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  • 1. Pediatric Special Article Clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock: 2007 update from the American College of Critical Care Medicine* Joe Brierley, MD; Joseph A. Carcillo, MD; Karen Choong, MD; Tim Cornell, MD; Allan DeCaen, MD; Andreas Deymann, MD; Allan Doctor, MD; Alan Davis, MD; John Duff, MD; Marc-Andre Dugas, MD; Alan Duncan, MD; Barry Evans, MD; Jonathan Feldman, MD; Kathryn Felmet, MD; Gene Fisher, MD; Lorry Frankel, MD; Howard Jeffries, MD; Bruce Greenwald, MD; Juan Gutierrez, MD; Mark Hall, MD; Yong Y. Han, MD; James Hanson, MD; Jan Hazelzet, MD; Lynn Hernan, MD; Jane Kiff, MD; Niranjan Kissoon, MD; Alexander Kon, MD; Jose Irazusta, MD; John Lin, MD; Angie Lorts, MD; Michelle Mariscalco, MD; Renuka Mehta, MD; Simon Nadel, MD; Trung Nguyen, MD; Carol Nicholson, MD; Mark Peters, MD; Regina Okhuysen-Cawley, MD; Tom Poulton, MD; Monica Relves, MD; Agustin Rodriguez, MD; Ranna Rozenfeld, MD; Eduardo Schnitzler, MD; Tom Shanley, MD; Sara Skache, MD; Peter Skippen, MD; Adalberto Torres, MD; Bettina von Dessauer, MD; Jacki Weingarten, MD; Timothy Yeh, MD; Arno Zaritsky, MD; Bonnie Stojadinovic, MD; Jerry Zimmerman, MD; Aaron Zuckerberg, MD Background: The Institute of Medicine calls for the use of ters that implemented the 2002 guidelines reported best practice clinical guidelines and practice parameters to promote “best outcomes (hospital mortality 1%–3% in previously healthy, and 7%– practices” and to improve patient outcomes. 10% in chronically ill children). Early use of 2002 guidelines was Objective: 2007 update of the 2002 American College of Critical associated with improved outcome in the community hospital emer- Care Medicine Clinical Guidelines for Hemodynamic Support of gency department (number needed to treat 3.3) and tertiary Neonates and Children with Septic Shock. pediatric intensive care setting (number needed to treat 3.6); every Participants: Society of Critical Care Medicine members with hour that went by without guideline adherence was associated with special interest in neonatal and pediatric septic shock were a 1.4-fold increased mortality risk. The updated 2007 guidelines identified from general solicitation at the Society of Critical Care continue to recognize an increased likelihood that children with Medicine Educational and Scientific Symposia (2001–2006). septic shock, compared with adults, require 1) proportionally larger Methods: The Pubmed/MEDLINE literature database (1966 – quantities of fluid, 2) inotrope and vasodilator therapies, 3) hydro- 2006) was searched using the keywords and phrases: sepsis, cortisone for absolute adrenal insufficiency, and 4) ECMO for refrac- septicemia, septic shock, endotoxemia, persistent pulmonary hy- tory shock. The major new recommendation in the 2007 update is pertension, nitric oxide, extracorporeal membrane oxygenation earlier use of inotrope support through peripheral access until central (ECMO), and American College of Critical Care Medicine guide- access is attained. lines. Best practice centers that reported best outcomes were Conclusion: The 2007 update continues to emphasize early use of identified and their practices examined as models of care. Using age-specific therapies to attain time-sensitive goals, specifically a modified Delphi method, 30 experts graded new literature. Over recommending 1) first hour fluid resuscitation and inotrope therapy 30 additional experts then reviewed the updated recommenda- directed to goals of threshold heart rates, normal blood pressure, and tions. The document was subsequently modified until there was capillary refill <2 secs, and 2) subsequent intensive care unit he- greater than 90% expert consensus. modynamic support directed to goals of central venous oxygen Results: The 2002 guidelines were widely disseminated, trans- saturation >70% and cardiac index 3.3– 6.0 L/min/m2. (Crit Care Med lated into Spanish and Portuguese, and incorporated into Society of 2009; 37:666 – 688) Critical Care Medicine and AHA sanctioned recommendations. Cen- KEY WORDS: guidelines; sepsis; severe sepsis *See also p. 785. clinical practice parameters for the critical care prac- of Health. The remaining authors have not disclosed The American College of Critical Care Medicine titioner. New guidelines and practice parameters are any potential conflicts of interest. (ACCM), which honors individuals for their achieve- continually developed, and current ones are system- For information regarding this article, E-mail: ments and contributions to multidisciplinary critical atically reviewed and revised. carcilloja@ccm.upmc.edu care medicine, is the consultative body of the Society Dr. Brierley received meeting travel expenses from Copyright © 2009 by the Society of Critical Care of Critical Care Medicine (SCCM) that possesses rec- USCOM Ltd. Dr. Nadel has consulted, received hono- Medicine and Lippincott Williams & Wilkins ognized expertise in the practice of critical care. The raria, and study funding from Eli Lilly. Dr. Shanley has College has developed administrative guidelines and received a research grant from the National Institutes DOI: 10.1097/CCM.0b013e31819323c6 666 Crit Care Med 2009 Vol. 37, No. 2
  • 2. N eonatal and pediatric severe Table 1. American College of Critical Care Medicine guidelines for evidence-based medicine rating sepsis outcomes were already system for strength of recommendation and quality of evidence supporting the references improving before 2002 with Rating system for references the advent of neonatal and a Randomized, prospective controlled trial pediatric intensive care (reduction in b Nonrandomized, concurrent or historical cohort investigations mortality from 97% to 9%) (1– 4), and c Peer-reviewed, state of the art articles, review articles, editorials, or substantial were markedly better than in adults (9% case series compared with 28% mortality) (3). In d Nonpeer reviewed published opinions, such as textbook statements or official organizational publications 2002, the American College of Critical Rating system for recommendations Care Medicine (ACCM) Clinical Practice Level 1 Convincingly justifiable on scientific evidence alone Parameters for Hemodynamic Support of Level 2 Reasonably justifiable by scientific evidence and strongly supported by expert critical Pediatric and Neonatal Shock (5) were care opinion published, in part, to replicate the re- Level 3 Adequate scientific evidence is lacking but widely supported by available data and ported outcomes associated with imple- expert opinion mentation of “best clinical practices” (mortality rates of 0%–5% in previously healthy [6 – 8] and 10% in chronically ill iterative fashion until 10% of the task force gue shock. Maitland et al (10) demon- children with septic shock [8]). There are disagreed with any specific or general recom- strated a reduction in mortality from two purposes served by this 2007 update mendation. This process occurred during a malaria shock from 18% to 4% when of these 2002 clinical practice parame- 1-year period. Reviewers from the ACCM then albumin was used for fluid resuscitation ters. First, this 2007 document examines requested further modifications that were rather than crystalloid. Han et al reported and grades new studies performed to test considered for inclusion if supported by evi- an association between early use of prac- the utility and efficacy of the 2002 rec- dence and best practice. Grading of the liter- tice consistent with the 2002 guidelines ommendations. Second, this 2007 docu- ature and levels of recommendations were in the community hospital and improved ment examines and grades relevant new based on published ACCM criteria (Table 1). outcomes in newborns and children treatment and outcome studies to deter- (mortality rate 8% vs. 38%; number mine to what degree, if any, the 2002 RESULTS needed to treat [NNT] 3.3). Every hour guidelines should be modified. that went by without restoration of nor- Successful Dissemination, mal blood pressure for age and capillary METHODS Acceptance, Implementation, refill 3 secs was associated with a two- and Outcome of 2002 fold increase in adjusted mortality odds More than 30 clinical investigators and cli- Guidelines ratio (11). Ninis et al (12) similarly re- nicians affiliated with the Society of Critical ported an association between delay in Care Medicine who had special interest in he- The 2002 guidelines were initially dis- inotrope resuscitation and a 22.6-fold modynamic support of pediatric patients with tributed in the English language with of- increased adjusted mortality odds ratio in sepsis volunteered to be members of the “up- ficial sanctioning by the Society for Crit- meningococcal septic shock. In a ran- date” task force. Subcommittees were formed ical Care Medicine with publication in Critical Care Medicine. The main pediat- domized controlled study, Oliveira et al to review and grade the literature using the ric algorithm was included in the Pediat- (13) reported that use of the 2002 guide- evidence-based scoring system of the ACCM. ric Advanced Life Support (PALS) manual lines with continuous central venous ox- The literature was accrued, in part, by search- ing Pubmed/MEDLINE using the following published by the American Heart Associ- ygen saturation (ScvO2) monitoring, and keywords and phrases: sepsis, septicemia, sep- ation. In addition, the pediatric and new- therapy directed to maintenance of ScvO2 tic shock, endotoxemia, persistent pulmonary born treatment algorithms were pub- 70%, reduced mortality from 39% to hypertension (PPHN), nitric oxide (NO), and lished in whole or part in multiple 12% (NNT 3.6). In a before and after extracorporeal membrane oxygenation textbooks. The guidelines were subse- study, Lin et al (14) reported that imple- (ECMO). The search was narrowed to identify quently published in Spanish and Portu- mentation of the 2002 guidelines in a studies specifically relevant to children. Best guese allowing for dissemination in U.S. tertiary center achieved best practice practice outcomes were identified and de- much of the American continents. There outcome with a fluid refractory shock 28- scribed; clinical practice in these centers was have been 57 peer-reviewed publications day mortality of 3% and hospital mortal- used as a model. ity of 6% (3% in previously healthy chil- since 2002 that have cited these guide- The clinical parameters and guidelines dren; 9% in chronically ill children). This lines. Taken together these findings dem- were drafted and subsequently revised using a outcome matched the best practice out- onstrate academic acceptance and dis- modification of the Delphi method. Briefly, semination of the 2002 guidelines (Tables comes targeted by the 2002 guidelines the initial step included review of the litera- 2 and 3). (6 – 8). Similar to the experience of St. ture and grading of the evidence by topic- Many studies have tested the observa- Mary’s Hospital before 2002 (7), Sophia based subcommittees during a 6-month pe- riod. Subcommittees were formed according tions and recommendations of the 2002 Children’s Hospital in Rotterdam also re- to participant interest in each subtopic. The guidelines. These studies reported evi- cently reported a reduction in mortality update recommendations from each subcom- dence that the guidelines were useful and rate from purpura and severe sepsis from mittee were incorporated into the preexisting effective without any evidence of harm. 20% to 1% after implementation of 2002 2002 document by the task force chairperson. For example, Wills et al (9) demonstrated guideline-based therapy in the referral All members commented on the unified up- near 100% survival when fluid resuscita- center, transport system, and tertiary date draft, and modifications were made in an tion was provided to children with den- care settings (15). Both of these centers Crit Care Med 2009 Vol. 37, No. 2 667
