” the causes of Roth spots, but as yet there is no app for demonstrating that they are present.

See related editorial

WHAT IS ‘EARLY’ SURGERY?

More than 50% of patients with infective endocarditis undergo cardiac surgery during their initial presentation.¹

The 2017 guidelines of the American Association for Thoracic Surgery (AATS) recommend surgery once a surgical indication has been established and effective antimicrobial therapy has been started.²

The American Heart Association/American College of Cardiology (ACC/AHA) guidelines recommend surgery during the initial hospitalization before completion of a full course of antibiotics.³

The European Society of Cardiology guidelines define surgery according to the time since the patient received intravenous antibiotic therapy: emergency surgery is performed within 24 hours of therapy, urgent surgery is performed within a few days, and elective surgery is performed after at least 1 to 2 weeks.⁴

These slight differences are due to the dearth of large randomized trials addressing this question.

INDICATIONS FOR EARLY SURGERY

Left ventricular dysfunction and heart failure

Of all the complications of infectious endocarditis, concomitant heart failure has the greatest impact on prognosis⁵ and is one of the most frequent indications for surgery.⁶

The guidelines recommend emergency surgery during the initial hospitalization for all patients with infective endocarditis who present with refractory pulmonary edema, worsening left ventricular dysfunction, or cardiogenic shock, regardless of whether they have completed a full course of antibiotics. This applies to both native valve endocarditis and prosthetic valve endocarditis.

Uncontrolled persistent infection

Persistent infection is defined as fever and positive cultures persisting after 1 week of appropriate antibiotic treatment.⁴ However, 1 week is a long time. Persistence of positive blood cultures more than 48 to 72 hours after starting antibiotic therapy is associated with poor outcome and is an independent predictor of in-hospital mortality.⁷

The ACC/AHA guidelines recommend early surgery in patients with left-sided infective endocarditis caused by fungi or highly resistant organisms such as vancomycin-resistant enterococci or multidrug-resistant gram-negative bacilli.³ Nonetheless, antibiotic resistance is an unusual reason for expediting surgery unless there are additional indications for it.

Extension of the infection beyond the valve annulus, which occurs in about 30% of cases of native valve endocarditis and 50% of cases of prosthetic valve endocarditis,⁸ is considered a more valid reason to expedite surgery. Similarly, urgent surgery should be considered if there is any evidence of locally uncontrolled infection causing perivalvular abscess, fistula, pseudoaneurysm, or conduction system abnormalities causing atrioventricular nodal block.^2–4

Some authors suggest reviewing the surgical pathology and microbial sequencing of excised cardiac valves after surgery to confirm the diagnosis and identify the culprit pathogen.^9,10

Right-sided infective endocarditis has a more favorable prognosis than left-sided infective endocarditis and usually responds well to medical therapy.¹¹

Nevertheless, surgery for right-sided infective endocarditis should be expedited in patients with right heart failure secondary to severe tricuspid regurgitation with poor response to medical therapy or in the case of large tricuspid valve vegetations.¹² Likewise, recurrent septic pulmonary emboli can be encountered in the setting of right-sided infective endocarditis and are an indication for early surgery.^4,12

Since many patients with right-sided infective endocarditis acquire the infection by intravenous drug use, there is often a reluctance to recommend surgery, given the risk of prosthetic valve infection if they continue to use intravenous drugs.^4,12 One study showed that the risk of death or reoperation between 3 and 6 months after surgery for infective endocarditis was 10 times higher in intravenous drug users. Yet their survival after surgery beyond this period was similar to that of patients with endocarditis who did not inject drugs.¹³ Therefore, the AATS guidelines recommend applying normal indications for surgery to those patients, with emphasis on the need for strict follow-up aimed at addiction treatment.²

Prevention of embolic events

Neurologic embolic events are a frequent complication of infective endocarditis, with the highest risk during the first few days after antibiotics are started. However, this risk decreases significantly after 2 weeks.¹⁴

