Postresuscitation management

POSTRESUSCITATION MANAGEMENT

Postresuscitation Management From Columbia University, New York Presbyterian Hospital, New York, NY*; Children’s Hospital of Eastern Ontario, Ottawa, Ontario, Canada‡; University of Pittsburgh, Children’s Hospital of Pittsburgh, Pittsburgh, PA§; University of Ottawa, Children’s Hospital of Eastern Ontario, Ottawa, Ontario, CanadaII; Franciscus Hospital, Roosendaal, The Netherlands¶; New York Presbyterian Medical Center, New York, NY#; Johannes Gutenberg-University, Mainz, Germany**; and The LeopoldFranzens-University of Innsbruck, Innsbruck, Austria.‡‡ Reprints of single articles are available online at www.mosby.com/AnnEmergMed for $35 per article. Address for correspondence: Charles L. Schleien, MD, New York Presbyterian Hospital, 3959 Broadway, BHN 10-23, New York, NY 10032; E-mail [email protected]. Joint copyright © 2001 by the American Heart Association and the American College of Emergency Physicians. 0196-0644/2001/$35.00 + 0 47/0/114170 doi:10.1067/mem.2001.114170

S 1 8 2

Panel Members: Charles L. Schleien, MD* Martin H. Osmond, MD, CM‡ Robert Hickey, MD§ Jaime Hutchison, MD, FRCPII Gerba Buunk, MD¶ Ivor S. Douglas, MD# Hendrik W. Gervais, MD, PhD** Volker Wenzel, MD‡‡

[Schleien CL, Osmond MH, Hickey R, Hutchison J, Buunk G, Douglas IS, Gervais HW, Wenzel V. Postresuscitation management. Ann Emerg Med. April 2001;37:S182-S195.] INTRODUCTION

The time after a cardiac arrest is a vulnerable period that requires meticulous medical care. Resuscitation medications such as epinephrine that are used during the cardiac arrest may result in arrhythmia, tachycardia, or hypertension. In addition, the ischemia that occurs as the result of the cardiac arrest may result in dysfunction of multiple organs, which requires close monitoring and the adjustment of medications. The postresuscitation panel discussed 3 topics central to postresuscitation care for which new evidence has emerged: (1) hyperventilation, (2) hypothermia, and (3) medications. The use of hyperventilation after resuscitation was discussed from its historic roots to more recent considerations about its potential downside. The pathophysiologic principles related to the control of cerebrovascular regulation during and after an ischemic insult and indications for the use of hyperventilation during the postresuscitation period were discussed. The discussion of hypothermia focused on 3 main issues: (1) indications and contraindications for passive cooling to protect the brain after a global ischemic insult, (2) strict avoidance of fever to protect the brain during this period, and (3) use of active hypothermia and its pathophysiologic considerations. The third discussion dealt with use of various medications, namely dopamine (as a single-use agent), corticosteroids (in high doses), and vasopressin during the postresuscitation period. New scientific evidence and controversies surrounding the use of these medications were highlighted during this discussion.

ANNALS OF EMERGENCY MEDICINE

37:4 APRIL 2001

POSTRESUSCITATION MANAGEMENT Schleien et al

Topic 1: Hyperventilation 1992 GUIDELINES

The Advanced Cardiac Life Support text states that, for cardiac arrest that is associated with trauma, there is no specific guideline that relates to the use of hyperventilation. The guidelines do state that airway assessment and ventilation should follow a traumatic episode and that intubation of the trachea is a priority. (Cummins RO, ed. Advanced Cardiac Life Support. Dallas: American Heart Association; 1997:11-5.) The Pediatric Advanced Life Support text states that hyperventilation is often necessary during initial stabilization of the pediatric trauma patient to eliminate excess CO2 and to maintain moderate hypocarbia (PaCO2=22-29 mm Hg). (Nadkarni V, ed. Pediatric Advanced Life Support. Dallas, TX: American Heart Association; 1997:8-4.) The 1992 guidelines do not address normal ventilatory parameters for patients without head trauma who are resuscitated from cardiac arrest. Pediatric advanced life support guidelines for postresuscitation management state that stabilization should follow the ABCs (airway, breathing, and circulation) of initial resuscitation and that vital signs should be frequently reassessed because of possibility of deterioration of the patient. Ventilation parameters are given without any direct mention of P CO2. The 1992 guidelines recommend that an arterial blood gas analysis be obtained after 10 to 15 minutes on the initial ventilatory settings with adjustments in ventilatory support made accordingly, but there is no recommendation for the desirable level of P CO2. For the pediatric trauma victim initial use of hyperventilation is recommended to correct hypoxemia and to lower Pa CO2 to 22 to 27 mm Hg and thus correct respiratory acidosis and decrease intracranial hypertension. PROPOSED ADDITION OR CHANGE

Use normal ventilation for patients who are comatose after cardiac arrest or head trauma. Use hyperventilation for patients who show signs of a cerebral herniation syndrome. Hyperventilation may also be beneficial for patients with known or suspected pulmonary hypertension.

APRIL 2001

37:4

ANNALS OF EMERGENCY MEDICINE

NEW SCIENCE

Since the publication of the 1992 Guidelines, a number of pathophysiologic principles related to the control of CO2 and the possibility of worsening cerebral ischemia with low PCO2 levels after brain ischemia have been questioned. After cardiac arrest, restoration of blood flow results in an initial but short-lived (10- to 30-minute) increase in cerebral blood low. This initial response is followed by a more prolonged period of low blood flow. During this period of delayed hypoperfusion, a mismatch between blood flow (oxygen delivery) and oxygen metabolism may exist. When the patient undergoes hyperventilation in this condition, the additional cerebral vasoconstriction that results from a low PCO2 may further decrease cerebral blood flow and worsen cerebral ischemia. There is currently no evidence that hyperventilation protects vital organs from further ischemic damage after cardiac arrest. The potential risk for further brain ischemia, however, is real; so the use of hyperventilation after cardiac arrest should be avoided. A number of studies that support these points were presented. These included 18 studies1-18 reviewed by Expert 1 (Dr Schleien) and 5 studies19-23 reviewed by Expert 2 (Dr Buunk). Expert 1 found 1 study with level 1 evidence, 6 studies with level 3 evidence, 4 studies with level 4 evidence, 1 study with level 5 evidence, and 6 studies with level 6 evidence. One study with opposing evidence was also presented.24 Muizelaar et al1 studied children older than 3 years of age with head injury and a Glasgow Coma Scale score of 6 or less. The investigators randomly assigned, in a nonblinded manner, 113 patients into 3 groups: (1) normal ventilation (PCO2=30-35 mm Hg), (2) hyperventilation to a PCO2 of 24 to 28 mm Hg, and (3) hyperventilation to the same level of PCO2 with administration of tromethamine, a buffer that crosses the blood-brain barrier and that may replenish the loss of bicarbonate buffer in cerebrospinal fluid that is caused by hyperventilation. Among the less severely injured patients (those with a Glasgow Coma Scale score of 5-6), outcome at 3 months was worse among those patients who underwent hyperventilation (only 18% had a good-to-moderate outcome) than among those patients who received normal ventilation (48% had a good-to-moderate outcome). This difference in outcome was also observed at 6 months (24% vs 57%, respectively) but not at 12 months (44% vs 57%, respectively). Use of tromethamine