  • 3. Table 2. American College of Critical Care Medicine hemodynamic definitions of shock itate placement of central lines and/or intubation. Multiple editorials and cohort Cold or warm shock Decreased perfusion manifested by altered decreased mental status, studies have since reported that the use capillary refill 2 secs (cold shock) or flash capillary refill (warm shock), diminished (cold shock) or bounding (warm of etomidate was associated with in- shock) peripheral pulses, mottled cool extremities (cold shock), creased severity of illness adjusted mor- or decreased urine output 1 mL/kg/h tality in adults and children with septic Fluid-refractory/ Shock persists despite 60 mL/kg fluid resuscitation (when shock. The 2007 update now states that dopamine-resistant appropriate) and dopamine infusion to 10 g/kg/min etomidate is not recommended for chil- shock dren with septic shock unless it is used in Catecholamine-resistant Shock persists despite use of the direct-acting catecholamines; a randomized controlled trial format. For shock epinephrine or norepinephrine Refractory shock Shock persists despite goal-directed use of inotropic agents, now, the majority of the committee uses vasopressors, vasodilators, and maintenance of metabolic atropine and ketamine for invasive pro- (glucose and calcium) and hormonal (thyroid, hydrocortisone, cedures in children with septic shock. insulin) homeostasis Little experience is available with ket- amine use in newborn septic shock and the committee makes no recommenda- tion in this population; 3) Since 2002, Table 3. Threshold heart rates and perfusion pres- and discussion of the new literature were cardiac output (CO) can be measured not sure mean arterial pressure-central venous pres- directed to the question of what changes, sure or mean arterial pressure-intra-abdominal only with a pulmonary artery catheter, if any, should be implemented in the up- but also with Doppler echocardiography, pressure for age date. The members of the committee or a pulse index contour cardiac output Mean Arterial were asked whether there are clinical catheter catheter, or a femoral artery Pressure-Central practices which the best outcome prac- thermodilution catheter. Titration of ther- Heart Venous Pressure tices are using in 2007 that were not apy to CO 3.3– 6.0 L/min/m2 remains the Threshold Rates Rate (bpm) (mm Hg) recommended in the 2002 guidelines and goal in patients with persistent catechol- should be recommended in the 2007 amine resistant shock in 2007 guidelines. Term newborn 120–180 55 guidelines? The changes recommended Up to 1 yr 120–180 60 Doppler echocardiography can also be were few. Most importantly, there was no Up to 2 yrs 120–160 65 used to direct therapies to a goal of su- Up to 7 yrs 100–140 65 change in emphasis between the 2002 perior vena cava (SVC) flow 40 mL/ Up to 15 yrs 90–140 65 guidelines and the 2007 update. The con- min/kg in very low birth weight (VLBW) tinued emphasis is directed to: 1) first bpm, beats per minute. infants; 4) There are several new poten- hour fluid resuscitation and inotrope Modified from The Harriet Lane Handbook. tial rescue therapies reported since the drug therapy directed to goals of thresh- Thirteenth Edition and National Heart, Lung, 2002 guidelines. In children, enoximone old heart rates (HR), normal blood pres- and Blood Institute, Bethesda. MD: Report of the and levosimendan have been highlighted second task force on blood pressure control in sure, and capillary refill 2 secs, and 2) subsequent intensive care unit hemody- in case series and case reports. Unlike children - 1987 (306, 307). vasopressin, which had been suggested by namic support directed to goals of ScvO2 70% and cardiac index 3.3– 6.0 L/min/ some as a vasoplegia rescue therapy, also used high flux continuous renal re- these agents are suggested by some as m2. New recommendations in the 2007 placement therapy (CRRT) and fresh frozen recalcitrant cardiogenic shock rescue update include the following: 1) The 2002 plasma infusion directed to the goal of nor- agents. In newborns, inhaled prostacyclin guidelines recommended not giving car- mal international normalized ratio (INR) and intravenous (IV) adenosine were re- diovascular agents until central vascular (prothrombin time). In a U.S. child health portedly successful in refractory PPHN. access was attained. This was because outcomes database (Kids’ Inpatient Data- The 2007 update recommends further there was and still is concern that admin- base or KID) analysis, hospital mortality evaluation of these new agents in appro- istration of peripheral vasoactive agents from severe sepsis was recently estimated priate patient settings; and 5) The 2002 (especially vasopressors) could result in to be 4.2% (2.3% in previously healthy chil- guidelines made no recommendation on peripheral vascular/tissue injury. How- dren, and 7.8% in children with chronic fluid removal. Although fluid resuscita- ever, after implementation of the 2002 illness) (16), a decrease compared with 9% tion remains the hallmark and first step guidelines, the literature showed that, de- in 1999 (4). Taken together, these studies of septic shock resuscitation, two cohort pending on availability of skilled person- indirectly and directly support the utility studies showed the importance of fluid nel, it could take two or more hours to and efficacy of implementation of the time- removal in fluid overloaded septic shock/ establish central access. Because mortal- sensitive, goal-directed recommendations multiple organ failure patients. The 2007 ity went up with delay in time to inotrope of the 2002 guidelines in the emergency/ update recommends that fluid removal drug use, the 2007 update now recom- delivery room and pediatric intensive care using diuretics, peritoneal dialysis, or mends use of peripheral inotropes (not unit/neonatal intensive care unit set- CRRT is indicated in patients who have vasopressors) until central access is at- tings. tained. The committee continues to rec- been adequately fluid resuscitated but ommend close monitoring of the periph- cannot maintain subsequent even-fluid New Major Recommendations eral access site to prevent peripheral balance through native urine output. in the 2007 Update vascular/tissue injury; 2) The 2002 guide- This can be done when such patients de- Because of the success of the 2002 lines made no recommendations on what velop new onset hepatomegaly, rales, or guidelines, the 2007 update compilation sedative/analgesic agent(s) to use to facil- 10% body weight fluid overload. 668 Crit Care Med 2009 Vol. 37, No. 2
  • 4. Literature and Best Practice Mortality from fluid-refractory, dopamine- understood. Most hemodynamic informa- Review resistant septic shock in this study (18%) tion is derived only from echocardio- was markedly reduced compared with graphic evaluation and there are few sep- Developmental Differences in the He- mortality in the 1985 study (58%) (29), in tic shock studies in this population. modynamic Response to Sepsis in New- which aggressive fluid resuscitation was Neonatology investigators often fold sep- borns, Children, and Adults. The predom- not used. Since 2002, investigators have tic shock patients into “respiratory dis- inant cause of mortality in adult septic used Doppler ultrasound to measure CO tress syndrome” and “shock” studies shock is vasomotor paralysis (17). Adults (34), and similarly reported that previ- rather than conduct septic shock studies have myocardial dysfunction manifested ously healthy children with meningococ- alone. Hence, the available clinical evidence as a decreased ejection fraction; however, cemia often had a low CO with a high on the hemodynamic response in prema- CO is usually maintained or increased by mortality rate, whereas CO was high and ture infants for the most part is in babies two mechanisms: tachycardia and re- mortality rate was low in septic shock with respiratory distress syndrome or duced systemic vascular resistance (SVR). related to catheter-associated blood shock of undescribed etiology. In the first Adults who do not develop this process to stream infections. 24 hrs after birth during the “transitional maintain CO have a poor prognosis (18, Neonatal septic shock can be compli- phase,” the neonatal heart must rapidly ad- 19). Pediatric septic shock is associated cated by the physiologic transition from just to a high vascular resistance state com- with severe hypovolemia, and children fetal to neonatal circulation. In utero, pared with the low resistance placenta. CO frequently respond well to aggressive vol- 85% of fetal circulation bypasses the and blood pressure may decrease when vas- ume resuscitation; however, the hemody- lungs through the ductus arteriosus and cular resistance is increased (40). However, namic response of fluid resuscitated vaso- foramen ovale. This flow pattern is main- the literature indicates that premature in- active-dependent children seems diverse tained by suprasystemic pulmonary vas- fants with shock can respond to volume compared with adults. Contrary to the cular resistance in the prenatal period. At and inotropic therapies with improved adult experience, low CO, not low SVR, is birth, inhalation of oxygen triggers a cas- stroke volume (SV), contractility, and blood associated with mortality in pediatric sep- cade of biochemical events that ulti- pressure (41–54). tic shock (20 –29). Attainment of the mately result in reduction in pulmonary Several other developmental consider- therapeutic goal of CI 3.3– 6.0 L/min/m2 vascular resistance and artery pressure ations influence shock therapy in the pre- may result in improved survival (21, 29). and transition from fetal to neonatal cir- mature infant. Relative initial deficien- Also contrary to adults, a reduction in culation with blood flow now being di- cies in the thyroid and parathyroid oxygen delivery rather than a defect in rected through the pulmonary circula- hormone axes have been reported and oxygen extraction, can be the major de- tion. Closure of the ductus arteriosus and can result in the need for thyroid hor- terminant of oxygen consumption in foramen ovale complete this transition. mone and/or calcium replacement.(55, children (22). Attainment of the thera- Pulmonary vascular resistance and artery 56) Hydrocortisone has been examined in peutic goal of oxygen consumption (VO2) pressures can remain elevated and the this population as well. Since 2002, ran- 200 mL/min/m2 may also be associated ductus arteriosus can remain open for domized controlled trials showed that with improved outcome (21). the first 6 wks of life, whereas the fora- prophylactic use of hydrocortisone on day It was not until 1998 that investiga- men ovale may remain probe patent for 1 of life reduced the incidence of hypo- tors reported patient outcome when ag- years. Sepsis-induced acidosis and hyp- tension in this population, (57) and a gressive volume resuscitation (60 mL/kg oxia can increase pulmonary vascular re- 7-day course of hydrocortisone reduced fluid in the first hour) and goal-directed sistance and thus arterial pressure and the need for inotropes in VLBW infants therapies (goal, CI 3.3– 6.0 L/min/m2 and maintain patency of the ductus arterio- with septic shock (58 – 60). Immature normal pulmonary capillary wedge pres- sus, resulting in PPHN of the newborn mechanisms of thermogenesis require at- sure) (21) were applied to children with and persistent fetal circulation. Neonatal tention to external warming. Reduced septic shock (29). Ceneviva et al (29) re- septic shock with PPHN can be associated glycogen stores and muscle mass for glu- ported 50 children with fluid-refractory with increased right ventricle work. De- coneogenesis require attention to main- ( 60 mL/kg in the first hour), dopamine- spite in utero conditioning, the thickened tenance of serum glucose concentration. resistant shock. The majority (58%) right ventricle may fail in the presence of Standard practices in resuscitation of showed a low CO/high SVR state, and systemic pulmonary artery pressures. De- preterm infants in septic shock use a 22% had low CO and low vascular resis- compensated right ventricular failure can more graded approach to volume resus- tance. Hemodynamic states frequently be clinically manifested by tricuspid re- citation and vasopressor therapy com- progressed and changed during the first gurgitation and hepatomegaly. Newborn pared with resuscitation of term neonates 48 hrs. Persistent shock occurred in 33% animal models of group B streptococcal and children. This more cautious ap- of the patients. There was a significant and endotoxin shock have also docu- proach is a response to anecdotal reports decrease in cardiac function over time, mented reduced CO, and increased pul- that preterm infants at risk for intraven- requiring addition of inotropes and vaso- monary, mesenteric, and SVR (35–39). tricular hemorrhage ( 30 wks gestation) dilators. Although decreasing cardiac Therapies directed at reversal of right can develop hemorrhage after rapid shifts function accounted for the majority of ventricle failure, through reduction of in blood pressure; however, some now patients with persistent shock, some pulmonary artery pressures, are com- question whether long-term neurologic showed a complete change from a low monly needed in neonates with fluid- outcomes are related to periventricular output state to a high output/low SVR refractory shock and PPHN. leukomalacia (a result of prolonged un- state (30 –33). Inotropes, vasopressors, The hemodynamic response in prema- der perfusion) more than to intraventric- and vasodilators were directed to main- ture, VLBW infants with septic shock ular hemorrhage. Another complicating tain normal CI and SVR in the patients. ( 32 wks gestation, 1000 g) is least factor in VLBW infants is the persistence Crit Care Med 2009 Vol. 37, No. 2 669