The timing of surgery largely depends on whether the patient has had previous neurologic embolic events and on the size and mobility of the vegetation. The current guidelines recommend early surgery for recurrent emboli and persistent or enlarging vegetations despite appropriate antibiotic therapy, or in case of large vegetations (> 10 mm) on a native valve even in the absence of embolic events.⁴

A randomized trial by Kang et al¹⁵ demonstrated that, compared with conventional care, early surgery (within 48 hours of diagnosis) in patients with native valve endocarditis with large vegetations (> 10 mm) and severe valve dysfunction was associated with a significant reduction in the risk of death and embolic events.

Timing of surgery after a neurologic complication

Determining the right time for surgery is challenging in patients with infective endocarditis who have had neurologic complications, given the risk of hemorrhagic conversion of existing stroke with anticoagulation or exacerbation of cerebral ischemia in case of intraoperative hypotension. The decision should take into account the severity of cardiac decompensation, weighed against the severity of neurologic symptoms.

In general, surgery should be postponed for at least 4 weeks after intracerebral hemorrhage. However, it should be expedited in the event of silent cerebral embolism or transient ischemic attack, or in patients with infective endocarditis with stroke who have other indications for early surgery, as long as cerebral hemorrhage has been excluded by appropriate imaging.⁴

Early surgery for prosthetic valve endocarditis

The timing of surgery for prosthetic valve endocarditis follows the same general principles as for native valve endocarditis.^2–4,12

One study showed that early surgery for prosthetic valve endocarditis was not associated with lower in-hospital and 1-year mortality rates compared with medical therapy.¹⁶ On the other hand, a subgroup analysis demonstrated surgery to be significantly beneficial in those with the strongest indications for surgery, including severe valve regurgitation, heart failure, paravalvular abscess, fistula, or prosthetic valve dehiscence.

The decision to proceed with surgery in prosthetic valve endocarditis should be weighed carefully, taking into consideration the patient’s overall clinical condition and estimated surgical risk.¹⁶

COLLABORATION IS HELPFUL

Early surgery is indicated for infective endocarditis patients presenting with:

• Refractory heart failure symptoms
• Persistent infection
• Large vegetations with a high risk of embolism.

Expeditious and successful treatment entails multidisciplinary collaboration among experts in cardiology and infectious diseases with access to cardiac surgery input early in the evaluation.

See related editorial

WHAT IS ‘EARLY’ SURGERY?

More than 50% of patients with infective endocarditis undergo cardiac surgery during their initial presentation.¹

The 2017 guidelines of the American Association for Thoracic Surgery (AATS) recommend surgery once a surgical indication has been established and effective antimicrobial therapy has been started.²

The American Heart Association/American College of Cardiology (ACC/AHA) guidelines recommend surgery during the initial hospitalization before completion of a full course of antibiotics.³

The European Society of Cardiology guidelines define surgery according to the time since the patient received intravenous antibiotic therapy: emergency surgery is performed within 24 hours of therapy, urgent surgery is performed within a few days, and elective surgery is performed after at least 1 to 2 weeks.⁴

These slight differences are due to the dearth of large randomized trials addressing this question.

INDICATIONS FOR EARLY SURGERY

Left ventricular dysfunction and heart failure

Of all the complications of infectious endocarditis, concomitant heart failure has the greatest impact on prognosis⁵ and is one of the most frequent indications for surgery.⁶

The guidelines recommend emergency surgery during the initial hospitalization for all patients with infective endocarditis who present with refractory pulmonary edema, worsening left ventricular dysfunction, or cardiogenic shock, regardless of whether they have completed a full course of antibiotics. This applies to both native valve endocarditis and prosthetic valve endocarditis.