S 1 8 3

POSTRESUSCITATION MANAGEMENT Schleien et al

improved outcome to a level equal to that of patients in the normal ventilation group. Whether these results from a study of patients with head injury (and likely focal brain injury) can be extrapolated to patients who have had a cardiac arrest (a global ischemic insult) is unclear. The level of normal ventilation used in this 1991 study (30-35 mm Hg) would now be considered mild hyperventilation. A more modern definition of normal ventilation would be a PCO2 level of more than 35 mm Hg. Interestingly, outcome continued to improve in all 3 groups over time, a common progression observed in children after head trauma. This finding illustrates that any benefit from an acute intervention may not be observed for a very long time. Various investigators have noted that the number of ischemic episodes (as defined by jugular venous bulb desaturation) may be associated with a worse clinical outcome. Gopinath et al14 showed that the mortality rate among adult patients who had more than 1 jugular bulb desaturation episode was 68%. The mortality rate was 41% among patients with only 1 desaturation episode and 17% among those with no jugular bulb desaturations. Likewise, poor neurologic outcome was directly related to the number of jugular bulb desaturations. These data are indirect evidence that hyperventilation with worsening ischemia and increased jugular bulb desaturations is related to worse neurologic outcome and increased mortality rates. Safar et al6 also found indirect evidence that hyperventilation results in worse neurologic outcome. In their study, outcome was improved in dogs that received mild hypothermia and blood flow promotion by hypertension after cardiac arrest. These animals also received normal ventilation, unlike the control group, which received “standard” hyperventilation. This finding points to a possible role of hyperventilation in worsening functional outcome after cardiac arrest. Dr Buunk also presented her own data, which pointed to the presence of ongoing cerebrovascular reactivity even after cardiac arrest. Mean blood flow velocity was measured in the middle cerebral artery after cardiac arrest in 10 patients.4 When these patients underwent hypoventilation transiently, mean blood flow velocity was significantly increased by almost 20% over the baseline measurement. Jugular bulb saturation was higher for as long as 24 hours after the ischemic insult when hypoventilation was performed for a short period. When these patients underwent hyperventilation for a short period of time, jugular bulb saturation was lower than when they underwent normal ventilation. This effect again lasted for as long as 24 hours. In 4 patients, jugular bulb saturation

S 1 8 4

decreased below the potential ischemic threshold of 55% when they underwent hyperventilation transiently. Cruz et al19,20,24 showed in a series of studies that hyperventilation may have a beneficial role. He and his colleagues showed that hyperventilation successfully counteracts pathologic changes in cerebral hemodynamics (identified as posttraumatic cerebral luxury perfusion) and normalizes the intracranial hypertension associated with this period of hyperemic cerebral blood flow.19 More recently, he studied the effects of hyperventilation on 33 adult patients after head trauma during the most acute phase of their illness. When hyperventilation therapy was maximized to lower intracranial hypertension, global cerebral glucose use was normalized.20 In contrast during normocapnia, global cerebral glucose extraction dropped below the normal range, which indicated impairment of cerebral glucose uptake. These studies, however, were performed in patients after head trauma, not cardiac arrest, and do not attest to improved functional outcome. E VA L U AT I O N A N D D E B AT E

After the presentations of the 2 experts, discussion centered on the definitions and pathophysiologic principles of global and focal ischemia (ie, head trauma). There was a strong opinion among audience members that we should deal primarily with resuscitation from cardiac arrest. Most audience members and panelists believed there was little evidence that hyperventilation was efficacious after a severe global ischemic insult (ie, cardiac arrest) and that the evidence shows at least a possible worsening of ischemia in the setting of hypocarbia. Although our discussions dealt mainly with cardiac arrest, panelists thought the possible detrimental effects of hyperventilation after head trauma should be mentioned because this topic is discussed in our guidelines for both advanced and pediatric advanced life support. The second discussion point was indications for hyperventilation. There was general agreement that, in the likely setting of pulmonary hypertension as the cause of cardiac arrest, hyperventilation may be an effective mode of treatment. Discussion about the use of hyperventilation for the treatment of metabolic acidosis was more divided. There was general agreement among audience members and panelists that, with restoration of cardiac output, metabolic acidosis would correct over time; so hyperventilation should not be used as a primary treatment. There was strong agreement that patients with any evidence of a cerebral herniation syndrome should be treated with

ANNALS OF EMERGENCY MEDICINE

37:4 APRIL 2001

POSTRESUSCITATION MANAGEMENT Schleien et al

hyperventilation and that the guidelines should retain this therapeutic option. The direct effects of hyperventilation on intrathoracic pressure and the indirect effects on increased intracerebral pressure were discussed. Hyperventilation can generate higher airway pressures and self-controlled (auto) positive end-expiratory pressure, which leads to an increase in cerebral venous and intracranial pressures. The increase in cerebral vascular pressure results in decreased cerebral blood flow and the worsening of brain ischemia. This mechanism is independent of the effects of PCO2 or pH on the reactivity of cerebral vessels. It was mentioned that hyperventilation is part of many of the algorithms for pediatric advanced life support and that these algorithms will require major revisions. There was overwhelming agreement among the experts, panelists, and audience members that the updated guidelines should specify that normal ventilation be used after resuscitation from cardiac arrest and that the use of hyperventilation after head trauma may be detrimental. Twentyone of 28 audience members thought these changes should be made Class IIa recommendations, and the experts agreed. PROPOSED GUIDELINES

Use normal ventilation for patients who are comatose after cardiac arrest or head trauma (Class IIa). Use hyperventilation for patients who show signs of a cerebral herniation syndrome (Class IIa). Hyperventilation may also be beneficial for patients with known or suspected pulmonary hypertension (Class IIa).

Topic 2: Hypothermia 1992 GUIDELINES

The 1992 guidelines stated in the Advanced Cardiac Life Support text section on Temperature Control that cerebral metabolic rate increases about 8% per degree centigrade of body temperature elevation. The regional cerebral metabolic rate determines the regional blood flow requirements. Thus, elevation of temperature above normal can create significant imbalance between oxygen supply and demand, and it should be aggressively treated in the postischemic period. (Cummins RO, ed. Advanced Cardiac Life Support. Dallas, TX: American Heart Association; 1997:15-2 to 15-3.)

APRIL 2001

37:4

ANNALS OF EMERGENCY MEDICINE

The text also states that hypothermia, on the other hand, suppresses cerebral metabolic activity. Although widely used during cardiovascular surgery, hypothermia has significant detrimental effects that might adversely affect the patient after cardiac arrest, including increased blood viscosity, decreased cardiac output, and increased susceptibility to infection. Many reports indicate benefit after brain ischemia, although some reports document detrimental effects or lack of improvement. Recent evidence indicates that mild levels of hypothermia (eg, 34°C) are effective in the mitigation of postischemic brain damage without detrimental side effects. The text continues: The delayed hypermetabolism believed to occur after normothermic cardiac arrest, with its attendant potential imbalance of cerebral oxygen supply and demand, also suggests a possible clinical role for induced hypothermia. Clinical investigation seems indicated, but at present therapeutic hypothermia cannot be recommended for routine clinical use after cardiac arrest. PROPOSED ADDITION OR CHANGE

The panelists recommended the following changes: (1) permitting hemodynamically stable patients after resuscitation in whom mild hypothermia (34°-37°C) develops to remain hypothermic (Class IIb), (2) close monitoring of temperatures and aggressive treatment of fever during the postresuscitation period (Class IIa), and (3) actively inducing mild hypothermia after resuscitation from cardiac arrest (Class Indeterminate). NEW SCIENCE Hypothermia

Interest in hypothermia as a treatment for brain injury was rekindled in the late 1980s and early 1990s and has continued since the publication of the 1992 Guidelines. Experiments that were performed with carefully controlled rodent models of brain ischemia (using cerebrovascular occlusion techniques)1,2 and dog models of cardiac arrest3 demonstrated that even mild intraischemic hypothermia could be neuroprotective. These studies were immediately followed by studies that demonstrated the effectiveness of resuscitative (postischemic) hypothermia in dog models of cardiac arrest4-8 and rodent models of incomplete forebrain ischemia.9-13 The results of the latter studies were encouraging for 2 reasons: (1) the hypothermia was mild and therefore unlikely to cause physiologic derangements

