Adverse Events Associated with Ketamine for Procedural Sedation in Adults Reuben J

American Journal of Emergency Medicine (2008) 26, 985–1028

www.elsevier.com/locate/ajem

Original Contribution Adverse events associated with ketamine for procedural sedation in adults Reuben J. Strayer MDa,⁎, Lewis S. Nelson MDb,c aEmergency Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA bEmergency Medicine, New York University School of Medicine, New York, NY 10016, USA cFellowship in Medical Toxicology, New York City Poison Control Center, New York, NY 10016, USA

Received 7 September 2007; accepted 14 December 2007

Abstract Study Objectives: Ketamine is widely used as a procedural sedation agent in pediatrics, where its safety and efficacy are supported by numerous studies. Emergency physicians use ketamine infrequently in adults, as it is believed to have a more significant side effect profile in this population. However, adult data on ketamine use in the emergency medicine literature are sparse. Our objective was to determine ketamine's adverse effect profile in adults when used for procedural sedation. Methods: We performed a literature review based on adverse effect research methodology recommendations. PubMed, EMBASE, TOXNET, and a variety of specialized databases were queried without regard to publication date or language. Experts were contacted to locate additional data. Inclusion criteria included adult study; ketamine used to facilitate the performance of painful procedures; dose of at least 1 mg/kg intravenous or at least 2 mg/kg intramuscular; original data and adverse events reported; spontaneously breathing patient, and no continuous cotherapies. Studies that met inclusion criteria were abstracted onto structured forms and their results qualitatively summarized. Results: Of the 5512 unique citations that were evaluated, 87 met criteria for inclusion. Most studies were performed in the 1970s and published in the anesthesia literature. Contexts, end points, and methodological quality varied widely across studies. Ketamine reliably produces conditions that facilitate the performance of painful procedures. Pharyngeal reflexes are generally preserved and cardiovascular tone stimulated, including a rise in blood pressure and myocardial oxygen demand. Laryngospasm and airway obstruction are reported, and though ketamine is a respiratory stimulant, a brief period of apnea around the time of injection is common. Reports of significant cardiorespiratory adverse events are rare, despite ketamine's frequent use in austere, poorly monitored settings. Dysphoric emergence phenomena occur in 10% to 20% of cases; sedating medications are effective in preventing and managing these reactions. Conclusion: When ketamine is used for procedural sedation in adults, emergence phenomena occur in 10% to 20% of patients. Although providers must be prepared to recognize and manage airway obstruction, cardiorespiratory adverse events are rare and typically do not affect outcomes. © 2008 Elsevier Inc. All rights reserved.

⁎ Corresponding author. Tel.: +1 212 659 1659; fax: +1 212 426 1946. E-mail addresses: [email protected] (R.J. Strayer), [email protected] (L.S. Nelson).

0735-6757/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.ajem.2007.12.005 986 R.J. Strayer, L.S. Nelson