Uncontrolled persistent infection

Persistent infection is defined as fever and positive cultures persisting after 1 week of appropriate antibiotic treatment.⁴ However, 1 week is a long time. Persistence of positive blood cultures more than 48 to 72 hours after starting antibiotic therapy is associated with poor outcome and is an independent predictor of in-hospital mortality.⁷

The ACC/AHA guidelines recommend early surgery in patients with left-sided infective endocarditis caused by fungi or highly resistant organisms such as vancomycin-resistant enterococci or multidrug-resistant gram-negative bacilli.³ Nonetheless, antibiotic resistance is an unusual reason for expediting surgery unless there are additional indications for it.

Extension of the infection beyond the valve annulus, which occurs in about 30% of cases of native valve endocarditis and 50% of cases of prosthetic valve endocarditis,⁸ is considered a more valid reason to expedite surgery. Similarly, urgent surgery should be considered if there is any evidence of locally uncontrolled infection causing perivalvular abscess, fistula, pseudoaneurysm, or conduction system abnormalities causing atrioventricular nodal block.^2–4

Some authors suggest reviewing the surgical pathology and microbial sequencing of excised cardiac valves after surgery to confirm the diagnosis and identify the culprit pathogen.^9,10

Right-sided infective endocarditis has a more favorable prognosis than left-sided infective endocarditis and usually responds well to medical therapy.¹¹

Nevertheless, surgery for right-sided infective endocarditis should be expedited in patients with right heart failure secondary to severe tricuspid regurgitation with poor response to medical therapy or in the case of large tricuspid valve vegetations.¹² Likewise, recurrent septic pulmonary emboli can be encountered in the setting of right-sided infective endocarditis and are an indication for early surgery.^4,12

Since many patients with right-sided infective endocarditis acquire the infection by intravenous drug use, there is often a reluctance to recommend surgery, given the risk of prosthetic valve infection if they continue to use intravenous drugs.^4,12 One study showed that the risk of death or reoperation between 3 and 6 months after surgery for infective endocarditis was 10 times higher in intravenous drug users. Yet their survival after surgery beyond this period was similar to that of patients with endocarditis who did not inject drugs.¹³ Therefore, the AATS guidelines recommend applying normal indications for surgery to those patients, with emphasis on the need for strict follow-up aimed at addiction treatment.²

Prevention of embolic events

Neurologic embolic events are a frequent complication of infective endocarditis, with the highest risk during the first few days after antibiotics are started. However, this risk decreases significantly after 2 weeks.¹⁴

The timing of surgery largely depends on whether the patient has had previous neurologic embolic events and on the size and mobility of the vegetation. The current guidelines recommend early surgery for recurrent emboli and persistent or enlarging vegetations despite appropriate antibiotic therapy, or in case of large vegetations (> 10 mm) on a native valve even in the absence of embolic events.⁴

A randomized trial by Kang et al¹⁵ demonstrated that, compared with conventional care, early surgery (within 48 hours of diagnosis) in patients with native valve endocarditis with large vegetations (> 10 mm) and severe valve dysfunction was associated with a significant reduction in the risk of death and embolic events.

Timing of surgery after a neurologic complication

Determining the right time for surgery is challenging in patients with infective endocarditis who have had neurologic complications, given the risk of hemorrhagic conversion of existing stroke with anticoagulation or exacerbation of cerebral ischemia in case of intraoperative hypotension. The decision should take into account the severity of cardiac decompensation, weighed against the severity of neurologic symptoms.

In general, surgery should be postponed for at least 4 weeks after intracerebral hemorrhage. However, it should be expedited in the event of silent cerebral embolism or transient ischemic attack, or in patients with infective endocarditis with stroke who have other indications for early surgery, as long as cerebral hemorrhage has been excluded by appropriate imaging.⁴

Early surgery for prosthetic valve endocarditis

The timing of surgery for prosthetic valve endocarditis follows the same general principles as for native valve endocarditis.^2–4,12

One study showed that early surgery for prosthetic valve endocarditis was not associated with lower in-hospital and 1-year mortality rates compared with medical therapy.¹⁶ On the other hand, a subgroup analysis demonstrated surgery to be significantly beneficial in those with the strongest indications for surgery, including severe valve regurgitation, heart failure, paravalvular abscess, fistula, or prosthetic valve dehiscence.