  • 5. of the patent ductus arteriosus. This can a HR 70 bpm or 150 bpm (67). Emer- Maintenance of MAP with norepinephrine occur because immature muscle is less gency department therapies should be di- has been shown to improve urine output able to constrict. The majority of infants rected toward restoring normal mental and creatinine clearance in hyperdy- with this condition are treated medically status, threshold HRs, peripheral perfu- namic sepsis (69). Producing a supranor- with indomethacin, or in some circum- sion (capillary refill 3 secs), palpable mal MAP above this point is likely not of stances with surgical ligation. Rapid ad- distal pulses, and normal blood pressure benefit (70). ministration of fluid may further increase for age (Table 3) (11). Orr et al reported Reduction in perfusion pressure below left to right shunting through the ductus that specific hemodynamic abnormalities the critical point necessary for adequate with ensuant pulmonary edema. in the emergency department were asso- splanchnic organ perfusion can also oc- One single-center randomized control ciated with progressive mortality (in pa- cur in disease states with increased intra- trial reported improved outcome with use renthesis); eucardia (1%) tachycardia/ abdominal pressure (IAP) such as bowel of daily 6-hr pentoxyfilline infusions in bradycardia (3%) hypotension with wall edema, ascites, or abdominal com- very premature infants with sepsis (61, capillary refill 3 secs (5%) normo- partment syndrome. If this increased IAP 62). This compound is both a vasodilator tension with capillary refill greater than 3 is not compensated for by an increase in and an anti-inflammatory agent. A Co- secs (7%) hypotension with capillary contractility that improves MAP despite chrane analysis agrees that this promis- refill greater than 3 secs (33%). Reversal the increase in vascular resistance, then ing therapy deserves evaluation in a mul- of these hemodynamic abnormalities us- splanchnic perfusion pressure is de- ticentered trial setting (63). ing ACCM/PALS recommended therapy creased. Therapeutic reduction of IAP was associated with a 40% reduction in (measured by intrabladder pressure) us- What Clinical Signs and mortality odds ratio regardless of the ing diuretics and/or peritoneal drainage Hemodynamic Variables Can be stage of hemodynamic abnormality at the for IAP 12 mm Hg, and surgical decom- Used to Direct Treatment of time of presentation (68). One member of pression for 30 mm Hg, results in res- Newborn and Pediatric Shock? the committee wishes to emphasize that toration of perfusion pressure and has these signs are important only if the pa- been shown to improve renal function in Shock can be defined by clinical vari- tients are considered ill. children with burn shock (71). ables, hemodynamic variables, oxygen In both neonates and children, shock Normative blood pressure values in utilization variables, and/or cellular vari- should be further evaluated and resusci- the VLBW newborn have been reassessed. ables; however, after review of the litera- tation treatment guided by hemodynamic A MAP 30 mm Hg is associated with ture, the committee continues to choose variables including perfusion pressure poor neurologic outcome and survival, to define septic shock by clinical, hemo- (mean arterial pressure [MAP] minus and is considered the absolute minimum dynamic, and oxygen utilization variables central venous pressure) and CO. As pre- tolerable blood pressure in the extremely only. This decision may change at the viously noted, blood flow (Q) varies di- premature infant (42). Because blood next update. For example, studies dem- rectly with perfusion pressure (dP) and pressure does not necessarily reflect CO, onstrate that blood troponin concentra- inversely with resistance (R). This is it is recommended that normal CO tions correlate well with poor cardiac mathematically represented by Q dP/R. and/or SVC flow, measured by Doppler function and response to inotropic sup- For the systemic circulation this is rep- echocardiography, be a primary goal as port in children with septic shock (64 – resented by CO (MAP central venous well (72– 82). 66). Lactate is recommended in adult pressure)/SVR. This relationship is im- Although perfusion pressure is used as septic shock laboratory testing bundles portant for organ perfusion. In the kid- a surrogate marker of adequate flow, the for both diagnosis and subsequent mon- ney, for example, renal blood flow previous equation shows that organ blood itoring of therapeutic responses. How- (mean renal arterial pressure mean flow (Q) correlates directly with perfusion ever, most adult literature continues to renal venous pressure)/renal vascular re- pressure and inversely with vascular re- define shock by clinical hypotension, and sistance. The kidney and brain have vaso- sistance. If the ventricle is healthy, an recommends using lactate concentration motor autoregulation, which maintains elevation of SVR results in hypertension to identify shock in normotensive adults. blood flow in low blood pressure (MAP or with maintenance of CO. Conversely, if For now the overall committee recom- renal arterial pressure) states. At some ventricular function is reduced, the pres- mends early recognition of pediatric sep- critical point, perfusion pressure is re- ence of normal blood pressure with high tic shock using clinical examination, not duced below the ability of the organ to vascular resistance means that CO is re- biochemical tests. Two members dissent maintain blood flow. duced. If the elevation in vascular resis- from this recommendation and suggest One goal of shock treatment is to tance is marked, the reduction in blood use of lactate as well. maintain perfusion pressure above the flow results in shock. Ideally, shock should be clinically di- critical point below which blood flow can- A CI between 3.3 and 6.0 L/min/m2 is agnosed before hypotension occurs by not be effectively maintained in individ- associated with best outcomes in septic clinical signs, which include hypother- ual organs. The kidney receives the sec- shock patients (21) compared with pa- mia or hyperthermia, altered mental sta- ond highest blood flow relative to its tients without septic shock for whom a CI tus, and peripheral vasodilation (warm mass of any organ in the body, and mea- above 2.0 L/min/m2 is sufficient (83). At- shock) or vasoconstriction with capillary surement of urine output (with the ex- tainment of this CO goal is often depen- refill 2 secs (cold shock). Threshold HR ception of patients with hyperosmolar dent on attaining threshold HRs. How- associated with increased mortality in states such as hyperglycemia which leads ever, if the HR is too high, then there is critically ill (not necessarily septic) in- to osmotic diuresis) and creatinine clear- not enough time to fill the coronary ar- fants are a HR 90 beats per minute ance can be used as an indicator of ade- teries during diastole, and contractility (bpm) or 160 bpm, and in children are quate blood flow and perfusion pressure. and CO will decrease. Coronary perfusion 670 Crit Care Med 2009 Vol. 37, No. 2
  • 6. may be further reduced when an unfavor- stress is too high due to an increased ing the effectiveness of shock therapies. able transmural coronary artery filling end-diastolic ventricular pressure and di- The SVC flow approximates blood flow pressure is caused by low diastolic blood astolic volume secondary to fluid over- from the brain. A value 40 mL/kg/min pressure (DBP) and/or high end-diastolic load, then a diuretic may be required to is associated with improved neurologic ventricular pressure. In this scenario, ef- improve SV by moving leftward on the outcomes and survival (78 – 82). ScvO2 forts should be made to improve coronary overfilled Starling function curve. The ef- saturation can be used in low birth perfusion pressure and reverse the tachy- fectiveness of these maneuvers will simi- weight infants but may be misleading in cardia by giving volume if the SV is low, larly be evidenced by improvement in the the presence of left to right shunting or an inotrope if contractility is low. Be- HR/systolic blood pressure shock index, through the patent ductus arteriosus. cause CO HR SV, therapies directed CO, and SVR along with improved distal Intravascular Access. Vascular access to increasing SV will often reflexively re- pulses, skin temperature, and capillary for fluid resuscitation and inotrope/ duce HR and improve CO. This will be refill. vasopressor infusion is more difficult to evident in improvement of the shock in- Shock should also be assessed and attain in newborns and children com- dex (HR/systolic blood pressure), as well treated according to oxygen utilization pared with adults. To facilitate a rapid as CO. Children have limited HR reserve measures. Measurement of CO and O2 approach to vascular access in critically compared with adults because they are consumption were proposed as being of ill infants and children, the American already starting with high basal HRs. For benefit in patients with persistent shock Heart Association and the American example, if SV is reduced due to endotox- because a CI between 3.3 and 6.0 Academy of Pediatrics developed neonatal in-induced cardiac dysfunction, an adult L/min/m2 and O2 consumption 200 resuscitation program and PALS guide- can compensate for the fall in SV by in- mL/min/m2 are associated with improved lines for emergency establishment of in- creasing HR two-fold from 70 to 140 survival (21). Low CO is associated with travascular support (85, 86). Essential bpm, but a baby cannot increase her HR increased mortality in pediatric septic age-specific differences include use of from 140 bpm to 280 bpm. Although shock (20 –29). In one study, children umbilical artery and umbilical venous ac- tachycardia is an important method for with fluid-refractory, dopamine-resistant cess in newborns, and rapid use of in- maintaining CO in infants and children, shock were treated with goal-directed traosseous access in children. Ultrasound the younger the patient, the more likely therapy (CI 3.3 and 6 L/min/m2) and guidance may have a role in the place- this response will be inadequate and the found to have improved outcomes com- ment of central lines in children. CO will fall. In this setting, the response pared with historical reports (29). Be- Fluid Therapy. Several fluid resuscita- to falling SV and contractility is to vaso- cause low CO is associated with increased tion trials have been performed since constrict to maintain blood pressure. In- O2 extraction, (22) ScvO2 saturation can 2002. For example, several randomized creased vascular resistance is clinically be used as an indirect indicator of trials showed that when children with identified by absent or weak distal pulses, whether CO is adequate to meet tissue mostly stage III (narrow pulse pressure/ cool extremities, prolonged capillary re- metabolic demand. If tissue oxygen deliv- tachycardia) and some stage IV (hypoten- fill, and narrow pulse pressure with rela- ery is adequate, then assuming a normal sion) World Health Organization classifi- tively increased DBP. The effective ap- arterial oxygen saturation of 100%, cation dengue shock received fluid proach for these children is vasodilator mixed venous saturation is 70%. As- resuscitation in the emergency depart- therapy with additional volume loading suming a hemoglobin concentration of ment, there was near 100% survival re- as vascular capacity is expanded. Vasodi- 10 g/dL and 100% arterial O2 saturation gardless of the fluid composition used (6, lator therapy reduces afterload and in- then a CI 3.3 L/min/m2 with a normal 9, 87, 88). In a randomized controlled creases vascular capacitance. This shifts oxygen consumption of 150 mL/min/m2 trial, Maitland et al (10) demonstrated a the venous compliance curve so that (O2 consumption CI [arterial O2 reduction in malaria septic shock mortal- more volume can exist in the right and content venous O2 content]) results in ity from 18% to 4% when albumin was left ventricles at a lower pressure. In this a mixed venous saturation of 70% be- used compared with crystalloid. The large setting, giving volume to restore filling cause 150 mL/min/m2 3.3 L/min/m2 randomized adult SAFE trial that com- pressure results in a net increase in end- [1.39 10 g/dL PaO2 0.003] 10 pared crystalloid vs. albumin fluid resus- diastolic volume (i.e., preload) and a [1 0.7]. In an emergency department citation reported a trend toward im- higher CO at the same or lower filling study in adults with septic shock, main- proved outcome (p 0.1) in septic shock pressures. Effective use of this approach tenance of SVC O2 saturation 70% by patients who received albumin (89). Pref- results in a decreased HR and improved use of blood transfusion to a hemoglobin erence for the exclusive use of colloid perfusion. of 10 g/dL and inotropic support to in- resuscitation was made based on a clini- At the other end of the spectrum, a crease CO, resulted in a 40% reduction cal practice position article from a group threshold minimum HR is also needed in mortality compared with a group in who reported outstanding clinical results because if the HR is too low then CO will whom MAP and central venous pressure in resuscitation of meningococcal septic be too low (CO HR SV). This can be were maintained at usual target values shock (5% mortality) both using 4% al- attained by using an inotrope that is also without attention to SVC O2 saturation bumin exclusively (20 mL/kg boluses a chronotrope. In addition to threshold (84). Since 2002, Oliveira et al (13) repro- over 5–10 mins) and intubating and ven- HRs, attention must also be paid to DBP. duced this finding in children with septic tilating all children who required greater If the DBP– central venous pressure is too shock reducing mortality from 39% to 12% than 40 mL/kg (7). In an Indian trial of low then addition of an inotrope/vaso- when directing therapy to the goal of ScvO2 fluid resuscitation of pediatric septic pressor agent such as norepinephrine saturation 70% (NNT 3.6). shock, there was no difference in out- may be required to improve diastolic cor- In VLBW infants, SVC blood flow mea- come with gelatin compared with crystal- onary blood flow. Conversely, if wall surement was reportedly useful in assess- loid (90). In the initial clinical case series Crit Care Med 2009 Vol. 37, No. 2 671