1. Introduction Terms] OR qketamine/ contraindicationsq[Mesh Terms] AND qhumansq[MeSH Terms]] OR [((qketamineq[MeSH Terms] OR Ketamine[Text Word]) AND (adverse[All Ketamine hydrochloride is a dissociative agent that was Fields] OR side[All Fields] OR ((qpsychomotor agitationq first used in humans in 1965 [1]. It is a phencyclidine [TIAB] NOT Medline[SB]) OR qpsychomotor agitationq derivative developed when the potential was appreciated for [MeSH Terms] OR agitation[Text Word]) OR psychologi- this class of compounds to produce a state resembling general cal[All Fields] OR ((qlaryngismusq[TIAB] NOT Medline anesthesia without cardiorespiratory depression at therapeu- [SB]) OR qlaryngismusq[MeSH Terms] OR laryngospasm tic doses. When given by the intravenous or intramuscular [Text Word]) OR ((qbodily secretionsq[TIAB] NOT Med- route, ketamine rapidly causes profound analgesia, amnesia, line[SB]) OR qbodily secretionsq[MeSH Terms] OR and sedation as the patient breathes spontaneously, and blood secretions[Text Word]))) NOT (qketamine/adverse q q q pressure, heart rate, and protective airway reflexes are effects [Mesh Terms] OR ketamine/ poisoning [Mesh q q maintained or stimulated [2]. These features, combined Terms] OR ketamine/toxicity [Mesh Terms] OR qketamine/contraindicationsq[Mesh Terms] AND with low cost and a large therapeutic window [3], have qhumansq[MeSH Terms]) AND qhumansq[MeSH Terms]] made ketamine the anesthetic of choice in resource-poor or austere environments, where monitoring equipment may be 2. All summaries not fulfilling the prior PubMed search rudimentary or absent and a single operator provides the string but fulfilling the following PubMed search string were anesthetic, monitors the patient, and performs the procedure reviewed (PubMed ketamine text search). [4]. In western emergency medical practice, ketamine is q q frequently used to facilitate painful procedures in children ( ketamine [MeSH Terms] OR ketamine[Text Word]) and has proven safe and effective in numerous studies [5-18]. In adults, however, it is commonly believed that ketamine's 3. All summaries fulfilling the following EMBASE adverse effect profile—most importantly so-called emer- search string were reviewed (EMBASE adverse effects and gence reactions—favors the use of other agents [19]. drug therapy search). Ketamine is accepted as a standard agent of pediatric exp KETAMINE/ae, dt procedural sedation [20]. However, usage studies, which are not experimental but report on the current practice of an 4. All summaries fulfilling the following TOXNET search institution or set of institutions, show that it is used string were reviewed (TOXNET ketamine title search). This infrequently in emergency departments (EDs) that treat included TOXLINE and 9 associated databases. both adults and children [21-23]. ketamine [title] Furthermore, a recently published registry showed that of all agents typically administered for procedural sedation, 5. The following databases were manually searched for ketamine was associated with the fewest adverse events yet relevant citations: The Cochrane Library; The Australian used the least often in this setting [23]. In a review of 979 Adverse Drug Reactions Bulletin; The European Public consecutive procedural sedation cases at an adult tertiary care Assessment Reports from the European Medicines Evalua- center, ketamine was used in 2.7% [24], and a survey of tion Agency; MedWatch, The FDA Safety Information and community ED directors showed that ketamine is unavail- Adverse Events Reporting Program; and UK Current able in 41% of departments [25]. A total of 3 trials evaluating Problems in Pharmacovigilance. ketamine for procedural sedation in adult patients have been 6. Selected textbooks in the fields of emergency medicine, published in the emergency medicine literature [26-28].We anesthesiology, and clinical pharmacology were reviewed therefore undertook to review all available literature with the and mined for references [33-43]. objective of determining ketamine's adverse effect profile in 7. Selected review articles in the emergency medicine, adults when used for procedural sedation. anesthesiology, and clinical pharmacology literature were mined for references [2,19,44-59]. 8. Selected experts in the field were petitioned for obscure 2. Methods or unpublished data. 9. The bibliographies of all included studies were mined for references. A search strategy was developed after a consideration of The literature search was executed in May 2006 and all adverse effect research methodology reviews [29-31] and in articles produced were evaluated by a single reviewer. Each accordance with criteria outlined in the adverse effects citation was marked for retrieval or put in 1 of 7 exclusion appendix to The Cochrane handbook [32]. categories as follows: 1. All abstracts fulfilling the following PubMed search string were reviewed (PubMed ketamine adverse effects i. Not ketamine. Articles that did not study ketamine heading and specific effects search). were excluded. [qketamine/adverse effectsq[Mesh Terms] OR qketamine/ ii. Not a human adult study. Animal studies and pediatric poisoningq[Mesh Terms] OR qketamine/toxicityq[Mesh studies were excluded. A pediatric study was defined Adverse events associated with ketamine for procedural sedation in adults 987