The decision to proceed with surgery in prosthetic valve endocarditis should be weighed carefully, taking into consideration the patient’s overall clinical condition and estimated surgical risk.¹⁶

COLLABORATION IS HELPFUL

Early surgery is indicated for infective endocarditis patients presenting with:

• Refractory heart failure symptoms
• Persistent infection
• Large vegetations with a high risk of embolism.

Expeditious and successful treatment entails multidisciplinary collaboration among experts in cardiology and infectious diseases with access to cardiac surgery input early in the evaluation.

See related editorial

WHAT IS ‘EARLY’ SURGERY?

More than 50% of patients with infective endocarditis undergo cardiac surgery during their initial presentation.¹

The 2017 guidelines of the American Association for Thoracic Surgery (AATS) recommend surgery once a surgical indication has been established and effective antimicrobial therapy has been started.²

The American Heart Association/American College of Cardiology (ACC/AHA) guidelines recommend surgery during the initial hospitalization before completion of a full course of antibiotics.³

The European Society of Cardiology guidelines define surgery according to the time since the patient received intravenous antibiotic therapy: emergency surgery is performed within 24 hours of therapy, urgent surgery is performed within a few days, and elective surgery is performed after at least 1 to 2 weeks.⁴

These slight differences are due to the dearth of large randomized trials addressing this question.

INDICATIONS FOR EARLY SURGERY

Left ventricular dysfunction and heart failure

Of all the complications of infectious endocarditis, concomitant heart failure has the greatest impact on prognosis⁵ and is one of the most frequent indications for surgery.⁶

The guidelines recommend emergency surgery during the initial hospitalization for all patients with infective endocarditis who present with refractory pulmonary edema, worsening left ventricular dysfunction, or cardiogenic shock, regardless of whether they have completed a full course of antibiotics. This applies to both native valve endocarditis and prosthetic valve endocarditis.

Uncontrolled persistent infection

Persistent infection is defined as fever and positive cultures persisting after 1 week of appropriate antibiotic treatment.⁴ However, 1 week is a long time. Persistence of positive blood cultures more than 48 to 72 hours after starting antibiotic therapy is associated with poor outcome and is an independent predictor of in-hospital mortality.⁷

The ACC/AHA guidelines recommend early surgery in patients with left-sided infective endocarditis caused by fungi or highly resistant organisms such as vancomycin-resistant enterococci or multidrug-resistant gram-negative bacilli.³ Nonetheless, antibiotic resistance is an unusual reason for expediting surgery unless there are additional indications for it.

Extension of the infection beyond the valve annulus, which occurs in about 30% of cases of native valve endocarditis and 50% of cases of prosthetic valve endocarditis,⁸ is considered a more valid reason to expedite surgery. Similarly, urgent surgery should be considered if there is any evidence of locally uncontrolled infection causing perivalvular abscess, fistula, pseudoaneurysm, or conduction system abnormalities causing atrioventricular nodal block.^2–4

Some authors suggest reviewing the surgical pathology and microbial sequencing of excised cardiac valves after surgery to confirm the diagnosis and identify the culprit pathogen.^9,10

Right-sided infective endocarditis has a more favorable prognosis than left-sided infective endocarditis and usually responds well to medical therapy.¹¹

Nevertheless, surgery for right-sided infective endocarditis should be expedited in patients with right heart failure secondary to severe tricuspid regurgitation with poor response to medical therapy or in the case of large tricuspid valve vegetations.¹² Likewise, recurrent septic pulmonary emboli can be encountered in the setting of right-sided infective endocarditis and are an indication for early surgery.^4,12