  • 7. that popularized the use of aggressive 10 g/dL to achieve ScvO2 70% is as- safely accomplished in the sedated, im- volume resuscitation for reversal of pedi- sociated with increased survival suggests mobilized patient. This step should be atric septic shock, a combination of crys- that this higher hemoglobin goal is war- considered in any patient who is not rap- talloid and colloid therapies was used ranted in this population. idly stabilized with fluid resuscitation and (91). Several new investigations exam- Fluid infusion is best initiated with peripherally administered inotropes. ined both the feasibility of the 2002 boluses of 20 mL/kg, titrated to assuring Ventilation also provides mechanical guideline recommendation of rapid fluid an adequate blood pressure and clinical support for the circulation. Up to 40% of resuscitation as well as the need for fluid monitors of CO including HR, quality of CO may be required to support the work removal in patients with subsequent oli- peripheral pulses, capillary refill, level of of breathing, and this can be unloaded by guria after fluid resuscitation. The 2002 consciousness, peripheral skin tempera- ventilation, diverting flow to vital organs. guideline recommended rapid 20 mL/kg ture, and urine output. Initial volume Increased intrathoracic pressure also re- fluid boluses over 5 mins followed by resuscitation commonly requires 40 60 duces left ventricular afterload that may assessment for improved perfusion or mL/kg but can be as much as 200 mL/kg be beneficial in patients with low CI and fluid overload as evidenced by new onset (28, 91, 97–104). Patients who do not high SVR. Ventilation may also provide rales, increased work of breathing, and respond rapidly to initial fluid boluses, or benefits in patients with elevated pulmo- hypoxemia from pulmonary edema, hep- those with insufficient physiologic re- nary vascular resistance. Mild hyperven- atomegaly, or a diminishing MAP central serve, should be considered for invasive tilation may also be used to compensate venous pressure. Emergency medicine hemodynamic monitoring. Monitoring for metabolic acidosis by altering the re- investigators reported that 20 mL/kg of filling pressures can be helpful to opti- spiratory component of acid-base bal- crystalloid or colloid can be pushed over mize preload and thus CO. Observation of ance. Caution must be exercised as exces- 5 mins, or administered via a pressure little change in the central venous pres- sive ventilation may impair CO, bag over 5 mins through a peripheral sure in response to a fluid bolus suggests particularly in the presence of hypovole- and/or central IV line (92). Ranjit et al that the venous capacitance system is not mia. Additional volume loading is often (93) reported improved outcome from overfilled and that more fluid is indi- necessary at this point. dengue and bacterial septic shock when cated. Observation that an increasing Sedation and ventilation also facilitate they implemented a protocol of aggres- central venous pressure is met with re- temperature control and reduce oxygen sive fluid resuscitation followed by fluid duced MAP central venous pressure consumption. Importantly but less com- removal using diuretics and/or peritoneal suggests that too much fluid has been monly, ventilation is required because of dialysis if oliguria ensued. In this regard, given. Large volumes of fluid for acute clinical and laboratory evidence of respi- Foland et al (94) similarly reported that stabilization in children have not been ratory failure, impaired mental state, or patients with multiple organ failure who shown to increase the incidence of the moribund condition. received CRRT when they were 10% acute respiratory distress syndrome (91, Sedation for Invasive Procedures or fluid overloaded had better outcomes 103) or cerebral edema (91, 104). In- Intubation. Airway and breathing can ini- than those who were 10% fluid over- creased fluid requirements may be evi- tially be managed according to PALS loaded. Similarly, two best outcome prac- dent for several days secondary to loss of guidelines using head positioning, and a tices reported routine use of CRRT to fluid from the intravascular compart- high flow oxygen delivery system. A re- prevent fluid overload while correcting ment when there is profound capillary port published since 2002 supports early prolonged INR with plasma infusion in leak (28). Routine fluid choices include management of dengue shock using high patients with purpura and septic shock crystalloids (normal saline or lactated flow nasal cannula O2/continuous posi- (7, 15). Ringers) and colloids (dextran, gelatin, or tive airway pressure (115). When intuba- The use of blood as a volume expander 5% albumin) (6, 105–114). Fresh frozen tion or invasive procedures are required, was examined in two small pediatric ob- plasma may be infused to correct abnor- patients are at risk of worsening hypoten- servational studies, but no recommenda- mal prothrombin time and partial throm- sion from the direct myocardial depres- tions were given by the investigators (95, boplastin time values, but should not be sant and vasodilator effects of induction 96). In the previously mentioned study by pushed because it may produce acute hy- agents as well as indirect effects due to Oliveira et al (13) reporting improved potensive effects likely caused by vasoac- blunting of endogenous catecholamine outcome with use of the 2002 ACCM tive kinins and high citrate concentra- release. Propofol, thiopental, benzodiaz- guidelines and continuous ScvO2 satura- tion. Because oxygen delivery depends on epines, and inhalational agents all carry tion monitoring, the treatment group re- hemoglobin concentration, hemoglobin these risks. Yamamoto (116) and others ceived more blood transfusions directed should be maintained at a minimum of (7, 15) suggest using ketamine with atro- to improvement of ScvO2 saturation to 10 g/dL (13, 84). Diuretics/peritoneal di- pine premedication for sedation and in- 70% (40% vs. 7%). This finding agrees alysis/CRRT are indicated for patients tubation in septic shock. Ketamine is a with the results of Rivers (84) who trans- who develop signs and symptoms of fluid central NMDA receptor blocker, which fused patients with a SVC oxygen satura- overload. blocks nuclear factor-kappa B transcrip- tion 70% to assure a hemoglobin of 10 Mechanical Ventilation. There are tion and reduces systemic interleukin-6 g/dL as part of goal-directed therapy several reasons to initiate intubation and production while maintaining an intact based on central venous oxygen satura- ventilation in relation to the hemody- adrenal axis, which in turn maintains tion. Although the members of the task namic support of patients with septic cardiovascular stability (117–125). Ket- force use conservative goals for blood shock. In practice, the first indication is amine can also be used as a sedation/ transfusion in routine critical illness, the usually the need to establish invasive he- analgesia infusion to maintain cardiovas- observations that for patients with septic modynamic monitoring. In uncoopera- cular stability during mechanical shock, transfusion to a goal hemoglobin tive, coagulopathic infants, this is most ventilation (126). Etomidate is popular as 672 Crit Care Med 2009 Vol. 37, No. 2
  • 8. an induction agent because it maintains and left ventricle work. The pulse index Inotropes cardiovascular stability through blockade contour cardiac output catheter estimates of the vascular K channel; however, global end-diastolic volume in the heart Dopamine (5–9 g/kg/min), dobut- even one dose used for intubation is in- (both chambers) and extravascular lung amine, or epinephrine (0.05– 0.3 g/kg/ dependently associated with increased water and can be used to assess whether min) can be used as first-line inotropic mortality in both children and adults preload is adequate. None of these tech- support. Dobutamine may be used when with septic shock, possibly secondary to niques is possible in neonates and smaller there is a low CO state with adequate or inhibition of adrenal corticosteroid bio- infants. Other noninvasive monitors under- increased SVR (29, 84, 153–165). Dobut- synthesis. Therefore, it is not recom- going evaluation in newborns and children amine or mid-dosage dopamine can be mended for this purpose (127–131). Only used as the first line of inotropic support include percutaneous venous oxygen satu- one member of the task force continues if supported by clinical and objective data ration, aortic ultrasound, perfusion index to support use of etomidate in pediatric (e.g., assessment of contractility by echo- (pulse-oximetry), near infrared spectros- septic shock with the caveat that stress cardiogram) when one of the initial goals copy, sublingual Pco2, and sublingual mi- is to increase cardiac contractility in pa- dose hydrocortisone be administered. Lit- tle has been published on the use of ket- crovascular orthogonal polarization spec- tients with normal blood pressure. How- amine or etomidate in newborns with troscopy scanning. All show promise; ever, children 12 months may be less shock so we cannot make recommenda- however, none have been tested in goal- responsive (161). Recent adult data raises tions for or against the use of these drugs directed therapy trials (145–152). the concern of increased mortality with in newborns. When intubation and venti- the use of dopamine (166). There is not a lation are required the use of neuromus- clear explanation for these observations. Cardiovascular Drug Therapy cular blocking agents should be consid- Possible explanations include the action ered. When considering the use of cardio- of a dopamine infusion to reduce the re- Intravascular Catheters and Monitor- lease of hormones from the anterior pi- vascular agents in the management of ing. Minimal invasive monitoring is neces- tuitary gland, such as prolactin, through infants and children with septic shock, sary in children with fluid-responsive stimulation of the DA2 receptor, which several important points need emphasis. shock; however, central venous access and can have important immunoprotective The first is that septic shock represents a arterial pressure monitoring are recom- effects, and inhibition of thyrotropin re- dynamic process so that the agents se- leasing hormone release. Adult data fa- mended in children with fluid-refractory shock. Maintenance of perfusion pressure lected and their infusion dose may have vors the use of norepinephrine as a first (MAP central venous pressure), or to be changed over time based on the line agent in fluid-refractory vasodilated (MAP IAP) if the abdomen is tense sec- need to maintain adequate organ perfu- (and often hypotensive) septic shock ondary to bowel edema or ascitic fluid, is sion. It is also important to recognize (167–170). Although the majority of considered necessary for organ perfusion that the vasoactive agents are character- adults with fluid-refractory, dopamine- (38). Echocardiography is considered an ized by varying effects on SVR and pul- resistant shock have high CO and low appropriate noninvasive tool to rule out the monary vascular resistance (i.e., vasodi- SVR, children with this condition pre- presence of pericardial effusion, evaluate lators or vasopressors), contractility (i.e., dominantly have low CO. contractility, and depending on the skills of inotropy) and HR (chronotropy). These Dobutamine- or dopamine-refractory the echocardiographer, check ventricular pharmacologic effects are determined by low CO shock may be reversed with epi- filling. Doppler echocardiography can be the pharmacokinetics of the agent and nephrine infusion (29, 171–174). Epi- used to measure CO and SVC flow. CO the pharmacodynamics of the patient’s nephrine is more commonly used in chil- 3.3 L/min/m2 6.0 L/min/m2 and SVC response to the agent. In critically ill sep- dren than in adults. Some members of flow 40 mL/kg/min in newborns are as- tic children, perfusion and function