as one in which more than half of study patients were period; these were variously described as hallucina- younger than 18 years. Several articles divided results tions, unpleasant dreams, and motor restlessness into adult and pediatric sections; the adult data from among many other terms. The rate of patient satisfac- these articles were included. tion with anesthesia was allowed as a surrogate for iii. Low dose. Only trials that studied ketamine in doses of psychiatric adverse event reporting when applicable. at least 1 mg/kg intravenously administered in a 30- v. Inappropriate use for the purposes of this study. The minute period or 2 mg/kg intramuscularly adminis- following types of studies were excluded: trials that tered in a 30-minute period were included. studied patients who were endotracheally intubated; iv. No adverse events. Only studies that reported either trials that used continuous cotherapies such as a psychiatric or cardiorespiratory adverse events were diazepam drip or an inhalational anesthetic (prepara- included. A cardiorespiratory adverse event was tory cotherapies or premedicants, such as diazepam defined as a change in patient condition that required given preinduction, were allowed); trials that studied bag-valve-mask (BVM) ventilation, invasive airway ketamine for a purpose other than facilitating painful management, or specific measures to correct alterations procedures (eg, asthma, perioperative pain, chronic in blood pressure, heart rate, or heart rhythm. A psy- pain); trials that used supplemental conduction chiatric adverse event was defined as any indication of anesthesia (eg, nerve blocks, epidural, or spinal fear, agitation, or psychologic distress in the recovery anesthesia); trials that did not study racemic ketamine;

Fig. 1 Abstraction Form. 988 R.J. Strayer, L.S. Nelson

Fig. 1 (continued).

volunteer studies; trials that studied ketamine for All articles not marked with an exclusion criterion were recreational use or for Rapid sequence intubation retrieved and their full text reviewed. Studies that then fell (RSI); and intranasal, regional, subcutaneous, intrathe- into an exclusion category on closer inspection were cal, subarachnoid, epidural, transdermal, intraarticular, marked as “Reviewed/not abstracted.” The remainder of jet injection, patient-controlled analgesia (PCA), lolli- the studies were abstracted onto structured forms (Fig. 1) pop, mouthwash, intraperitoneal, transmucosal, or that constitute the results of the present study. The rectal ketamine studies. adequacy of anesthesia, the use of antisialogogues, and vi. No abstract. Articles without an abstract available in the cardiostimulatory effect of ketamine were not abstracted the referring database were excluded unless the title unless of particular interest, as these elements showed little clearly suggested appropriateness. Foreign language variation across studies. articles without an abstract were excluded. Given the heterogeneity in design and quality of the vii. No original data. Articles that did not report original component studies, no attempt was made to combine data data were excluded, unless selected as a review article and no statistical analyses performed. Results are summar- to be mined for references. ized by qualitative analysis. Adverse events associated with ketamine for procedural sedation in adults 989