Since many patients with right-sided infective endocarditis acquire the infection by intravenous drug use, there is often a reluctance to recommend surgery, given the risk of prosthetic valve infection if they continue to use intravenous drugs.^4,12 One study showed that the risk of death or reoperation between 3 and 6 months after surgery for infective endocarditis was 10 times higher in intravenous drug users. Yet their survival after surgery beyond this period was similar to that of patients with endocarditis who did not inject drugs.¹³ Therefore, the AATS guidelines recommend applying normal indications for surgery to those patients, with emphasis on the need for strict follow-up aimed at addiction treatment.²

Prevention of embolic events

Neurologic embolic events are a frequent complication of infective endocarditis, with the highest risk during the first few days after antibiotics are started. However, this risk decreases significantly after 2 weeks.¹⁴

The timing of surgery largely depends on whether the patient has had previous neurologic embolic events and on the size and mobility of the vegetation. The current guidelines recommend early surgery for recurrent emboli and persistent or enlarging vegetations despite appropriate antibiotic therapy, or in case of large vegetations (> 10 mm) on a native valve even in the absence of embolic events.⁴

A randomized trial by Kang et al¹⁵ demonstrated that, compared with conventional care, early surgery (within 48 hours of diagnosis) in patients with native valve endocarditis with large vegetations (> 10 mm) and severe valve dysfunction was associated with a significant reduction in the risk of death and embolic events.

Timing of surgery after a neurologic complication

Determining the right time for surgery is challenging in patients with infective endocarditis who have had neurologic complications, given the risk of hemorrhagic conversion of existing stroke with anticoagulation or exacerbation of cerebral ischemia in case of intraoperative hypotension. The decision should take into account the severity of cardiac decompensation, weighed against the severity of neurologic symptoms.

In general, surgery should be postponed for at least 4 weeks after intracerebral hemorrhage. However, it should be expedited in the event of silent cerebral embolism or transient ischemic attack, or in patients with infective endocarditis with stroke who have other indications for early surgery, as long as cerebral hemorrhage has been excluded by appropriate imaging.⁴

Early surgery for prosthetic valve endocarditis

The timing of surgery for prosthetic valve endocarditis follows the same general principles as for native valve endocarditis.^2–4,12

One study showed that early surgery for prosthetic valve endocarditis was not associated with lower in-hospital and 1-year mortality rates compared with medical therapy.¹⁶ On the other hand, a subgroup analysis demonstrated surgery to be significantly beneficial in those with the strongest indications for surgery, including severe valve regurgitation, heart failure, paravalvular abscess, fistula, or prosthetic valve dehiscence.

The decision to proceed with surgery in prosthetic valve endocarditis should be weighed carefully, taking into consideration the patient’s overall clinical condition and estimated surgical risk.¹⁶

COLLABORATION IS HELPFUL

Early surgery is indicated for infective endocarditis patients presenting with:

• Refractory heart failure symptoms
• Persistent infection
• Large vegetations with a high risk of embolism.

Expeditious and successful treatment entails multidisciplinary collaboration among experts in cardiology and infectious diseases with access to cardiac surgery input early in the evaluation.

In this issue of the Journal, Soud et al discuss the timing of referral of patients with infective endocarditis to surgery.¹ When having this discussion, it is important to understand the nature of the disease and the role of surgery in its treatment.

See related article

Unless successfully treated and cured, infective endocarditis is fatal. It is associated with septic embolism (systemic with left-sided infective endocarditis and pulmonary with right-sided infective endocarditis), destruction of valve tissue, and invasion outside the aortic root or into the atrioventricular groove. Antimicrobials kill sensitive and exposed organisms but cannot reach those hiding in vegetations or biofilm, on foreign material, or in invaded extravascular tissue.

The objectives of surgery are to eliminate the source of embolism, debride and remove infected tissue and foreign material, expose and make residual organisms vulnerable to antimicrobials, and restore functional valves and cardiac integrity. Surgery to treat infective endocarditis is difficult and high-risk and requires an experienced surgeon. But final cure of the infection is still by antimicrobial treatment.