of the committee recommended use of low- sociated with improved survival and neuro- the liver and kidney are often altered, dose epinephrine as a first-line choice for logic function. Goal-directed therapy to leading to changes in drug pharmacoki- cold hypodynamic shock. It is clear that achieve an ScvO2 saturation 70% is asso- netics with higher concentrations ob- epinephrine has potent inotropic and ciated with improved outcome (13). To served than anticipated. Thus, the infu- chronotropic effects, but its effects on gain accurate measures of ScvO2, the tip of sion doses quoted in many textbooks are peripheral vascular resistance and the en- the catheter must be at or close to the docrine stress response may result in ad- approximations of starting rates and SVC-right atrial or inferior vena cava-right ditional problems. At lower infusion should be adjusted based on the patient’s atrial junction (132). A pulmonary artery doses ( 0.3 /kg/min) epinephrine has response. The latter is also determined by catheter, pulse index contour cardiac out- greater beta-2-adrenergic effects in the the pharmacodynamic response to the peripheral vasculature with little alpha- put catheter, or femoral artery thermodilu- tion catheter can be used to measure CO agent, which is commonly altered in sep- adrenergic effect so that SVR falls, partic- (133) in those who remain in shock despite tic patients. For example, patients with ularly in the skeletal musculature and therapies directed to clinical signs of per- sepsis have a well-recognized reduced re- skin. This may redirect blood flow away fusion, MAP-central venous pressure, sponse to alpha-adrenergic agonists that from the splanchnic circulation even ScvO2, and echocardiographic analyses is mediated by excess NO production as though blood pressure and CO increases. (134 –144). The pulmonary artery catheter well as alterations in the alpha-adrener- This effect of epinephrine likely explains measures the pulmonary artery occlusion gic receptor system. Similarly, cardiac the observation that epinephrine tran- pressure to help identify selective left ven- beta-adrenergic responsiveness may be siently reduces gastric intramucosal pH tricular dysfunction, and can be used to reduced by the effect of NO and other in adults and animals with hyperdynamic determine the relative contribution of right inflammatory cytokines. sepsis (175), but there are no data avail- Crit Care Med 2009 Vol. 37, No. 2 673
  • 9. able to evaluate whether gut injury does during adult septic shock (183). Nitrova- be discontinued at the first sign of ar- or does not occur with epinephrine use in sodilators can be titrated to the desired rhythmia, or hypotension caused by ex- children. Epinephrine stimulates glu- effect, but use of nitroprusside is limited cessively diminished SVR. Hypotension- coneogenesis and glycogenolysis, and in- if there is reduced renal function second- related toxicity can also be potentially hibits the action of insulin, leading to ary to the accumulation of sodium thio- overcome by beginning norepinephrine increased blood glucose concentrations. cyanate; use of nitroglycerin may also or vasopressin. Norepinephrine counter- In addition, as part of the stimulation of have limited utility over time through the acts the effects of increased cAMP in vas- gluconeogenesis, epinephrine increases depletion of tissue thiols that are impor- cular tissue by stimulating the alpha re- the shuttle of lactate to the liver as a tant for its vasodilating effect. Other va- ceptor resulting in vasoconstriction. substrate for glucose production (the sodilators that have been used in children Norepinephrine has little effect at the vas- Cori cycle). Thus, patients on epineph- include prostacyclin, pentoxifylline, cular 2 receptor. rine infusion have increased plasma lac- dopexamine, and fenoldopam (184 –189). Rescue from refractory shock has been tate concentrations independent of An alternative approach to improve described in case reports and series using changes in organ perfusion, making this cardiac contractility and lower SVR is two medications with type III phosphodi- parameter somewhat more difficult to in- based on the use of type III phosphodies- esterase activity. Levosimendan is a terpret in children with septic shock. terase inhibitors (PDEIs) (190 –196). This promising new medication that increases Ideally, epinephrine should be admin- class of agents, which includes milrinone Ca /actin/tropomyosin complex bind- istered by a secure central venous route, and inamrinone (formerly amrinone, but ing sensitivity and also has some type III but in an emergency it may be infused the name was changed to avoid confusion PDEI and adenosine triphosphate-sensi- through a peripheral IV route or through with amiodarone), has a synergistic effect tive K channel activity. Because one of an intraosseous needle while attaining with beta-adrenergic agonists since the the pathogenic mechanisms of endotox- central access. The American Heart Asso- latter agents stimulate intracellular cy- in-induced heart dysfunction is desensi- ciation/PALS guidelines for children rec- clic adenosine monophosphate (cAMP) tization of Ca /actin/tropomyosin com- ommends the initial use of epinephrine production, whereas the PDEIs increase plex binding (197–202), this drug allows by peripheral IV or interosseous for car- intracellular cAMP by blocking its hydro- treatment at this fundamental level of diopulmonary resuscitation or post- lysis. Because the PDEIs do not depend signal transduction overcoming the loss cardiopulmonary resuscitation shock, on a receptor mechanism, they maintain of contractility that characterizes septic and by the intramuscular route for ana- their action even when the beta-adrener- shock. Enoximone is a type III PDEI with phylaxis (176). Even though a common gic receptors are down-regulated or have 10 times more 1 cAMP hydrolysis inhi- perception, there is no data clarifying if reduced functional responsiveness. The bition than 2 cAMP hydrolysis inhibition the peripheral infiltration of epinephrine main limitation of these agents is their (203–205). Hence, it can be used to in- produces more local damage than ob- need for normal renal function (for mil- crease cardiac performance with less risk served with dopamine. The severity of rinone clearance) and liver function (for of undesired hypotension. local symptoms likely depends on the inamrinone clearance). Inamrinone and concentration of the vasoactive drug in- milrinone are rarely used in adults with Vasopressor Therapy fusion and the duration of the peripheral septic shock because catecholamine re- infiltration before being discovered. If pe- fractory low CO and high vascular resis- Dopamine remains the first-line vaso- ripheral infiltration occurs with any cat- tance is uncommon; however, this hemo- pressor for fluid-refractory hypotensive echolamine, its adverse effects may be dynamic state represents a major shock in the setting of low SVR. However, antagonized by local subcutaneous infil- proportion of children with fluid-refrac- there is some evidence that patients tration with phentolamine, 1–5 mg di- tory, dopamine-resistant shock. Fluid bo- treated with dopamine have a worse out- luted in 5 mL of normal saline. luses are likely to be required if inamri- come than those treated without dopa- none or milrinone are administered with mine (206) and that norepinephrine, Vasodilators full loading doses. Because milrinone and when used exclusively in this setting, inamrinone have long half lifes (1 10 leads to adequate outcomes (168). There When pediatric patients are normo- hrs depending on organ function) it can is also literature demonstrating an age- tensive with a low CO and high SVR, take 3–30 hrs to reach 90% of steady state specific insensitivity to dopamine (207– initial treatment of fluid-refractory pa- if no loading dose is used. Although rec- 216). Dopamine causes vasoconstriction tients consists of the use of an inotropic ommended in the literature some indi- by releasing norepinephrine from sympa- agent such as epinephrine or dobutamine viduals in the committee choose not to thetic vesicles as well as acting directly that tends to lower SVR. In addition, a use boluses of inamrinone or milrinone. on alpha-adrenergic receptors. Immature short-acting vasodilator may be added, This group administers the drugs as a animals and young humans ( 6 months) such as sodium nitroprusside or nitro- continuous infusion only. Other mem- may not have developed their full compo- glycerin to recruit microcirculation bers divide the bolus in five equal aliquots nent of sympathetic innervation so they (177–182) and reduce ventricular after- administering each aliquot over 10 mins have reduced releasable stores of norepi- load resulting in better ventricular ejec- if blood pressure remains within an ac- nephrine. Dopamine-resistant shock tion and global CO, particularly when ceptable range. If blood pressure falls, it commonly responds to norepinephrine or ventricular function is impaired. Orthog- is typically because of the desired vasodi- high-dose epinephrine (29, 217–219). onal polarizing spectroscopy showed that lation and can be reversed by titrated Some committee members advocate the addition of systemic IV nitroglycerin to (e.g., 5 mL/kg) boluses of isotonic crys- use of low-dose norepinephrine as a first- dopamine/norepinephrine infusion re- talloid or colloid. Because of the long line agent for fluid-refractory hypotensive stored tongue microvascular blood flow elimination half-life, these drugs should hyperdynamic shock. Based on experi- 674 Crit Care Med 2009 Vol. 37, No. 2
  • 10. mental and clinical data, norepinephrine nine vasopressin on clinically important care should be taken to not overtreat as is recommended as the first-line agent in outcomes such as mortality remains un- calcium toxicity may occur with elevated adults with fluid-refractory shock. If the certain. The Vasopressin and Septic concentrations. patient’s clinical state is characterized by Shock Trial, a randomized controlled Replacement with thyroid and/or hy- low SVR (e.g., wide pulse pressure with clinical trial that compared low-dose ar- drocortisone can also be lifesaving in DBP that is less than one-half the systolic ginine vasopressin with norepinephrine children with thyroid and/or adrenal in- pressure), norepinephrine is recom- in patients with septic shock, showed no sufficiency and catecholamine-resistant mended alone. Other experts have recom- difference between regimens in the 28- shock (29, 55, 242–260). Infusion therapy mended combining norepinephrine with day mortality primary end point (236). with triiodothyronine has been beneficial dobutamine, recognizing that dobut- The safety and efficacy of low-dose argi- in postoperative congenital heart disease amine is a potent inotrope that has in- nine vasopressin have yet to be demon- patients but has yet to be studied in chil- trinsic vasodilating action that may be strated in children with septic shock, and dren with septic shock (253). Hypothy- helpful to counteract excessive vasocon- await the results of an ongoing random- roidism is relatively common in children striction from norepinephrine. Improved ized controlled trial (237, 238). with trisomy 21 and children with central capillary and gut blood flow were ob- Glucose, Calcium, Thyroid, and Hy- nervous system pathology (e.g., pituitary served in animal and human studies with drocortisone Replacement. It is impor- abnormality). Unlike adults, children are norepinephrine plus dobutamine in com- tant to maintain metabolic and hormonal more likely to have absolute adrenal in- parison with high-dose dopamine or epi- homeostasis in newborns and children. sufficiency defined by a basal cortisol nephrine. Hypoglycemia can cause neurologic dev- 18 g/dL and a peak adrenocortico- Vasopressin has been shown to in- astation when missed. Therefore, hypo- tropic hormone (ACTH)-stimulated corti- crease MAP, SVR, and urine output in glycemia must be rapidly diagnosed and sol concentration 18 g/dL. Nonsurvi- patients with vasodilatory septic shock promptly treated. Required glucose infu- vors have exceedingly high ACTH/cortisol and hyporesponsiveness to catecholamines sion rates for normal humans are age ratios within the first 8 hrs of meningo- (167, 220 –229). Vasopressin’s action is specific but can be met by delivering a coccal shock (206). Aldosterone levels are independent of catecholamine receptor D10%-containing solution at mainte- also markedly depressed in meningococ- stimulation, and therefore its efficacy is nance fluid rates (8 mg/kg/min glucose in cemia (261). Patients at risk of inade- not affected by alpha-adrenergic receptor newborns, 5 mg/kg/min glucose in chil- quate cortisol/aldosterone production in down-regulation often seen in septic dren, and 2 mg/kg/min in adolescents). the setting of shock include children with shock. Terlipressin, a long acting form of Patients with liver failure will require purpura fulminans and Waterhouse- vasopressin, has