S 1 8 5

POSTRESUSCITATION MANAGEMENT Schleien et al

and (2) the protection was remarkably robust. Favorable results have also been documented in cardiac arrest models that used cats14 and rats.15-17 The ability to lower body temperature safely in braininjured humans and to improve neurologic outcome was recently demonstrated by Marion et al18 in a randomized, controlled trial that compared the effects of moderate hypothermia (32°-33°C for 24 hours) with those effects of normothermia in 82 patients with severe closed head injuries. Holzer et al19 in Austria and Bernard et al20 in Australia simultaneously published their preliminary experiences in treating adult victims of out-of-hospital cardiac arrest with resuscitative hypothermia. Holzer et al19 treated 27 patients with mild hypothermia (33°C) for 24 hours after cardiac arrest and demonstrated an increase in the number of patients who achieved good neurologic outcome (52% of treated patients vs 27% of historic control subjects). Bernard et al20 treated 22 patients and found improved neurologic outcome (11/22 treated patients vs 3/22 historic control subjects achieved good neurologic outcome) and a decreased mortality rate (10/22 treated patients vs 17/22 control subjects died). A randomized, multicenter trial of resuscitative hypothermia after cardiac arrest is now under way in Europe. About one half of the anticipated 500 patients are enrolled. Side effects of hypothermia include coagulopathy, cardiac dysrhythmia, impaired cardiac function, and increased susceptibility to infection. The prevalence and severity of these side effects are proportional to the depth and duration of hypothermia. To date, human studies that involve the induction of mild-to-moderate hypothermia (minimum temperature, ≥32°C) for 24 to 36 hours have not demonstrated hypothermia-related side effects. Frank et al,21 however, documented an increased risk of perioperative cardiac morbidity (unstable angina, cardiac arrest, or myocardial infarction) in high-risk patients with cardiac disease who were undergoing noncardiac surgery. These patients were allowed to become mildly hypothermic in the operating room and to remain hypothermic for the first 2 hours after the operation and were compared with patients who were kept normothermic in the operating room. Although the clinical scenario and design of the study are only tangentially related to resuscitation from cardiac arrest, the results demonstrate a potential for detrimental cardiac effects with even mild hypothermia in patients with “sick hearts.” Hyperthermia

Many studies that used animal models of brain injury have demonstrated exacerbation of injury as the result of

S 1 8 6

elevated body and brain temperature during (intraischemic) and after (postischemic) the insult. Two studies in particular merit discussion. Baena et al22 demonstrated that moderate, transient whole-body hyperthermia (39°40°C for 3 hours) imposed 24 hours after a brief episode of forebrain ischemia in rats increased neuronal injury in the hippocampus 2.6-fold. The study is remarkable because it demonstrates that fever can be detrimental even when it is of short duration and occurs the day after an injury. Coimbra et al23,24 demonstrated that treatment with the antipyretic/anti-inflammatory drug dipyrone prevented the natural occurrence of postischemic fever in a rat model of forebrain ischemia and that treated rats had improved neurologic outcome compared with untreated rats. Several studies have documented worse neurologic outcome in humans who have fever after ischemic brain injury (reviewed by Ginsberg and Busto25). Most studies are limited to patients with stroke or trauma. One chart review study26 documented worse outcome in febrile adults after cardiac arrest. It is not possible to determine from these descriptive studies whether fever exacerbates the injury or is simply a comarker of the severity of injury or both. For example, longer durations of cardiac arrest are more likely to result in gut ischemia and translocation of bacteria that can induce fever. Similarly, patients with more severe insults might have increased risk of aspiration with the attendant development of fever. On the other hand, the 2 animal studies discussed earlier persuasively demonstrate that fever can independently exacerbate brain injury. The clinical relevance of changes in temperature after cardiac arrest is supported by studies that documented that hypothermia and hyperthermia are common clinical occurrences.26-28 E VA L U AT I O N A N D D E B AT E Permissive hypothermia

There was general consensus among panelists and audience members that permitting mild, spontaneous hypothermia after resuscitation from cardiac arrest should be a Class IIb recommendation. This is more of an issue for physicians caring for children, for whom heating lamps and warm blankets are commonly used to aggressively warm patients to normothermia. Although aggressive warming is not common in adults, adults are more likely to have cardiac disease and are therefore less likely to tolerate hypothermia.

ANNALS OF EMERGENCY MEDICINE

37:4 APRIL 2001

POSTRESUSCITATION MANAGEMENT Schleien et al

The importance of weighing the potentially beneficial cerebral effects against the potentially detrimental cardiac effects to determine the most appropriate therapy for individual patients was discussed. Several participants mentioned that terms (eg, mild, moderate, severe) were used inconsistently in the literature and were a source of confusion. It was agreed that the use of specific numeric values (eg, ≥32°C) rather than terms such as “mild-to-moderate” would be less confusing. It was noted that hypothermia is unlikely to benefit patients who rapidly recover baseline neurologic status. Hypothermia is unnecessary in these patients and may result in discomfort and shivering. Spontaneous hypothermia is also least likely to develop in patients with brief events and rapid recoveries. There was then a general discussion about the methods of measuring body temperature. It was recognized that “body” temperature may not reflect brain temperature and that brain temperature is the most important (yet least measurable) variable. The accuracy of measurements (and interpretations) of oral, rectal, axillary, esophageal, and tympanic temperatures was discussed. There was no consensus on the best, most practical measure. The decision of which method to use is left to the individual practitioner. The International Guidelines 2000 state only that a “reliable means” of measuring temperature should be used. Treatment of fever

There was general consensus among panelists and audience members that the recommendation of close monitoring of temperature and aggressive treatment of fever after resuscitation from cardiac arrest should be a Class IIa recommendation. Methods of measuring temperature and the definition of fever were discussed. The means of determining temperature and the threshold for fever are left to the practitioner. The definition of aggressive treatment also is left to the practitioner. Guidelines for use of antipyretics and environmental “comfort” measures (eg, removing blankets) are applicable to most, if not all, patients. The decision to use cooling blankets, ice packs, and medications to stop shivering should be made on an individual basis. Induced hypothermia

Many audience participants thought there was enough evidence to recommend induced hypothermia as a treatment strategy (most likely Class IIb). A slightly greater number of participants, however, thought the evidence was indeterminate and that practitioners should await the completion of ongoing clinical trials. Dr Sterz (Vienna, Austria) discussed the randomized, multicenter European

APRIL 2001

37:4

ANNALS OF EMERGENCY MEDICINE

trial of induced hypothermia for postresuscitation management of comatose patients. Approximately one half of the anticipated 500 patients have been enrolled. The efficacy of this treatment will not be known until the trial is completed, but so far the treatment seems to be safe. The panel on postresuscitation management reviewed the proposed new guidelines from the Evidence Evaluation Conference. Testimony and critiques from panelists and audience members emphasized the original observations that permitting hypothermia in adults during the postresuscitation period was supported by weak, or at best fair, evidence from predominately small animal studies. The recommendation to treat fever aggressively was supported more by extrapolations from studies that had not addressed this specific question. Nevertheless, because of the consistency of results and homogeneity of the studies, the recommendations are Class IIa rather than Class IIb recommendations. Definite conclusions about induced hypothermia during the postresuscitation period were difficult to reach. This topic has not been studied to an extensive degree in humans. The key element (prospective, randomized, controlled studies in human beings) is lacking. Findings from the large-scale, European multicenter study of induced hypothermia are eagerly awaited. PROPOSED GUIDELINES

Hemodynamically stable patients after resuscitation in whom mild hypothermia (34°-37°C) spontaneously develops can be allowed to remain hypothermic (Class IIb). Closely monitor postresuscitation temperatures and treat fever aggressively (Class IIa). Actively induce mild hypothermia after resuscitation from cardiac arrest (Class Indeterminate).

Topic 3: Medications G E N E R A L S TAT E M E N T

Profound cardiovascular and hemodynamic derangements are experienced by patients in whom return of spontaneous circulation occurs after cardiopulmonarycerebral resuscitation. These derangements may range from states of hypovolemic and cardiogenic shock to the more frequently encountered vasodilatory shock state of systemic inflammatory response syndrome. The main goal of the continued postresuscitation phase of cardiovascular support is the complete re-establishment

S 1 8 7

POSTRESUSCITATION MANAGEMENT Schleien et al

of regional organ and tissue perfusion. Increasing blood pressure per se and attempts to boost indicators of tissue gas exchange (including cardiac index and mixed venous oxygen) with goal-directed hypervolemic or hyperdynamic circulatory resuscitation and hyperoxic ventilation have not improved survival in most critically ill patients in the post–cardiac arrest state.1,2 Notably these end points do not necessarily lead to the efficient resuscitation of heterogeneous, high- and low-flow, time-constant tissue beds, particularly the splanchnic circulation. With adequate ventilation and reperfusion, the acidemia that is frequently present during cardiac arrest improves spontaneously in most cases. But persistent unrecognized splanchnic hypoperfusion requires specific monitoring and targeted therapy. In addition to invasive hemodynamic monitoring with the use of pulmonary artery catheters (which remains controversial), splanchnic resuscitation should be directed by quantitative gastric tonometric measurement of the systemic-to-gastric mucosal PCO2 gradient (PCO2 gap). Targeted correction of the systemic-to-gastric PCO2 gap is an important adjunct to invasive hemodynamic monitoring in the intensive care unit. The purpose is to maximize splanchnic perfusion during the early postresuscitation phase and avoid progression to multiorgan dysfunction syndrome. The modifications to the current advanced cardiac life support guidelines described in this report integrate these evolving understandings of the hemodynamic derangements encountered in patients who survive resuscitation. The recommendations are generally based on data derived from studies of posttraumatic and medical systemic inflammatory response and sepsis syndromes. Very few studies that deal specifically with hemodynamic support after neurocerebral resuscitation from cardiac arrest have been published. The recognized limitations of direct generalization of these results to the postresuscitation state are indicated throughout this report. DOPAMINE 1992 Guidelines