INFECTIVE ENDOCARDITIS NEEDS MULTIDISCIPLINARY CARE

Every aspect of infective endocarditis—diagnosis, medical management, management of complications, and surgery—is difficult. Recent guidelines^2–6 therefore favor care by a multidisciplinary team that includes an infectious disease specialist, cardiologist, and cardiac surgeon from the very beginning, with access to any other needed discipline, often including neurology, neurosurgery, nephrology, and dependence specialists. Patients with infective endocarditis should be referred early to a center with access to a full endocarditis treatment team. The need for surgery and the optimal timing of it are team decisions. The American Association for Thoracic Surgery infective endocarditis guidelines are question-based and address most aspects that surgeons must consider before, during, and after operation.²

IF SURGERY IS INDICATED, IT IS BEST DONE SOONER

Once there is an indication to operate, the operation should be expedited. Delays mean continued risk of disease progression, invasion, heart block, and embolic events. Determining the timing of surgery is difficult in patients who have suffered an embolic stroke—nonhemorrhagic or hemorrhagic—or who have suffered brain bleeding; management of these issues has recently triggered expert opinion and review articles.^7,8 The recommendation for early surgery is based on the conviction that once the patient has been stabilized (or has overwhelming mechanical hemodynamic problems requiring emergency surgery) and adequate antimicrobial coverage is on board, there are no additional benefits to delaying surgery.⁹ When the indication to operate is large mobile vegetations associated with a high risk of stroke, surgery before another event can make all the difference.

In the operating room, the first aspect addressed is adequate debridement. There is wide agreement that repair is preferable to replacement for the mitral and tricuspid valves, but there is no agreement that an allograft (although favored by our team) is the best replacement alternative for a destroyed aortic root. The key is that surgeons and their surgical teams must have the experience and tools that work for them.

Our recommendation is to refer all patients with infective endocarditis to a center with access to a full team of experienced experts able to address all aspects of the disease and its complications.

In this issue of the Journal, Soud et al discuss the timing of referral of patients with infective endocarditis to surgery.¹ When having this discussion, it is important to understand the nature of the disease and the role of surgery in its treatment.

See related article

Unless successfully treated and cured, infective endocarditis is fatal. It is associated with septic embolism (systemic with left-sided infective endocarditis and pulmonary with right-sided infective endocarditis), destruction of valve tissue, and invasion outside the aortic root or into the atrioventricular groove. Antimicrobials kill sensitive and exposed organisms but cannot reach those hiding in vegetations or biofilm, on foreign material, or in invaded extravascular tissue.

The objectives of surgery are to eliminate the source of embolism, debride and remove infected tissue and foreign material, expose and make residual organisms vulnerable to antimicrobials, and restore functional valves and cardiac integrity. Surgery to treat infective endocarditis is difficult and high-risk and requires an experienced surgeon. But final cure of the infection is still by antimicrobial treatment.

INFECTIVE ENDOCARDITIS NEEDS MULTIDISCIPLINARY CARE

Every aspect of infective endocarditis—diagnosis, medical management, management of complications, and surgery—is difficult. Recent guidelines^2–6 therefore favor care by a multidisciplinary team that includes an infectious disease specialist, cardiologist, and cardiac surgeon from the very beginning, with access to any other needed discipline, often including neurology, neurosurgery, nephrology, and dependence specialists. Patients with infective endocarditis should be referred early to a center with access to a full endocarditis treatment team. The need for surgery and the optimal timing of it are team decisions. The American Association for Thoracic Surgery infective endocarditis guidelines are question-based and address most aspects that surgeons must consider before, during, and after operation.²

IF SURGERY IS INDICATED, IT IS BEST DONE SOONER

Once there is an indication to operate, the operation should be expedited. Delays mean continued risk of disease progression, invasion, heart block, and embolic events. Determining the timing of surgery is difficult in patients who have suffered an embolic stroke—nonhemorrhagic or hemorrhagic—or who have suffered brain bleeding; management of these issues has recently triggered expert opinion and review articles.^7,8 The recommendation for early surgery is based on the conviction that once the patient has been stabilized (or has overwhelming mechanical hemodynamic problems requiring emergency surgery) and adequate antimicrobial coverage is on board, there are no additional benefits to delaying surgery.⁹ When the indication to operate is large mobile vegetations associated with a high risk of stroke, surgery before another event can make all the difference.