been reported to reverse higher glucose infusion rates (up to 16 Friderichsen syndrome, children who vasodilated shock as well (228, 230). mg/kg/min). Hyperglycemia is also a risk previously received steroid therapies for Although angiotensin can also be used factor for mortality. Lin and Carcillo chronic illness, and children with pitu- to increase blood pressure in patients (239) reported that children with septic itary or adrenal abnormalities. Review of who are refractory to norepinephrine, its shock, who had hyperglycemia ( 140 the pediatric literature found case series clinical role is not as well defined (231). mg/dL) and an elevated anion gap, (251, 252) and randomized trials (242, Phenylephrine is another pure vasopres- showed resolution of their anion gap 243) that used “shock dose” hydrocorti- sor with no beta-adrenergic activity when insulin was added to their glucose sone in children. The first randomized (232). Its clinical role is also limited since regimen. This was associated with rever- controlled trial showed improved out- it may improve blood pressure but reduce sal of catabolism as measured by urinary come with hydrocortisone therapy in blood flow through its action to increase organic acids. Infants with metabolic dis- children with dengue shock. The second SVR. Vasopressors can be titrated to end ease are particularly vulnerable to cata- study was underpowered and showed no points of perfusion pressure (MAP-central bolic failure and must be treated with effect of hydrocortisone therapy on out- venous pressure) or SVR that promote appropriate glucose delivery, and when come in children with dengue shock. The optimum urine output and creatinine needed insulin to assure glucose uptake, reported shock dose of hydrocortisone is clearance (69, 71, 217, 218), but excessive during septic shock. It is important to 25 times higher than the stress dose (242, vasoconstriction compromising micro- note that insulin requirements decrease 243, 247, 248, 250 –252, 258, 259). At circulatory flow should be avoided. NO at approximately 18 hrs after the onset of present the committee makes no changes inhibitors and methylene blue are consid- shock. Infusion of insulin and glucose are from the 2002 recommendation. The ered investigational therapies (233–235). also effective inotropes. Two members of committee only recommends hydrocorti- Studies have shown an increased mortal- the task force preferred using D5%- sone treatment for patients with absolute ity with nonselective NO synthase inhib- containing solution for patients with hy- adrenal insufficiency (peak cortisol con- itors suggesting that simply increasing perglycemia. Greater than 90% of the centration attained after corticotropin blood pressure through excessive vaso- committee agreed with meeting glucose stimulation 18 g/dL) or adrenal- constriction has adverse effects (138). requirements and treating hyperglycemia pituitary axis failure and catecholamine- Low-dose arginine vasopressin (in doses with insulin. Hypocalcemia is a frequent, resistant shock. Some support the use of 0.04 units/kg/min) as an adjunctive reversible contributor to cardiac dysfunc- stress dose only whereas others support agent has short-term hemodynamic ben- tion as well (56, 240, 241). Calcium re- the use of shock dosage when needed. In efits in adults with vasodilatory shock. It placement should be directed to normal- the absence of any new studies shedding is not currently recommended for treat- ize ionized calcium concentration. One light on the subject since 2002, the dose ment of cardiogenic shock, hence it member of the task force did not agree can be titrated to resolution of shock should not be used without ScvO2/CO that calcium replacement should be using between 2 mg/kg and 50 mg/kg/day monitoring. The effect of low-dose argi- given for hypocalcemia. All agreed that as a continuous infusion or intermittent Crit Care Med 2009 Vol. 37, No. 2 675
  • 11. dosing if desired. The treatment should 1.7–2.2). An important liability of this fused to attempt to neutralize these ef- be weaned off as tolerated to minimize investigation relates to lack of illness se- fects. Hemolysis can be avoided, in part, potential long-term toxicities. verity data. Although steroids may have by using the proper-sized cannula for age Administration of prolonged hydro- been given preferentially to more severely and limiting ECMO total blood flow to no cortisone and fludrocortisone (6 mg/kg/ ill children, their use was associated with greater than 110 mL/kg/min. Additional day cortisol equivalent 7 days) had increased mortality. Steroid use was CO can be attained using inotrope/ been recommended for adults with do- linked to disseminated candidiasis in a vaspodilator therapies. pamine-resistant septic shock and rela- case report (269). The committee contin- Investigators also reported that the tive adrenal insufficiency (basal cortisol ues to maintain equipoise on the ques- use of high flux CRRT ( 35 mL/kg/h 18 g/dL with cortisol increment after tion of adjunctive steroid therapy for pe- filtration-dialysis flux), with concomitant corticotropin stimulation 9 g/dL) diatric sepsis (outside of classic adrenal FFP or antithrombotic protein C infusion (260); however, adult guidelines now rec- or hypophyseal pituitary axis (HPA) axis to reverse prolonged INR without causing ommend this therapy for any adult with insufficiency), pending prospective ran- fluid overload, reduced inotrope/vaso- dopamine-resistant septic shock. The domized clinical trials. pressor requirements in children with re- continuing debate on whether this Persistent Pulmonary Artery Hyper- fractory septic shock and purpura (7, 15, should similarly be an adjunctive therapy tension of the Newborn Therapy. Inhaled 300 –305). The basis of this beneficial ef- for pediatric sepsis will likely only be re- NO therapy is the treatment of choice for fect remains unknown. It could result solved with yet-to-be done pediatric tri- uncomplicated PPHN (270, 271). However, from prevention of fluid overload, clear- als. Since 2002, a randomized trial of a metabolic alkalinization remains an impor- ance of lactate and organic acids, binding 7-day course of 3 mg/kg/day of intermit- tant initial resuscitative strategy during of inflammatory mediators, reversal of tent hydrocortisone therapy for dopam- shock because PPHN can reverse when ac- coagulopathy, or some combination of ine-treated septic shock in premature ba- idosis is corrected (272). For centers with these actions. bies was performed. These babies had access to inhaled NO, this is the only selec- reduced dopamine requirements but no tive pulmonary vasodilator reported to be RECOMMENDATIONS improvement in mortality (58, 262, 264). effective in reversal of PPHN (270, 271, Unlike dexamethasone, which was associ- 273–278). Milrinone or inamrinone may be Pediatric Septic Shock ated with neurologic consequences in added to improve heart function as toler- premature babies (261), hydrocortisone ated (279 –281). ECMO remains the ther- Diagnosis: The inflammatory triad of did not cause similar complications in apy of choice for patients with refractory fever, tachycardia, and vasodilation are premature babies (263). PPHN and sepsis (282–285). New investiga- common in children with benign infec- Multiple pediatric studies conducted tions support use of inhaled iloprost (syn- tions (Fig. 1). Septic shock is suspected over the interval 1999 –2006 provide con- thetic analog of prostacyclin) or adenosine when children with this triad have a sistent evidence that children who suc- infusion as modes of therapy for PPHN change in mental status manifested as cumbed from septic shock exhibited (286 –291). irritability, inappropriate crying, drowsi- lower cortisol levels than those who sur- Extracorporeal Therapies. ECMO is ness, confusion, poor interaction with vived, and that septic shock nonsurvivors not routinely used in adults (with the parents, lethargy, or becoming unarous- had lower random plasma cortisol con- notable exception of the University of able. The clinical diagnosis of septic centrations compared with septic shock Michigan) (282). ECMO is a viable ther- shock is made in children who 1) have a survivors; the latter had lower random apy for refractory septic shock in neo- suspected infection manifested by hypo- plasma cortisol concentrations compared nates (283) and children because neo- thermia or hyperthermia, and 2) have with sepsis survivors (254, 255, 265–267). nates (approximately 80% survival) and clinical signs of inadequate tissue perfu- This effect is not attributable to inade- children (approximately 50% survival) sion including any of the following; de- quate ACTH adrenal stimulation; on the (292–295) have the same outcomes creased or altered mental status, pro- contrary, an opposite trend prevails, whether the indication for ECMO is re- longed capillary refill 2 secs (cold namely septic shock nonsurvivors exhibit fractory respiratory failure or refractory shock), diminished pulses (cold shock) high circulating ACTH concentrations shock from sepsis or not. It is also effec- mottled cool extremities (cold shock) or compared with septic shock survivors, tive in adult hantavirus victims with low flash capillary refill (warm shock), who in turn have higher circulating CO/high SVR shock (296, 297). Although bounding peripheral pulses, and wide ACTH concentrations compared with pa- ECMO survival is similar in pediatric pa- pulse pressure (warm shock) or decreased tients with sepsis. One retrospective co- tients with and without sepsis, throm- urine output 1 ml/kg/h. Hypotension is hort study using the Pediatric Health In- botic complications can be more com- not necessary for the clinical diagnosis of formation System database examined mon in sepsis. Efforts are warranted to septic shock; however, its presence in a factors associated with outcome in chil- reduce ECMO-induced hemolysis because child with clinical suspicion of infection dren with severe sepsis as operationally free heme scavenges NO, adenosine, and is confirmatory. identified by a combination of infection a disintegrin and metalloprotease with plus need for a vasoactive infusion and thrombospondin motifs-13 (ADAMTS-13; ABCs: The First Hour of mechanical ventilation (268). Among von Willebrand factor cleaving protease) Resuscitation (Emergency 6693 children meeting the definition of leading to microvascular thrombosis, re- Room Resuscitation) severe sepsis, mortality was 30% for chil- versal of portal blood flow and multiple dren who received steroids compared organ failure (298, 299). Nitroglycerin Goals: (Level III). Maintain or restore with 18% for those who did not (crude (NO donor), adenosine, and fresh frozen airway, oxygenation, and ventilation (Table odds ratio 1.9) (95% confidence interval plasma (FFP) (ADAMTS-13) can be in- 1); maintain or restore circulation, defined 676 Crit Care Med 2009 Vol. 37, No. 2
  • 12. ondary to a combination of parenchymal lung disease and/or inadequate respira- tory effort due to altered mental status. The decision to intubate and ventilate is based on clinical assessment of increased work of breathing, hypoventilation, or impaired mental status. Waiting for con- firmatory laboratory tests is discouraged. Up to 40% of CO is used for work of breathing. Therefore, intubation and me- chanical ventilation can reverse shock. If possible, volume loading and peripheral or central inotropic/vasoactive drug sup- port is recommended before and during intubation because of relative or absolute hypovolemia, cardiac dysfunction, and the risk of suppressing endogenous stress hormone response with agents that facil- itate intubation. Etomidate is not recom- mended. Ketamine with atropine pretreat- ment and benzodiazepine postintubation can be used as a sedative/induction regimen of choice to promote cardiovascular in- tegrity. A short-acting neuromuscular blocker can facilitate intubation if the provider is confident she/he can maintain airway patency. Circulation (Level II). Vascular access should be rapidly attained. Establish in- traosseous access if reliable venous access cannot be attained in minutes. Fluid re- suscitation should commence immedi- ately unless hepatomegaly/rales are present. Recall that rales may be heard in children with pneumonia as a cause of sepsis, so it does not always imply that Figure 1. Algorithm for time sensitive, goal-directed stepwise management of hemodynamic support the patient is fluid overloaded. If pneu- in infants and children. Proceed to next step if shock persists. 1) First hour goals—Restore and monia is suspected or confirmed, fluid maintain heart rate thresholds, capillary refill 2 sec, and normal blood pressure in the first resuscitation should proceed with careful hour/emergency department. Support oxygenation and ventilation as appropriate. 