The 1992 advanced cardiac life support guidelines endorse the use of dopamine as a single-agent vasopressor. This practice is of particular concern in view of a firm line of evidence suggesting an adverse effect of high-dose (>10 µg/kg per minute) dopamine therapy on splanchnic perfusion. Dopamine, in addition to functioning as a central neurotransmitter, is a potent peripheral autonomic dopamine and

S 1 8 8

adrenergic receptor agonist that works in a dose-dependent manner. In the dose range of 2 to 4 µg/kg per minute, it lacks an inotropic effect and has been demonstrated not to augment renosplanchnic perfusion. In doses of 5 to 10 µg/kg per minute, β1 and β2 inotropy predominates. Serotoninand dopaminergic-mediated venoconstriction are also noted in this dose range. In doses of 10 to 20 µg/kg/min, α receptor effects are noted with substantial systemic and splanchnic arteriolar vasoconstriction. In contrast, dobutamine is predominantly a β1-selective ventricular inotrope that decreases sympathetic nervous tone while augmenting cardiac output. Dobutamine decreases or has little effect on systemic and pulmonary vascular resistance. Proposed addition or change

The use of dopamine as a single-agent inotrope or vasoconstrictor is associated with significant adverse effects on splanchnic perfusion as measured by mucosal perfusion indices and hepatic lactate/pyruvate markers. Avoid the use of high-dose dopamine as a single-agent vasopressor in hypotensive patients. Use of dopamine in combination with other agents, including dobutamine, should remain an option for management of postresuscitation shock. New science

The evidence that supported the proposed revisions consisted of 5 studies of good quality, 1 with level 1 evidence,3 2 with level 2 evidence,4,5 and 2 with level 3 evidence.6,7 Four studies, one8 of good quality and another9 of fair quality (both level 1 evidence), provided neutral evidence. An additional 2 studies10,11 with level 6 neutral evidence were of fair quality. Evaluation and debate

Marik and Mohedin3 compared the effects of dopamine and norepinephrine on systemic and splanchnic oxygen use in patients with hyperdynamic sepsis. Twenty septic patients with a cardiac index of more than 3.2 L/min/m2 and a mean arterial pressure (MAP) of less than 60 mm Hg or a systemic vascular resistance index (SVRI) of less than 1200 dyne·s/cm5/m2 were randomly assigned to receive an infusion of dopamine or norepinephrine. Therapy was titrated to achieve an MAP of more than 75 mm Hg. The hemodynamic profile, oxygen delivery, oxygen consumption (determined by indirect calorimetry), and gastric intramucosal pH (pHi; determined by gastric tonometry) were determined at baseline and 3 hours after the target MAP was achieved. Dopamine increased MAP largely by increasing cardiac index, whereas norepineph-

ANNALS OF EMERGENCY MEDICINE

37:4 APRIL 2001

POSTRESUSCITATION MANAGEMENT Schleien et al

rine increased MAP by increasing SVRI while maintaining cardiac index. Although oxygen delivery and oxygen consumption increased in both groups of patients, pHi increased significantly in patients who were treated with norepinephrine (from 7.16±0.07 at baseline to 7.23±0.07 3 hours after target MAP was achieved; P=.008) but decreased significantly in patients treated with dopamine (from 7.24±0.04 to 7.18±0.05; P<.02 for corrected 3-hour value; P<.001). Other than marked tachycardia in the dopamine group, other hemodynamic parameters were similar at 3 hours. The results of this study suggest that despite comparable hemodynamic recruitment in septic patients with both dopamine and norepinephrine, dopamine may cause an uncompensated increase in splanchnic oxygen requirements. This contention is supported by the findings of Ruokonen et al,12 who used selective splanchnic and hepatic cannulation in 10 septic patients. Infusion of dopamine resulted in a 65% increase in splanchnic oxygen delivery (DO2), whereas infusion of norepinephrine resulted in a 33% increase. There was not, however, a similar increase in oxygen extraction (as compared with oxygen delivery) in the dopamine group (16% increase in splanchnic oxygen consumption [VO2]), whereas the increase in oxygen extraction in the norepinephrine group (28%) was similar to the increase in oxygen delivery in that group. This difference between the increases in DO2 and VO2 in the dopamine group represents significant wasted oxygenation and splanchnic shunting with resultant mucosal hypoxia. This important randomized study, although small, raises significant concerns about the use of high-dose dopamine infusion in septic patients. The inference is that the impairment in gastric oxygenation would result in gut translocation and the potential for worsened multiorgan dysfunction syndrome. Additionally, Neviere et al5 studied 10 septic patients and evaluated systemic hemodynamics, oxygen transport, and gastric perfusion (pHi), using laser Doppler flowmetry to directly evaluate gastric perfusion. Administration of dobutamine or dopamine (5 µg/kg per minute) increased DO2. In response to dobutamine, gastric mucosal blood flow increased (+32%±14% from baseline; P<.05), gastric tonometered PCO2 and the gastric arterial PCO2 difference decreased (from 58±7 to 52±7 mm Hg; P<.05; and from 16.8±7.0 to 10.5±7.2 mm Hg; P<.05, respectively), and pHi increased (from 7.23±0.05 to 7.29±0.06; P<.05). In response to dopamine gastric mucosal blood flow decreased (–28%±8% from baseline; P<.05), and gastric tonometered PCO2, gastric arterial PCO2 difference, and calculated pHi were unchanged (58±7 vs 61±9 mm Hg;

APRIL 2001

37:4

ANNALS OF EMERGENCY MEDICINE

P=NS; 16.8±7.0 vs 18.9±8.4 mm Hg; P=NS; and 7.24±0.05 vs 7.21±0.06; P=NS, respectively). Thus, as in the study by Ruokonen et al,12 despite an increase in oxygen transport with both drugs, dobutamine and dopamine affected gastric mucosal perfusion differently in septic patients. Dopamine, in particular, resulted in a substantial reduction in gastric mucosal flow. A corollary to that study is the study by Hannemann et al,4 who prospectively studied 15 septic patients who were stabilized after operation with dobutamine and 10 septic patients who were stabilized with dobutamine and norepinephrine. The stabilizing catecholamine infusion was replaced in a stepwise manner by dopamine to achieve a similar MAP (dopamine doses: group 1, mean=22±15 µg/kg per minute, range=6-52 µg/kg per minute; group 2, mean=57±41 µg/kg per minute, range=15-130 µg/kg per minute). The change to dopamine resulted in increases in cardiac index (dobutamine-only group: 20%; P<.01; dobutamine and norepinephrine group: 33%; P<.01) and DO2 (dobutamineonly group: 19%; P<.01; dobutamine and norepinephrine group: 27%; P<.01). VO2, whether measured directly from respiratory gases or calculated by the cardiovascular Fick principle, did not change in either group with infusion of dopamine, whereas the oxygen extraction ratio decreased significantly in both groups with infusion of dopamine. Heart rate, pulmonary artery occlusion pressure, and pulmonary shunt fraction all increased with the infusion of dopamine. PaO2 decreased, but oxygen saturation remained stable in both groups with infusion of dopamine. Thus, short-term dopamine infusion in patients with hyperdynamic septic shock, despite producing higher global DO2 levels, was not superior to the infusion of dobutamine or the combination of dobutamine and norepinephrine in improving global systemic oxygenation exchange. This is probably because of extensive shunting. Shock may be resistant to the potent pressor and constrictor effects of single-agent dopamine therapy. Levy et al8 randomly assigned 30 patients with hyperdynamic, dopamine-resistant septic shock after volume loading and dopamine infusion (20 µg/kg per minute) to receive either norepinephrine and dobutamine or epinephrine alone titrated to obtain an MAP of more than 80 mm Hg. The investigators then measured the effect of the treatment on hemodynamics, lactate metabolism, and gastric tonometric variables. No statistical difference in systemic hemodynamic measurements was found between patients who received epinephrine alone and those patients who received norepinephrine and dobutamine.