In the operating room, the first aspect addressed is adequate debridement. There is wide agreement that repair is preferable to replacement for the mitral and tricuspid valves, but there is no agreement that an allograft (although favored by our team) is the best replacement alternative for a destroyed aortic root. The key is that surgeons and their surgical teams must have the experience and tools that work for them.

Our recommendation is to refer all patients with infective endocarditis to a center with access to a full team of experienced experts able to address all aspects of the disease and its complications.

In this issue of the Journal, Soud et al discuss the timing of referral of patients with infective endocarditis to surgery.¹ When having this discussion, it is important to understand the nature of the disease and the role of surgery in its treatment.

See related article

Unless successfully treated and cured, infective endocarditis is fatal. It is associated with septic embolism (systemic with left-sided infective endocarditis and pulmonary with right-sided infective endocarditis), destruction of valve tissue, and invasion outside the aortic root or into the atrioventricular groove. Antimicrobials kill sensitive and exposed organisms but cannot reach those hiding in vegetations or biofilm, on foreign material, or in invaded extravascular tissue.

The objectives of surgery are to eliminate the source of embolism, debride and remove infected tissue and foreign material, expose and make residual organisms vulnerable to antimicrobials, and restore functional valves and cardiac integrity. Surgery to treat infective endocarditis is difficult and high-risk and requires an experienced surgeon. But final cure of the infection is still by antimicrobial treatment.

INFECTIVE ENDOCARDITIS NEEDS MULTIDISCIPLINARY CARE

Every aspect of infective endocarditis—diagnosis, medical management, management of complications, and surgery—is difficult. Recent guidelines^2–6 therefore favor care by a multidisciplinary team that includes an infectious disease specialist, cardiologist, and cardiac surgeon from the very beginning, with access to any other needed discipline, often including neurology, neurosurgery, nephrology, and dependence specialists. Patients with infective endocarditis should be referred early to a center with access to a full endocarditis treatment team. The need for surgery and the optimal timing of it are team decisions. The American Association for Thoracic Surgery infective endocarditis guidelines are question-based and address most aspects that surgeons must consider before, during, and after operation.²

IF SURGERY IS INDICATED, IT IS BEST DONE SOONER

Once there is an indication to operate, the operation should be expedited. Delays mean continued risk of disease progression, invasion, heart block, and embolic events. Determining the timing of surgery is difficult in patients who have suffered an embolic stroke—nonhemorrhagic or hemorrhagic—or who have suffered brain bleeding; management of these issues has recently triggered expert opinion and review articles.^7,8 The recommendation for early surgery is based on the conviction that once the patient has been stabilized (or has overwhelming mechanical hemodynamic problems requiring emergency surgery) and adequate antimicrobial coverage is on board, there are no additional benefits to delaying surgery.⁹ When the indication to operate is large mobile vegetations associated with a high risk of stroke, surgery before another event can make all the difference.

In the operating room, the first aspect addressed is adequate debridement. There is wide agreement that repair is preferable to replacement for the mitral and tricuspid valves, but there is no agreement that an allograft (although favored by our team) is the best replacement alternative for a destroyed aortic root. The key is that surgeons and their surgical teams must have the experience and tools that work for them.

Our recommendation is to refer all patients with infective endocarditis to a center with access to a full team of experienced experts able to address all aspects of the disease and its complications.