2) Subsequent monitoring of the child’s work of breath- intensive care unit goals—If shock is not reversed, intervene to restore and maintain normal perfusion ing and oxygen saturation. In the fluid- pressure (mean arterial pressure [MAP]-central venous pressure [CVP]) for age, central venous O2 refractory patient, begin a peripheral ino- saturation 70%, and CI 3.3, 6.0 L/min/m2 in pediatric intensive care unit (PICU). Hgb, hemo- trope (low-dose dopamine or epinephrine) globin; PICCO, pulse contour cardiac output; FATD, femoral arterial thermodilution; ECMO, extra- corporeal membrane oxygenation; CI, cardiac index; CRRT, continuous renal replacement therapy; IV, if a second peripheral IV/intraosseus intravenous; IO, interosseous; IM, intramuscular. catheter is in place, while establishing a central venous line. When administered through a peripheral IV/intraosseus cath- as normal perfusion and blood pressure; pressure and diastolic pressure to help eter, the inotrope should be infused ei- maintain or restore threshold HR. distinguish between low SVR (wide pulse ther as a dilute solution or with a second Therapeutic End Points (Level III). pressure due to low DBP) and high SVR carrier solution running at a flow rate to Capillary refill 2 secs, normal pulses (narrow pulse pressure). Temperature, assure that it reaches the heart in a with no differential between the quality of urine output, glucose, ionized calcium. timely fashion. Care must be taken to peripheral and central pulses, warm ex- Airway and Breathing (Level III). Air- reduce dosage if evidence of peripheral tremities, urine output 1 mL/kg/h, nor- way and breathing should be rigorously infiltration/ischemia occurs as alpha- mal mental status, normal blood pressure monitored and maintained. Lung compli- adrenergic receptor-mediated effects oc- for age (noninvasive blood pressure only ance and work of breathing may change cur at higher concentrations for epineph- reliable when pulses palpable), normal precipitously. In early sepsis, patients of- rine and dopamine. Central dopamine, glucose concentration, normal ionized ten have a respiratory alkalosis from cen- epinephrine, or norepinephrine can be calcium concentration. trally mediated hyperventilation. As sepsis administered as a first line drug as indi- Monitoring (Level III). Pulse oximeter, progresses, patients may have hypoxemia as cated by hemodynamic state when a cen- continuous electrocardiography, blood well as metabolic acidosis and are at high tral line is in place. It is generally appro- pressure and pulse pressure. Note pulse risk to develop respiratory acidosis sec- priate to begin central venous infusion Crit Care Med 2009 Vol. 37, No. 2 677
  • 13. and wait until a pharmacologic effect is Therapeutic End Points: (Level III). volumes of D10%) will not provide glu- observed before stopping the peripheral Capillary refill 2 secs, threshold HRs, cose delivery requirements. infusion. normal pulses with no differential be- Hemodynamic support (Level II). He- Fluid Resuscitation (Level II). Rapid tween the quality of the peripheral and modynamic support can be required for fluid boluses of 20 mL/kg (isotonic crys- central pulses, warm extremities, urine days in children with fluid-refractory do- talloid or 5% albumin) can be adminis- output 1 mL/kg/h, normal mental sta- pamine resistant shock. Children with tered by push or rapid infusion device tus, CI 3.3 and 6.0 L/min/m2 with catecholamine resistant shock can (pressure bag) while observing for signs normal perfusion pressure (MAP central present with low CO/high SVR, high CO/ of fluid overload (i.e., the development of venous pressure, or MAP IAP) for age, low SVR, or low CO/low SVR shock. Al- increased work of breathing, rales, gallop ScvO2 70%; maximize preload to maxi- though children with persistent shock rhythm, or hepatomegaly). In the ab- mize CI, MAP central venous pressure; commonly have worsening cardiac fail- sence of these clinical findings, repeated normal INR, anion gap, and lactate. ure, hemodynamic states may completely fluid boluses can be administered to as Monitoring (Level III). Pulse oximetry, change with time. A pulmonary artery, much as 200 mL/kg in the first hour. continuous electrocardiogram, continuous pulse index contour cardiac output, or Children commonly require 40 – 60 intra-arterial blood pressure, temperature femoral artery thermodilution catheter, mL/kg in the first hour. Fluid can be (core), urine output, central venous pres- or Doppler ultrasound should be used pushed with the goal of attaining normal sure/O2 saturation and/or pulmonary artery when poor perfusion, including reduced perfusion and blood pressure. Hypoglyce- pressure/O2 saturation, CO, glucose and urine output, acidosis, or hypotension mia and hypocalcemia should be cor- calcium, INR, lactate, and anion gap. persists despite use of hemodynamic rected. A D10%-containing isotonic IV Fluid Resuscitation (Level II). Fluid therapies guided by clinical examination, solution can be run at maintenance IV losses and persistent hypovolemia sec- blood pressure analysis, and arterial and fluid rates to provide age appropriate glu- ondary to diffuse capillary leak can con- Scv O 2 analysis. Children with cate- cose delivery and to prevent hypoglyce- tinue for days. Ongoing fluid replacement cholamine-resistant shock can respond to mia. should be directed at clinical end points a change in hemodynamic therapeutic Hemodynamic Support (Level II). including perfusion, central venous pres- regimen with resolution of shock. Ther- Central dopamine may be titrated sure, echocardiographic determination of apies should be directed to maintain through central venous access. If the end-diastolic volume, pulmonary capil- mixed venous/ScvO2 70%, CI 3.3 child has fluid refractory/dopamine resis- lary wedge pressure/end-diastolic volume L/min/m2 6.0 L/min/m2, and a normal tant shock, then central epinephrine can (when available), and CO. Crystalloid is perfusion pressure for age (MAP-central be started for cold shock (0.05– 0.3 g/ the fluid of choice in patients with hemo- venous pressure). kg/min) or norepinephrine can be ti- globin 10 g/dL. Red blood cell transfu- Shock with Low CI, Normal Blood trated for warm shock to restore normal sion can be given to children with hemo- Pressure, and High Systemic Vascular perfusion and blood pressure. globin 10 g/dL. FFP is recommended Resistance (Level II). This clinical state is Hydrocortisone Therapy (Level III). If for patients with prolonged INR but as an similar to that seen in a child with car- a child is at risk of absolute adrenal in- infusion, not a bolus. After shock resus- diogenic shock in whom afterload reduc- sufficiency or adrenal pituitary axis fail- citation, diuretics/peritoneal dialysis/ tion is a mainstay of therapy designed to ure (e.g., purpura fulminans, congenital high flux CRRT can be used to remove improve blood flow by reducing ventric- adrenal hyperplasia, prior recent steroid fluid in patients who are 10% fluid over- ular afterload and thus increasing ven- exposure, hypothalamic/pituitary abnor- loaded and unable to maintain fluid bal- tricular emptying. Thus, nitroprusside or mality) and remains in shock despite epi- ance with native urine output/extrarenal nitroglycerin is first line vasodilators in nephrine or norepinephrine infusion, losses. patients with epinephrine-resistant septic then hydrocortisone can be administered Elevated lactate concentration and an- shock and normal blood pressure. If cya- ideally after attaining a blood sample for ion gap measurement can be treated by nide or isothiocyanate toxicity develops subsequent determination of baseline assuring both adequate oxygen delivery from nitroprusside, or methemoglobin cortisol concentration. Hydrocortisone and glucose utilization. Adequate oxygen toxicity develops from nitroglycerin, or may be administered as an intermittent delivery (indicated by a ScvO2 70%) can there is a continued low CO state, then be achieved by attaining hemoglobin 10 the clinician should substitute milrinone or continuous infusion at a dosage which g/dL and CO 3.3 L/min/m2 using ade- or inamrinone. As noted above, the long may range from 1–2 mg/kg/day for stress quate volume loading and inotrope/ elimination half-life of these drugs can coverage to 50 mg/kg/day titrated to re- vasodilator support when needed (as de- lead to slowly reversible toxicities (hypo- versal of shock. scribed below). Appropriate glucose tension, tachyarrhythmias, or both) par- delivery can be attained by giving a D10% ticularly if abnormal renal or liver func- Stabilization: Beyond the First containing isotonic IV solution at fluid tion exists. Such toxicities can be Hour (Pediatric Intensive Care maintenance rate. Appropriate glucose reversed, in part, with norepinephrine or Unit Hemodynamic Support) uptake can be attained in subsequently vasopressin infusion. Additional volume hyperglycemic patients by titrating an in- loading may be necessary to prevent hy- Goals: (Level III). Normal perfusion; sulin infusion to reverse hyperglycemia potension when loading doses of milri- capillary refill 2 secs, threshold HRs. (keep glucose concentration 150 mg/ none or inamrinone are used. Levosi- perfusion pressure (MAP central venous dL) while carefully monitoring to avoid mendan and enoximone may have a role pressure, or MAP IAP) appropriate for hypoglycemia (keep glucose concentra- in recalcitrant low CO syndrome. Thyroid age. ScvO2 70%; CI 3.3 L/min/m2 and tion 80 mg/dL). The use of lesser glu- replacement with triiodothyronine is 6.0 L/min/m2. cose infusion rates (e.g., D5% or lower warranted for thyroid insufficiency, and 678 Crit Care Med 2009 Vol. 37, No. 2
  • 14. hydrocortisone replacement can be war- ECMO becomes an important alternative ABCs: The First Hour of ranted for adrenal or hypothalamic- to consider. Currently, however, the ex- Resuscitation (Delivery Room pituitary-adrenal axis insufficiency. pected survival with ECMO is no greater Resuscitation) Shock with Low CI, Low Blood Pres- than 50%. If the clinician suspects that sure, and Low Systemic Vascular Resis- outcome will be better with ECMO, flows Goals: (Level III). Maintain airway, ox- tance (Level II). Norepinephrine can be greater than 110 mL/kg/min should be ygenation, and ventilation; restore and added to epinephrine to increase DBP and discouraged as they may be associated maintain circulation, defined as normal SVR. Once an adequate blood pressure is with hemolysis. Measure free hemoglobin perfusion and blood pressure; maintain achieved, dobutamine, type III PDEI (par- and maintain concentration 10 g/dL neonatal circulation; and maintain ticularly enoximone, which has little va- by using adequate catheter, circuit, and threshold HRs. sodilatory properties), or levosimendan oxygenator sizes for age. Calcium con- Therapeutic End Points (Level III). can be added to norepinephrine to im- centration should be normalized in the Capillary refill 2 secs, normal pulses prove CI and ScvO2. Thyroid replacement with no differential in quality between red blood cell pump prime (usually re- with triiodothyronine is warranted for peripheral and central pulses, warm ex- quires 300 mg CaCl2 per unit of packed thyroid insufficiency, and hydrocortisone tremities, urine output 1 mL/kg/h, nor- red blood cells). Additional venous access replacement is warranted for adrenal or mal mental status, normal blood pressure may be required if ECMO flow is 110 hypothalamic-pituitary-adrenal axis in- for age, normal glucose, and calcium mL/kg/min with a negative pressure 25 sufficiency. concentrations. mm Hg. This may require the addition of Shock with High CI and Low Systemic Difference in preductal and postductal intrathoracic drainage as well. Cannula Vascular Resistance (Level II). When ti- O2 saturation 5%. placement should be checked using both 95% arterial oxygen saturation. tration of norepinephrine and fluid does chest radiograph and ultrasound guid- Monitoring (Level III). Temperature, not resolve hypotension, then low dose ance. High flux CRRT ( 35 mL/kg/h) preductal and postductal pulse oximetry, vasopressin, angiotensin, or terlipressin should also be considered, particularly in intra-arterial (umbilical or peripheral) can be helpful in restoring blood pres- patients at risk for fluid overload, with blood pressure, continuous electrocar- sure; however, these potent vasocon- strictors can reduce CO, therefore it is septic shock and purpura. This extracor- diogram, blood pressure, arterial pH, recommended that these drugs are used poreal therapy can reduce inotrope/ urine output, and glucose, ionized cal- with CO/ScvO2 monitoring. In this sit- vasopressor needs within 6 hrs of use. cium concentration. uation, additional inotropic therapies Airway and Breathing (Level III). Air- may be required, such as low-dose epi- Newborn Septic Shock way patency and adequate oxygenation nephrine or dobutamine, or the vaso- and ventilation should be rigorously pressor infusion may be reduced. Terli- Diagnosis. Septic shock should be sus- monitored and maintained. The decision pressin is a longer-acting drug than pected in any newborn with tachycardia, to intubate and ventilate is based on clin- angiotensin or vasopressin so toxicities ical diagnosis