S 1 8 9

POSTRESUSCITATION MANAGEMENT Schleien et al

After 6 hours, epinephrine infusion was associated with an increase in lactate levels (from 3.1±1.5 to 5.9±1.0 mmol/L; P<.01), whereas the infusion of norepinephrine and dobutamine was associated with a decrease in lactate levels (from 3.1±1.5 to 2.7±1.0 mmol/L; P<.05). The lactate/pyruvate ratio increased in the epinephrine-only group (from 15.5±5.4 to 21±5.8; P<.01) but did not change significantly in the norepinephrine and dobutamine group (13.8±5 vs 14±5.0). Gastric pHi decreased (from 7.29±0.11 to 7.16±0.07; P<.01) and the PCO2 gap (between tonometered PCO2 and arterial PCO2) increased (from 10±2.7 to 14±2.7 mm Hg; P<.01) in the epinephrine-only group. In the norepinephrine and dobutamine group, pHi was normalized within 6 hours (from 7.30±0.11 to 7.35±0.07; P<.01), as was the PCO2 gap (from 10±3.0 to 4±2.0 mm Hg; P<.01). The decrease in pHi and the increase in the lactate/pyruvate ratio in the epinephrine-only group were transient because this ratio returned to normal within 24 hours. The gastric mucosal acidosis and global metabolic changes observed in the patients treated with epinephrine are consistent with markedly inadequate although transient splanchnic oxygen use. The results of this study suggest that, even in patients treated preferentially with dopamine as a sole pressor for septic shock, a combination of norepinephrine and dobutamine improves pHi more than epinephrine, a well-established splanchnic vasoconstrictor. Results of several studies, including that by Maynard et al,6 strongly suggest the efficacy of dopexamine in preserving renosplanchnic perfusion in septic patients. This agent is not currently approved by the US Food and Drug Administration, although it is used in other areas of the world. Discussions of dopexamine were limited, and no recommendations on use of dopexamine were made. Proposed guidelines

Avoid the use of dopamine (high dose) as a single-agent vasopressor in hypotensive patients (Class III). If hypotension persists after filling pressure is optimized, inotropic (dobutamine), vasopressor (norepinephrine), or vasodilator (nitroprusside or nitroglycerin) therapy may be indicated (Class Indeterminate). (This recommendation was initially classified as a Class IIa recommendation at the Evidence Evaluation Conference. After extensive discussion the panelists decided to classify this recommendation as Indeterminate because of the lack of studies of these treatments during the postresuscitation period. The panel strongly suggested that more studies be performed to determine the most effective therapies for this vulnerable period.) The target of these therapies is

S 1 9 0

correction and maintenance of systemic and splanchnic perfusion as documented by invasive hemodynamic monitoring and possibly gastric tonometry. CORTICOSTEROIDS 1992 Guidelines

The use of glucocorticoid therapy in patients with septic shock has been the subject of the most enduring and substantially unresolved debates in circulatory critical care for almost one half of the century. The predominant controversies rage over the normal adrenal responses to sepsis, appropriate cortisol levels in the stressed state, concerns for the exacerbation of prevailing microbial infectious processes, and significant metabolic derangements. Conversely, it has been broadly recognized that the potentiated inflammatory state of the sepsis syndrome and enormous outpouring of proinflammatory mediators is independently deleterious and not amenable to modification with nonsteroidal anti-inflammatory agents or antibiotics alone. What is most apparent from these debates is that relative hypoadrenalism occurs even in the presence of normal and high cortisol levels. This probably reflects receptor and postreceptor modulation. In particular, the effect may be unrelated to the adrenal insufficiency and more likely is related to modulations of catecholamine receptor expression. Receptor hyporesponsiveness is a well-established phenomenon in the septic state. On the basis of data from a series of animal studies conducted in the late 1980s, Bone et al13 and other investigators conducted studies in septic patients using bolus “megadoses” (30 mg/kg) of methylprednisolone to abrogate the septic inflammatory response. These studies failed to demonstrate resolution of the pathophysiologic process or improvement in mortality rates, so this approach was abandoned for almost a decade. More recently, molecular mechanisms of shock have been elucidated; adrenergic receptor pharmacology has become better understood, and 2 studies that used lower, supraphysiologic doses of corticosteroids have been published. Both studies demonstrated impressive salutary effects by shortening the pressor-dependent phase of shock and limiting dysfunction in various organ systems. Proposed addition or change

Supraphysiologic doses of corticosteroids may be beneficial in patients with persistent vasopressor-resistant shock who are maximally treated with broad-spectrum or organism-specific antimicrobial therapy.

ANNALS OF EMERGENCY MEDICINE

37:4 APRIL 2001

POSTRESUSCITATION MANAGEMENT Schleien et al

New science

Data that supported and opposed the proposal were divided into 2 subgroups, studies of supraphysiologic doses of corticosteroids and studies of megadoses of steroids. The evidence that supported the proposal consisted of 2 studies of supraphysiologic doses of steroids14,15 with level 1 evidence that were of good14 and excellent15 quality. Three studies provided neutral or opposing evidence: 1 study16 of megadose steroid therapy with level 1 evidence was of excellent quality, and 2 studies13,16 with level 2 evidence were of fair quality. Evaluation and debate

In a prospective, randomized, double-blind, placebocontrolled study,16 41 patients with septic shock who required catecholamine therapy for more than 48 hours were randomly assigned to receive hydrocortisone (100 mg intravenously 3 times daily for 5 days) or placebo. Reversal of shock was defined by a stable systolic arterial pressure (>90 mm Hg) for 24 hours or more without catecholamine or fluid infusion. The median Simplified Acute Physiology Score was 14, which implied significant illness. Nineteen of 22 patients who were treated with hydrocortisone and 14 of 19 patients who were treated with placebo received epinephrine as the major inotrope (mean dose=0.4 µg/kg per minute in both groups) in addition to dopamine (3 µg/kg per minute). Shock was reversed in 15 patients who received hydrocortisone (68%) and 4 patients who received placebo (21%), a difference of 47% (95% confidence interval=17%-77%; P=.007). Serial invasive hemodynamic measurements were obtained for 5 days but did not reveal significant differences. At the 28-day follow-up examination, reversal of shock was higher in the hydrocortisone group (P=.005). The crude 28-day mortality rate was impressively different, but the difference was not statistically significant: 7 of 22 patients (32%) who were treated with hydrocortisone and 12 of 19 patients (63%) who received placebo had died by 28 days, a difference of 31% (95% confidence interval=1%-61%; P=.091). Reversal of shock within 7 days after the onset of corticosteroid therapy was a very strong predictor of survival. There were no significant differences between responders and nonresponders in outcome of a short corticotropin test, which supports the contention that the response reflects a relative hypoadrenal state. The rates of gastrointestinal bleeding and secondary infections did not differ between groups. This carefully performed study was limited by early termination at the time of interim analysis, but significance was

APRIL 2001

37:4

ANNALS OF EMERGENCY MEDICINE

demonstrated for the primary outcome of reversal of sepsis. The study, however, had insufficient power to determine a difference in crude 28-day mortality rates. A notable confounder was maximal responsiveness to cosyntropin, which differed significantly between groups. In 8 of 19 patients (42%) in the placebo group and 4 of 22 patients (18%) in the treatment group, the serum cortisol concentration did not increase more than 6 µg/dL in response to stimulation with low doses of cosyntropin. In a later study by Briegel et al,15 the time required for the reversal of shock was significantly reduced by the administration of supraphysiologic “stress” doses of hydrocortisone. A 100-mg bolus of hydrocortisone was administered within 30 minutes after the onset of shock and followed by infusion of hydrocortisone at a rate of 0.18 mg/kg per hour with shock reversal, the rate of infusion was reduced to 0.08 mg/kg per hour for 6 days. Forty consecutive patients with septic shock who were receiving vasopressor support but not positive inotropes were randomly assigned to receive hydrocortisone or placebo. Hydrocortisone significantly reduced the time to cessation of vasopressor support. The median duration of vasopressor support was 2 days (first and third quartiles, 1 and 6 days, respectively) in the hydrocortisone group and 7 days (first and third quartiles, 3 and 19 days, respectively) in the placebo group (P=.005, Breslow test). There was a trend toward earlier resolution of organ dysfunction syndrome in the hydrocortisone group. Overall shock reversal and mortality rates were not significantly different. Physiologic parameters were dramatically and significantly improved in the hydrocortisone group over 5 days of follow-up: SVRI and MAP increased (area under the curve, t test, P<.001 for both), and the VO2 and DO2 indexes were lowered (P<.004 and P<.04, respectively). An increase in the serum concentration of sodium was the most common adverse outcome identified: 6 patients in the treatment group and 1 in the placebo group had a serum sodium concentration of more than 155 mmol/L with no obvious consequences. One patient in the treatment group had a nonfatal hemorrhage in the upper gastrointestinal tract. There was no difference between groups in the rate of complications caused by infections. Although the overall number of organ failures and the crude mortality rate did not differ between groups in this small study, the significant reduction in time to reversal of shock and the hemodynamic and gas exchange parameters that support it suggest the outcome to be consistent although less dramatic than in the study of Bollaert et al.14