of increased work of respiratory distress, poor feeding, poor are more long acting. As with other breathing, inadequate respiratory effort, tone, poor color, tachypnea, diarrhea, or forms of severe shock, thyroid hormone marked hypoxemia, or a combination of reduced perfusion, particularly in the or adrenocortical replacement therapy these abnormalities. Volume loading is presence of a maternal history of chorio- may be added for appropriate indica- often necessary before intubation and amnionitis or prolonged rupture of mem- tions. ventilation because positive pressure ven- branes (Fig. 2). It is important to distin- Refractory Shock (Level II). Children tilation can reduce preload. guish newborn septic shock from cardiogenic with refractory shock must be suspected to Circulation (Level III). Vascular access shock caused by closure of the patent can be rapidly attained according to neo- have one or more of the following some- ductus arteriosus in newborns with natal resuscitation program guidelines. times occult morbidities (treatment in pa- renthesis), including pericardial effusion ductal-dependent complex congenital Placement of an umbilical arterial and (pericardiocentesis), pneumothorax (thora- heart disease. Any newborn with shock venous line is preferred. centesis), hypoadrenalism (adrenal hor- and hepatomegaly, cyanosis, a cardiac Fluid Resuscitation (Level II). Fluid mone replacement), hypothyroidism (thy- murmur, or differential upper and boluses of 10 mL/kg can be administered, roid hormone replacement), ongoing lower extremity blood pressures or observing for the development of hepato- blood loss (blood replacement/hemosta- pulses should be started on prostaglan- megaly and increased work of breathing. sis), increased IAP (peritoneal catheter, din infusion until complex congenital Up to 60 mL/kg may be required in the or abdominal release), necrotic tissue (ni- heart disease is ruled out by echocar- first hour. Fluid should be infused with a dus removal), inappropriate source con- diographic analysis. Inborn errors of me- goal of attaining normal perfusion and trol of infection (remove nidus and use tabolism resulting in hyperammonemia or blood pressure. A D10%-containing iso- antibiotics with the lowest minimum in- hypoglycemia may simulate septic shock tonic IV solution run at maintenance rate hibitory concentration possible, prefera- and appropriate laboratory tests should will provide age appropriate glucose de- bly 1, use IV immunoglobulin for toxic be obtained to rule out these conditions. livery to prevent hypoglycemia. shock), excessive immunosuppression Newborn septic shock is typically accom- Hemodynamic Support (Level II). Pa- (wean immunesuppressants), or immune panied by increased pulmonary vascular tients with severe shock uniformly re- compromise (restore immune function; resistance and artery pressures. PPHN quire cardiovascular support during fluid e.g., white cell growth factors/transfusion can cause right ventricle failure with resuscitation. Although dopamine can be for neutropenic sepsis). When these po- right to left shunting at the atrial/ductal used as the first-line agent, its effect on tentially reversible causes are addressed, levels causing cyanosis. pulmonary vascular resistance should be Crit Care Med 2009 Vol. 37, No. 2 679
  • 15. natal circulation; ScvO2 70%; CI 3.3 L/min/m2; SVC flow 40 mL/kg/min. Therapeutic End points (Level III). Capillary refill 2 secs, normal pulses with no differential between peripheral and central pulses, warm extremities, urine output 1 mL/kg/h, normal men- tal status, normal blood pressure for age. 95% arterial oxygen saturation. 5% difference in preductal and post- ductal arterial oxygen saturation. ScvO2 70%. Absence of right-to-left shunting, tri- cuspid regurgitation, or right ventricular failure on echocardiographic analysis. Normal glucose and ionized calcium concentrations. SVC flow 40 mL/kg/min. CI 3.3 L/min/m2. Normal INR. Normal anion gap and lactate. Fluid overload 10%. Monitoring (Level III). Pulse oximetry, blood gas analysis, electrocardiogram, con- tinuous intra-arterial blood pressure, tem- perature, glucose and calcium concentra- tion, “ins and outs,” urine output, central venous pressure/O2 saturation, CO, SVC flow, INR, and anion gap and lactate. Fluid Resuscitation (Level II). Fluid losses and persistent hypovolemia sec- ondary to diffuse capillary leak can con- tinue for days. Ongoing fluid replacement should be directed at clinical end points, including perfusion and central venous pressure. Crystalloid is the fluid of choice in neonates with hemoglobin 12 g/dL. Packed red blood cells can be transfused Figure 2. Algorithm for time sensitive, goal-directed stepwise management of hemodynamic support in newborns with hemoglobin 12 g/dL. in newborns. Proceed to next step if shock persists. 1) First hour goals—Restore and maintain heart Diuretics or CRRT is recommended in rate thresholds, capillary refill 2 sec, and normal blood pressure in the (first hour), and 2) newborns who are 10% fluid overloaded Subsequent intensive care unit goals—Restore normal perfusion pressure (mean arterial pressure and unable to attain fluid balance with [MAP]-central venous pressure [CVP]), preductal and postductal O2 saturation difference 5%, and either central venous O2 saturation (ScvO2) 70%, superior vena cava (SVC) flow 40 ml/kg/min or native urine output/extrarenal losses. A cardiac index (CI) 3.3 L/min/m2 in neonatal intensive care unit (NICU). RDS, respiratory distress D10%-containing isotonic IV solution syndrome; NRP, Neonatal Resuscitation Program; PDA, patent ductus arteriosus; ECMO, extracorpo- run at maintenance rate can provide age real membrane oxygenation. appropriate glucose delivery to prevent hypoglycemia. Insulin infusion can be used to correct hyperglycemia. Diuretics considered. A combination of dopamine tion to produce a respiratory alkalosis can are indicated in hypervolemic patients to at low dosage ( 8 g/kg/min) and dobut- also be instituted until 100% O2 satura- prevent fluid overload. amine (up to 10 g/kg/min) is initially tion and 5% difference in preductal and Hemodynamic Support (Level II). A recommended. If the patient does not ad- postductal saturations are obtained. In- 5-day, 6-hr per day course of IV pentoxi- equately respond to these interventions, haled NO should be administered as the fylline can be used to reverse septic shock then epinephrine (0.05– 0.3 g/kg/min) first treatment when available. in VLBW babies. In term newborns with can be infused to restore normal blood PPHN, inhaled NO is often effective. Its pressure and perfusion. Stabilization: Beyond the First greatest effect is usually observed at 20 Persistent Pulmonary Hypertension Hour (Neonatal Intensive Care ppm. In newborns with poor left ventricle Therapy (Level II). Hyperoxygenate ini- Unit Hemodynamic Support) function and normal blood pressure, the tially with 100% oxygen and institute addition of nitrosovasodilators or type III metabolic alkalinization (up to pH 7.50) Goals: (Level III). Restore and main- phosphodiesterase inhibitors to epineph- with NaHCO3 or tromethamine until in- tain threshold HR; maintain normal per- rine (0.05– 0.3 g/kg/min) can be effec- haled NO is available. Mild hyperventila- fusion and blood pressure; maintain neo- tive but must be monitored for toxicities. 680 Crit Care Med 2009 Vol. 37, No. 2
  • 16. It is important to volume load based on ACKNOWLEDGMENTS TX), Steven E. Lucking, MD (Hershey, clinical examination and blood pressure PA), Lucy Lum, MD (Kuala Lampur, Ma- changes when using these systemic vaso- Approval Committee— Andrew Argent laysia), Kath Maitland (Kilif, Kenya), dilators. Triiodothyronine is an effective (South Africa), Anton (Indonesia), Ro- Michele Mariscalco, MD (Houston, TX), I. inotrope in newborns with thyroid insuf- naldo Arkader (Sao Paolo, Brazil), Debbie Matok (Hashomer, Israel), Cris Mangia ficiency. Norepinephrine can be effective Bills, RN (Pittsburgh, PA), Desmond J. (Sao Paolo, Brazil), F.O. Odetola (Ann for refractory hypotension but ScvO2 Bohn, MBBS (Toronto, Canada), Booy Arbor, MI), Jean-Christophe Mercier should be maintained 70%. An addi- (London, England), Robert Boxer, MD (Paris, France), Richard B. Mink (Los An- tional inotrope therapy should be added if (Roslyn, NY), George Briassoulis (Crete, geles, CA), M. Michelle Moss, MD (Little warranted. Hydrocortisone therapy can Greece), Joe Briely (London, England), Rock, AR), C. Munter (London, England), be added if the newborn has adrenal in- Richard Brilli, MD (Cincinnati, OH), Cyn- A.I. Murdoch (London, England), P.C. Ng sufficiency (defined by a peak cortisol af- thia W. Broner, MD (Columbus, OH), Tim (Hong Kong), Ninis (London, England), ter ACTH 18 g/dL, or basal cortisol Bunchman (Grand Rapids, MI), Warwick Daniel A. Notterman, MD (Newark, NJ), 18 g/dL in an appropriately volume- Butt (Melbourne, Australia), Hector Car- William Novotny (Greenville, NC), Clau- loaded patient requiring epinephrine). illo (Mexico City, Mexico), Juan Casado- dio Oliveira (Sao Paolo, Brasil), D. Os- The rescue use of vasopressin, terlipres- Flores, MD (Spain), Billy Casey (Dublin, born (Sydney, Australia), Kristan M. Out- sin, or angiotensin can be considered in Ireland), Leticia Castillo, MD (Boston, water, MD (Saginaw, MI), J.F. Padbury the presence of adequate CO, SVC flow, MA), Gary D. Ceneviva, MD (Hershey, (Providence, RI), Hector S. Pabon, MD and/or ScvO2 monitoring. PA), Karen Choong (Ontario, Canada), (Brandon, FL), Margaret M. Parker, MD Paolo Cogo (London, England), Andrew (Stonybrook, NY), J. Alan Paschall, MD (Ta- T. Costarino, MD (Wilmington, DE), Pe- koma, WA), Andy Petros (London, En- ECMO and CRRT Therapy for ter Cross (Toronto, Canada), Heidi J. Dal- gland), Jefferson P. Piva (Porto Alegre, Bra- Refractory Shock (Level II) ton, MD (Washington, DC), Alan L. Davis, zil), Ronald M. Perkin, MD (Greenville, MD (Summit, NJ), M. den Brinker (Rot- NC), Pollard (London, England), Francois Newborns with refractory shock must terdam, The Netherlands), DeKleign Proulx (Montreal, Canada), J. Ranjit (Chen- be suspected to have unrecognized mor- (Rotterdam, NE), Lesley A. Doughty, MD nai, India), E.M. Reynolds (Boston, MA), bidities (requiring specific treatment) in- (Providence, RI), Michelle Dragotta, RN Gerardo Reyes, MD (Oak Lawn, IL), cluding pericardial effusion (pericardio- (Pittsburgh, PA), Trevor Duke (Mel- Gustavo Rios (Vina del Mar, Chile), Han- centesis), pneumothorax (thoracentesis), bourne, Australia), Alan W. Duncan nelore Ringe (Berlin, Germany), Ricardo ongoing blood loss (blood replacement/ (Perth, Australia), J.R. Evans (Philadel- Ronco, MD (Santiago, Chile), Cathy H. hemostasis), hypoadrenalism (hydrocor- phia, PA), N. Evans (Sydney, Australia), Rosenthal-Dichter, MN, CCRN (Yorktown, tisone), hypothyroidism (triiodothyro- Elizabeth A. Farrington, PharmD IN), James Royall, MD (Oklahoma City, nine), inborn errors of metabolism (Durham, NC), Timothy F. Feltes, MD OK), Istvan Seri (Los Angeles, CA), Thomas (responsive to glucose and insulin infu- (Columbus, OH), Kate Felmet (Pitts- Shanley (Ann Arbor, MI), Billie L. Short, sion or ammonia scavengers), and/or cy- burgh, PA), Melinda Fiedor (Pittsburgh, MD (Washington, DC), Sunit Singhi (Chan- anotic or obstructive heart disease (re- PA), Jason Foland (Atlanta, GA), James digarh, India), Peter Skippen (Vancouver, sponsive to prostaglandin E 1 ), or a Fortenberry (Atlanta, GA), Brett P. Giroir, BC), N.V. Subhedar (Liverpool, England), critically large patent ductus arteriosus MD (Dallas, TX), Brahm Goldstein, MD Rod Tarrago (Minneapolis/St. Paul, MN), (patent ductus arteriosus closure). When (Portland, OR), Bruce Greenwald, MD Neal Thomas (Hershey, PA), S.M. Tibby these causes have been excluded, ECMO (New York, NY), Mark Hall, MD (Colum- (London, England), Joseph Tobias (Colum- becomes an important therapy to con- bus, OH), Yong Y. Han (Ann Arbor, MI), bia, MO), Scott Watson (Pittsburgh, PA), sider in term newborns. The current Steven E. Haun, MD (Sioux City, SD), Wills (London, England), Arno Zaritsky ECMO survival rate for newborn sepsis is Gabriel J. Hauser, MD (Washington, DC), (Gainesville, FL), Jerry Zimmerman (Seat- 80%. Most centers accept refractory Jan Hazelzet, MD (Rotterdam, The Neth- tle, WA). shock or a PaO2 40 mm Hg after max- erlands), Sabrina Heidemann, MD (De- imal therapy to be sufficient indication troit, MI), Lyn Hernan, MD (Buffalo, NY), for ECMO support. ECMO flows greater Ronald B. Hirschl, MD (Ann Arbor, MI), REFERENCES than 110 mL/kg should be discouraged Steven A. Hollenberg, MD (Chicago, IL), because hemolysis can ensue. With veno- Jorge Irazusta, MD (Boston, MA), Brian 1. DuPont HL, Spink WW: Infections due to venous ECMO, persistent hypotension Jacobs, MD (Cincinnati, OH), Stephen R. gram negative organisms: An analysis of and/or shock should be treated with do- Johnson, MD (Los Angeles, CA), K.F. 860 patients with bacteremia at University pamine/dobutamine or epinephrine. 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