S 1 9 1

POSTRESUSCITATION MANAGEMENT Schleien et al

Proposed guidelines

New science

Consistent evidence shows that corticosteroids can shorten the time to resolution of sepsis in patients who are pressor dependent and are being treated with antibiotics, although no studies with level 1 evidence have demonstrated an improvement in the rate of survival among these patients. Supraphysiologic doses of corticosteroids may be beneficial for patients with persistent vasopressorresistant shock who are treated with appropriate antimicrobial therapy (Class Indeterminate). (This recommendation was initially classified as a Class IIb recommendation at the Evidence Evaluation Conference. After extensive discussion, the panelists decided to classify this recommendation as Indeterminate because of the lack of studies of this treatment during the postresuscitation period. The panel strongly suggested that more studies be performed to study the most effective therapies for this vulnerable period.)

The proposed recommendation of continuous vasopressin infusion in patients with vasodilatory shock was supported by 4 studies17-20 with level 1 evidence that were of excellent quality and 1 study21 with level 3 evidence that was of excellent quality. No studies with neutral or opposing evidence were presented. In a patient who was successfully resuscitated from cardiac arrest but who later experienced the development of septicemia, 6.4 µg/min norepinephrine and 5.0 µg/min epinephrine were required to maintain a systolic arterial pressure of approximately 90 mm Hg.17 Systemic vascular resistance was consistent with vasodilatory shock; blood cultures showed infection with Acinetobacter calcoaceticus. Intravenous administration of vasopressin (0.04 U/min) immediately increased the patient’s response to vasopressor therapy, and cardiac output remained stable at 4.5 L/min. The administration of vasopressin was associated with an increase in urine output from 6 to more than 50 mL/h. Stepwise withdrawal of vasopressin resulted in a decrease in arterial pressure, which again required norepinephrine to maintain systolic arterial pressure at 90 to 100 mm Hg. Moreover, urine output decreased to 30 mL/h. At 15 hours the readministration of vasopressin again caused a vasopressor response that allowed discontinuation of norepinephrine. Six hours later systolic arterial pressure was maintained at approximately 105 mm Hg with use of vasopressin alone. This clinical observation prompted the authors to conduct a prospective, randomized trial of vasopressin in the treatment of vasodilatory shock after the placement of a left ventricular assist device.18 Vasopressin (0.1 U/min) increased MAP (from 57±4 to 84±2 mm Hg; P<.001) with the decreased administration of norepinephrine. In another study that was conducted in 11 of 145 patients who underwent general cardiac operation and later experienced the development of post-bypass vasodilatory shock (defined as an MAP<70 mm Hg, a cardiac index >2.5 L/min/m2, and norepinephrine dependence), vasodilatory shock was associated with inappropriately low serum concentrations of vasopressin (12.0±6.6 pg/mL), which reflected endogenous vasopressin deficiency.21 In these patients who were undergoing highrisk cardiac operations, replacement of vasopressin increased blood pressure and reduced catecholamine pressor requirements. Similar results with vasopressin were found in patients with refractory vasodilation after cardiopulmonary bypass operation for heart transplantation who were treated with combined amiodarone and

VASOPRESSIN: CONTINUOUS INFUSION OF VA S O P R E S S I N D U R I N G VA S O D I L AT O R Y S H O C K 1992 Guidelines

None. Proposed addition or change

Standard treatment of vasodilatory septic shock includes extracellular volume expansion and the administration of antibiotics, vasopressors, and drugs that increase myocardial contractility. The vasopressor action of inotropes and vasoconstrictors such as norepinephrine may be reduced in patients with vasodilatory shock; alternatives to adrenergic vasopressors may be useful in these patients. Immunomodulatory and unconventional anti-inflammatory therapies have been unsuccessful when used alone, mainly because of the highly complex and massive proinflammatory cytokine networks that modulate the systemic inflammatory response. There has been increasing recognition that the systemic inflammatory response state may be associated with a relative deficiency or resistance to vasopressin (antidiuretic hormone) and that this may in turn exacerbate the pressorresistant state. If hypotension or hypoperfusion persists after the filling pressure is optimized, inotropic (dobutamine), vasopressor (dopamine or norepinephrine), or vasodilator (nitroprusside or nitroglycerin) therapy may be indicated.

S 1 9 2

ANNALS OF EMERGENCY MEDICINE

37:4 APRIL 2001

POSTRESUSCITATION MANAGEMENT Schleien et al

angiotensin-converting enzyme inhibitor therapy.20 The basic mechanism of these beneficial effects may be the inappropriately low vasopressin plasma levels observed in vasodilatory shock, which are caused by impaired baroreflex-mediated secretion. Thus, continuous infusion of vasopressin may be beneficial when adrenergic vasopressors do not maintain or support systemic vascular resistance. The applicability of these data to patients who have had a cardiac arrest is indirect. The patients described in these clinical investigations were extremely sick and had hemodynamic derangements comparable to, if not precisely like, those that occur during the postresuscitation period. In a clinical study that evaluated perioperative hypotension refractory to common vasopressor therapy,18 51 consecutive patients who had undergone vascular operation and who had been treated with long-term angiotensinconverting enzyme inhibitor or angiotensin II–receptor antagonist therapy were studied. All patients received a standardized dose of an opioid-propofol anesthetic. Thirty-two of the 51 patients had at least 1 episode of hypotension, which responded to epinephrine or phenylephrine. In 10 other patients, systolic arterial pressure did not remain above 100 mm Hg for 1 minute, despite the administration of 3 bolus doses of ephedrine or phenylephrine. In these patients, the investigators injected a 1-mg bolus of terlipressin (an agonist of the vasopressin system); this bolus was repeated twice if necessary. In 8 patients, arterial pressure was restored with 1 injection of terlipressin; in the 2 other patients, 3 injections were necessary. One minute after the last injection of terlipressin, the systolic arterial pressure increased from 88±3 to 100±4 mm Hg; systolic arterial pressure reached 117±5 mm Hg (P=.001) 3 minutes after the injection and remained stable around this value. This increase in systolic arterial pressure was associated with significant changes in left ventricular end-diastolic area (17.9±2 vs 20.2±2.2 cm2; P=.003), end-systolic area (8.1±1.3 vs 9.6±1.5 cm2; P=.004), end-systolic wall stress (45±8 vs 66±12; P=.001), and heart rate (60±4 vs 55±3 beats/min; P=.001). Fractional area and velocity of fiber shortening did not change significantly. No additional injection of any vasopressor was required during the perioperative period, and no change in the ST segment was observed after the injection. The investigators concluded that terlipressin rapidly corrected refractory hypotension in patients who had undergone long-term therapy with antagonists of the renin-angiotensin system without impairing left ventricular function.

APRIL 2001

37:4

ANNALS OF EMERGENCY MEDICINE

The addition of vasopressin to the therapeutic armamentarium for the treatment of post–cardiac arrest septic shock is a significant advance. Physiologic replacement of vasopressin dramatically improves survival and potentiates pressor responsiveness. The direct applicability of this intervention must be evaluated in a prospective study of the post–cardiac arrest patient population before it can be classified as a Class I recommendation. Proposed guidelines

If vasodilatory shock is refractory to adrenergic vasopressor agents, a continuous infusion of vasopressin may be beneficial (Class Indeterminate). (This recommendation was initially classified as a Class IIa recommendation at the Evidence Evaluation Conference. After extensive discussion the panelists decided to classify this recommendation as indeterminate because of the lack of studies of this treatment during the postresuscitation period. The panel strongly suggested that more studies be performed to study the most effective therapies for this vulnerable period.) REFERENCES, TOPIC 1 1. Muizelaar JP, Marmarou A, Ward JD, et al. Adverse effects of prolonged hyperventilation in patients with severe head injury: a randomized clinical trial. J Neurosurg. 1991;75:731-739. 2. Obrist WD, Langfitt TW, Jaggi JL, et al. Cerebral blood flow and metabolism in comatose patients with acute head injury: relationship to intracranial hypertension. J Neurosurg. 1984;61:241-253. 3. Cold GE. Does acute hyperventilation provoke cerebral oligaemia in comatose patients after acute head injury? Acta Neurochir (Wien). 1996;89:100-106. 4. Buunk G, van der Hoeven JG, Meinders AE. Cerebrovascular reactivity in comatose patients resuscitated from a cardiac arrest. Stroke. 1997;28:1569-1573. 5. Muizelaar JP, van der Poel HG, Li ZC, et al. Pial arteriolar vessel diameter and CO2 reactivity during prolonged hyperventilation in the rabbit. J Neurosurg. 1988;69:923-927. 6. Safar P, Xiao F, Radovsky A, et al. Improved cerebral resuscitation from cardiac arrest in dogs with mild hypothermia plus blood flow promotion. Stroke. 1996;27:105-113. 7. Marion DW, Bouma GJ. The use of stable xenon-enhanced computed tomographic studies of cerebral blood flow to define changes in cerebral carbon dioxide vasoresponsivity caused by a severe head injury. Neurosurgery. 1991;29:869-873. 8. Skippen P, Seear M, Poskitt K, et al. Effect of hyperventilation on regional cerebral blood flow in head-injured children. Crit Care Med. 1997;25:1402-1409. 9. Sutton LN, McLaughlin AC, Dante S, et al. Cerebral venous oxygen content as a measure of brain energy metabolism with increased intracranial pressure and hyperventilation. J Neurosurg. 1990;73:927-932. 10. Yoshida K, Marmarou A. Effects of tromethamine and hyperventilation on brain injury in the cat. J Neurosurg. 1991;74:87-96. 11. Froman C. Adverse effects of low carbon dioxide tensions during mechanical over-ventilation of patients with combined head and chest injuries. Br J Anaesth. 1968;40:383-386. 12. Paul RL, Polanco O, Turney SZ, et al. Intracranial pressure responses to alterations in arterial carbon dioxide pressure in patients with head injuries. J Neurosurg. 1972;36:714-720. 13. Sheinberg M, Kanter MJ, Robertson CS, et al. Continuous monitoring of jugular venous oxygen saturation in head-injured patients. J Neurosurg. 1992;76:212-217. 14. Gopinath SP, Robertson CS, Contant CF, et al. Jugular venous desaturation and outcome after head injury. J Neurol Neurosurg Psychiatry. 1994;57:717-723.

S 1 9 3

POSTRESUSCITATION MANAGEMENT Schleien et al

15. Wilson DF, Pastuszko A, Schneiderman R, et al. Effect of hyperventilation on oxygenation of the brain cortex of neonates. Adv Exp Med Biol. 1992;316:341-346. 16. Ruta TS, Drummond JC, Cole DJ. The effect of acute hypocapnia on local cerebral blood flow during middle cerebral artery occlusion in isoflurane anesthetized rats. Anesthesiology. 1993;78:134-140. 17. Robertson CS, Contant CF, Gokaslan ZL, et al. Cerebral blood flow, arteriovenous oxygen difference, and outcome in head injured patients. J Neurol Neurosurg Psychiatry. 1992;55:594603. 18. Cold GE, Christensen MS, Schmidt K. Effect of two levels of induced hypocapnia on cerebral autoregulation in the acute phase of head injury coma. Acta Anaesthesiol Scand. 1981;25:397-401. 19. Cruz J, Jaggi JL, Hoffstad OJ. Cerebral blood flow and oxygen consumption in acute brain injury with acute anemia: an alternative for the cerebral metabolic rate of oxygen consumption? Crit Care Med. 1993;21:1218-1224. 20. Cruz J. An additional therapeutic effect of adequate hyperventilation in severe acute brain trauma: normalization of cerebral glucose uptake. J Neurosurg. 1995;82:379-385. 21. Lassen NA, Palvolgyi R. Cerebral steal during hypercapnia and the inverse reaction during hypocapnea observed by the 133 xenon technique in man [abstract]. Scand J Clin Lab Invest Suppl. 1968;102:XIII:D. 22. Cold GE. Measurements of CO2 reactivity and barbiturate reactivity in patients with severe head injury. Acta Neurochir (Wien). 1989;98:153-163. 23. Bouma GJ, Muizelaar JP. Cerebral blood flow, cerebral blood volume, and cerebrovascular reactivity after severe head injury. J Neurotrauma. 1992;9:S333-S348. 24. Cruz J, Miner ME, Allen SJ, et al. Continuous monitoring of cerebral oxygenation in acute brain injury: injection of mannitol during hyperventilation. J Neurosurg. 1990;73:725-730.

ADDITIONAL READINGS Bricolo A, Formenton A, Turella G, et al. Clinical and EEG effects of mechanical hyperventilation in acute traumatic coma. Eur Neurol. 1972;8:219-224. Bouma GJ, Muizelaar JP, Bandoh K, et al. Blood pressure and intracranial pressure-volume dynamics in severe head injury: relationship with cerebral blood flow. J Neurosurg. 1992;77:1519. Darby JM, Yonas H, Marion DW, et al. Local “inverse steal” induced by hyperventilation in head injury. Neurosurgery. 1988;23:84-88.

7. Kuboyama K, Safar P, Radovsky A, et al. Delay in cooling negates the beneficial effect of mild resuscitative cerebral hypothermia after cardiac arrest in dogs: a prospective, randomized study [see comment]. Crit Care Med. 1993;21:1348-1358. 8. Safar P, Xiao F, Radovsky A, et al. Improved cerebral resuscitation from cardiac arrest in dogs with mild hypothermia plus blood flow promotion. Stroke. 1996;27:105-113. 9. Chopp M, Chen H, Dereski MO, et al. Mild hypothermic intervention after graded ischemic stress in rats. Stroke. 1991;22:37-43. 10. Colbourne F, Corbett D. Delayed and prolonged post-ischemic hypothermia is neuroprotective in the gerbil. Brain Res. 1994;654:265-272. 11. Coimbra C, Wieloch T. Moderate hypothermia mitigates neuronal damage in the rat brain when initiated several hours following transient cerebral ischemia. Acta Neuropathol (Berl). 1994;87:325-331. 12. Colbourne F, Corbett D. Delayed postischemic hypothermia: a six month survival study using behavioral and histological assessments of neuroprotection. J Neurosci. 1995;15:7250-7260. 13. Busto R, Dietrich WD, Globus MY, et al. Postischemic moderate hypothermia inhibits CA1 hippocampal ischemic neuronal injury. Neurosci Lett. 1989;101:299-304. 14. Horn M, Schlote W, Henrich HA. Global cerebral ischemia and subsequent selective hypothermia: a neuropathological and morphometrical study on ischemic neuronal damage in cat. Acta Neuropathol (Berl). 1991;81:443-449. 15. Yli-Hankala A, Edmonds HL Jr, Jiang YD, et al. Outcome effects of different protective hypothermia levels during cardiac arrest in rats. Acta Anaesthesiol Scand. 1997;41:511-515. 16. Kawai K, Nakayama H, Tamura A. Limited but significant protective effect of hypothermia on ultra-early-type ischemic neuronal injury in the thalamus. J Cereb Blood Flow Metab. 1997;17:543-552. 17. Xiao F, Safar P, Radovsky A. Mild protective and resuscitative hypothermia for asphyxial cardiac arrest in rats. Am J Emerg Med. 1998;16:17-25. 18. Marion DW, Penrod LE, Kelsey SF, et al. Treatment of traumatic brain injury with moderate hypothermia. N Engl J Med. 1997;336:540-546. 19. Holzer M, Behringer W, Schorkhuber W, et al. Mild hypothermia and outcome after CPR. Hypothermia for Cardiac Arrest (HACA) Study Group. Acta Anaesthesiol Scand Suppl. 1997;111:55-58. 20. Bernard SA, Jones BM, Horne MK. Clinical trial of induced hypothermia in comatose survivors of out-of-hospital cardiac arrest. Ann Emerg Med. 1997;30:146-153.

Engel GL, Ferris EB, Logan M. Hyperventilation: analysis of clinical symptomatology. Ann Intern Med. 1947;27:683-704.

21. Frank SM, Fleisher LA, Breslow MJ, et al. Perioperative maintenance of normothermia reduces the incidence of morbid cardiac events: a randomized clinical trial [see comment]. JAMA. 1997;277:1127-1134.

Gotoh F. Meyer JS, Takagi Y. Cerebral effects of hyperventilation in man. Arch Neurol. 1965;12:410-423.

22. Baena RC, Busto R, Dietrich WD, et al. Hyperthermia delayed by 24 hours aggravates neuronal damage in rat hippocampus following global ischemia. Neurology. 1997;48:768-773.

Lundberg N, Kjallquist A, Bien C. Reduction of increased intracranial pressure by hyperventilation. Acta Psychiatr Scand. 1959;34:4-64.

23. Coimbra C, Boris-Moller F, Drake M, et al. Diminished neuronal damage in the rat brain by late treatment with the antipyretic drug dipyrone or cooling following cerebral ischemia. Acta Neuropathol (Berl). 1996;92:447-453.

Raichle ME, Posner JB, Plum F. Cerebral blood flow during and after hyperventilation. Arch Neurol. 1970;23:394-403.

REFERENCES, TOPIC 2 1. Busto R, Dietrich WD, Globus MY, et al. Small differences in intraischemic brain temperature critically determine the extent of ischemic neuronal injury. J Cereb Blood Flow Metab. 1987;7:729-738.

24. Coimbra C, Drake M, Boris-Moller F, et al. Long-lasting neuroprotective effect of postischemic hypothermia and treatment with an anti-inflammatory/antipyretic drug: evidence for chronic encephalopathic processes following ischemia. Stroke. 1996;27:1578-1585. 25. Ginsberg MD, Busto R. Combating hyperthermia in acute stroke: a significant clinical concern. Stroke. 1998;29:529-534. 26. Takino M, Okada Y. Hyperthermia following cardiopulmonary resuscitation [see comment]. Intensive Care Med. 1991;17:419-420.

2. Welsh FA, Sims RE, Harris VA. Mild hypothermia prevents ischemic injury in gerbil hippocampus. J Cereb Blood Flow Metab. 1990;10:557-563.

27. Gaussorgues P, Gueugniaud PY, Vedrinne JM, et al. Bacteremia following cardiac arrest and cardiopulmonary resuscitation. Intensive Care Med. 1988;14:575-577.

3. Safar P. Resuscitation from clinical death: pathophysiologic limits and therapeutic potentials. Crit Care Med. 1988;16:923-941.

28. Albrecht RF II, Wass CT, Lanier WL. Occurrence of potentially detrimental temperature alterations in hospitalized patients at risk for brain injury. Mayo Clin Proc. 1998;73:629-635.

4. Leonov Y, Sterz F, Safar P, et al. Mild cerebral hypothermia during and after cardiac arrest improves neurologic outcome in dogs. J Cereb Blood Flow Metab. 1990;10:57-70. 5. Leonov Y, Sterz F, Safar P, et al. Moderate hypothermia after cardiac arrest of 17 minutes in dogs: effect on cerebral and cardiac outcome. Stroke. 1990;21:1600-1606. 6. Sterz F, Safar P, Tisherman S, et al. Mild hypothermic cardiopulmonary resuscitation improves outcome after prolonged cardiac arrest in dogs [see comments]. Crit Care Med. 1991;19:379-389.

S 1 9 4

REFERENCES, TOPIC 3 1. Gattinoni L, Brazzi L, Pelosi P, et al. A trial of goal-oriented hemodynamic therapy in critically ill patients. SvO2 Collaborative Group. N Engl J Med. 1995;333:1025-1032. 2. Hayes MA, Timmins AC, Yau EH, et al. Elevation of systemic oxygen delivery in the treatment of critically ill patients. N Engl J Med. 1994;330:1717-1722.

ANNALS OF EMERGENCY MEDICINE

37:4 APRIL 2001

POSTRESUSCITATION MANAGEMENT Schleien et al

3. Marik PE, Mohedin M. The contrasting effects of dopamine and norepinephrine on systemic and splanchnic oxygen utilization in hyperdynamic sepsis. JAMA. 1994;272:1354-1357. 4. Hannemann L, Reinhart K, Grenzer O, et al. Comparison of dopamine to dobutamine and norepinephrine for oxygen delivery and uptake in septic shock. Crit Care Med. 1995;23:19621970. 5. Neviere R, Mathieu D, Chagnon JL, et al. The contrasting effects of dobutamine and dopamine on gastric mucosal perfusion in septic patients. Am J Respir Crit Care Med. 1996;154:1684-1688. 6. Maynard ND, Bihari DJ, Dalton RN, et al. Liver function and splanchnic ischemia in critically ill patients. Chest. 1997;111:180-187. 7. Oud L, Haupt MT. Persistent gastric intramucosal ischemia in patients with sepsis following resuscitation from shock. Chest. 1999;115:1390-1396. 8. Levy B, Bollaert PE, Charpentier C, et al. Comparison of norepinephrine and dobutamine to epinephrine for hemodynamics, lactate metabolism, and gastric tonometric variables in septic shock: a prospective, randomized study. Intensive Care Med. 1997;23:282-287. 9. Meier-Hellmann A, Reinhart K, Bredle DL, et al. Epinephrine impairs splanchnic perfusion in septic shock [see comments]. Crit Care Med. 1997;25:399-404. 10. Neviere R, Chagnon JL, Vallet B, et al. Dobutamine improves gastrointestinal mucosal blood flow in a porcine model of endotoxic shock. Crit Care Med. 1997;25:1371-1377. 11. Priebe HJ, Noldge GF, Armbruster K, et al. Differential effects of dobutamine, dopamine, and noradrenaline on splanchnic haemodynamics and oxygenation in the pig. Acta Anaesthesiol Scand. 1995;39:1088-1096. 12. Ruokonen E, Takala J, Kari A, et al. Regional blood flow and oxygen transport in septic shock. Crit Care Med. 1993;21:1296-1303. 13. Bone RC, Fisher CJ Jr, Clemmer TP, et al. A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock. N Engl J Med. 1987;317:653-658. 14. Bollaert PE, Charpentier C, Levy B, et al. Reversal of late septic shock with supraphysiologic doses of hydrocortisone. Crit Care Med. 1998;26:645-650. 15. Briegel J, Forst H, Haller M, et al. Stress doses of hydrocortisone reverse hyperdynamic septic shock: a prospective, randomized, double-blind, single-center study. Crit Care Med. 1999;27:723-732. 16. Bernard GR, Luce JM, Sprung CL, et al. High-dose corticosteroids in patients with the adult respiratory distress syndrome. N Engl J Med. 1987;317:1565-1570. 17. Argenziano M, Chen JM, Choudhri AF, et al. Management of vasodilatory shock after cardiac surgery: identification of predisposing factors and use of a novel pressor agent. J Thorac Cardiovasc Surg. 1998;116:973-980. 18. Argenziano M, Choudhri AF, Oz MC, et al. A prospective randomized trial of arginine vasopressin in the treatment of vasodilatory shock after left ventricular assist device placement. Circulation. 1997;96(suppl):II-286–II-290. 19. Landry DW, Levin HR, Gallant EM, et al. Vasopressin pressor hypersensitivity in vasodilatory septic shock. Crit Care Med. 1997;25:1279-1282. 20. Mets B, Michler RE, Delphin ED, et al. Refractory vasodilation after cardiopulmonary bypass for heart transplantation in recipients on combined amiodarone and angiotensin-converting enzyme inhibitor therapy: a role for vasopressin administration. J Cardiothorac Vasc Anesth. 1998;12:326-329. 21. Landry DW, Levin HR, Gallant EM, et al. Vasopressin deficiency contributes to the vasodilation of septic shock. Circulation. 1997;95:1122-1125.

APRIL 2001

37:4

ANNALS OF EMERGENCY MEDICINE

S 1 9 5