3. Results ketamine is delivered rapidly by the intravenous route but when used as monotherapy is rarely, if ever, of clinical The search strategy produced 5512 citations, of which significance. Respiratory depression requiring BVM ventila- 223 met inclusion criteria for retrieval. Of these, 87 met tion does occur when agents known to depress respiration, criteria for inclusion after close inspection and were such as those in the benzodiazepine class, are given abstracted [4,23,24,26-28,60-138]. Four articles published concurrently [27,28,66,129]. in a language other than English are included in the results A transient mild increase in heart rate and significant [137-140]. Non-English language articles in Spanish, Ger- increase in systolic and diastolic blood pressure almost man, Portuguese, Russian, and French were evaluated; other always accompany ketamine administration [142,143]. These non-English language articles were excluded. cardiostimulatory effects can be mitigated by sympatholytic Results are presented in Table 1. agents [61,108,139,144]. Psychiatric adverse events are reported in 0% to 76% of patients emerging from ketamine anesthesia. Unfortunately, end points of clinical significance (dysphoria, patient 4. Analysis/narrative summary satisfaction) were often not studied and frequently markers of uncertain consequence (dreams, hallucinations, delirium) Of 83 studies applicable to emergency medicine, 36 used as a surrogate. reported on 100 or more patients; of these, 10 reported on In those studies of ketamine monotherapy where patient- 500 or more patients. Most experimental trials were oriented outcomes are assessed, the rate of psychiatric performed in the 1970s and published in the anesthesia adverse events is 10% to 20% [61,79,92,93,100,101,115]. literature; these studies are of variable methodological Sedating agents are highly effective at both preventing and quality and use a wide variety of comedications, many of terminating ketamine emergence reactions [27,61,68,70, which are not available in modern EDs. 71,74,79,93,97,101,108,114,115], and environmental inter- This sample of studies indicates that ketamine is ventions such as preinduction counseling and the provision of dependable in its efficacy. In dissociative doses, ketamine music are also successful in reducing the occurrence of these reliably produces analgesia. Several studies report that in events [73,75,116,145]. patients who receive ketamine regularly (eg, for burn-related The incidence of vomiting varied widely across studies procedures), tolerance does develop, and the dose must be but can be expected in 5% to 15% of patients [27,67,78, increased [116,128]. 100,106,115]. These episodes generally occur after the Ketamine demonstrates a high degree of safety. In more patient has emerged from a dissociative state. than 70 000 patients described in this review, a single adverse An evanescent patchy erythematous rash about the upper cardiorespiratory event of lasting significance in an adult is torso occurs in 5% to 20% of patients shortly after ketamine attributed to the drug—a case report describing “Hypoxic injection and disappears within 20 minutes. It requires no cardiac arrest secondary to respiratory depression...in a treatment and does not recur with further ketamine admin- debilitated adult [91].” No further circumstances or details istrations [101,119,120,128]. are provided. Ketamine commonly causes purposeless movements Despite work demonstrating radiologic evidence of [100] and infrequently causes hypertonus that on occasion contrast aspiration under ketamine anesthesia [99], there can interfere with the procedure it was given to facilitate are no reported cases of clinically detected aspiration [94,146]. associated with ketamine. Fully dissociated patients maintain Anticholinergic medications are routinely given to their pharyngeal reflexes and will swallow a liquid if children to prevent hypersalivation; this occurs less challenged [99]. Many articles report, however, on patients frequently in adults and is rarely of clinical significance, who required airway maneuvers such as a chin-lift or jaw- though most studies included an antisialogogue in their thrust for positional obstruction [26,66,67,104,106]. Laryn- comedication regimen. gospasm, a rare [10] complication in children, is reported even less frequently in the larger adult airway and is either transient or responsive to BVM ventilation [4,27]. The specter of laryngospasm is often cited to contraindicate 5. Discussion ketamine for procedures involving the posterior oropharynx, though studies describing its use for endoscopic; ear, nose, The ideal agent for facilitating painful procedures in the and throat; and dental procedures suggest that it may be safe ED would be reliably effective as an analgesic, anesthetic, in this context [46,131,134]. amnestic, and anxiolytic with a wide therapeutic index across Ketamine is a respiratory stimulant [141] but produces the spectrum of patients, conditions, and routes of admin- transient respiratory depression, which may include apnea, istration; cause a rapid, titratable, and reversible response usually within the first 2 to 3 minutes of administration with a short duration of action; preserve protective reflexes [76,81,87,90,110]. This effect appears to be more likely if and cardiorespiratory tone; and be free of adverse effects. 990

Table 1 Results AB C D E F 1 Citation no. Citation Study design Adverse event reporting Results Possible confounders methodology 2 86 Abajian JC, Page P, 60 patients undergoing Cardiorespiratory status was “Respiratory obstruction PO premedicants unlikely Morgan M. Effects of minor surgical procedures continuously monitored. necessitating intervention to be used in modern droperidol and nitrazepam received per orem (oral) Psychiatric adverse events on the part of the emergency practice. on emergence reactions droperidol, 20 mg, were prospectively sought. anesthesiologist” following ketamine and PO nitrazepam, occurred in 12% of patients. anesthesia. Anesth Analg 10 mg, followed Seventeen percent of 52:3, 385-9(1973) eng. 60-90 min later by patients reported having intravenous ketamine unpleasant dreams and 2-2.2 mg/kg given for 10% of patients reported 45-60 s. Supplementary having terrifying dreams. half doses were given as Eighteen percent of needed during the patients reported the procedure. anesthetic unacceptable. 3 121 Abu Khalaf A, Takrouri M, 12 patients undergoing Cardiorespiratory status was No cardiorespiratory Toukan A, Abu Khalaf M, open liver biopsy received continuously monitored. adverse events occurred. Amr S. Ketamine IV ketamine 2 mg/kg for No psychiatric adverse event Of 12 patients, 2 had hydrochloride as sole 60 s, followed by reporting methodology is unpleasant dreams; anesthetic for open liver supplementary doses of presented. Liver function 3 patients in this cohort biopsy. Middle East J 0.75 mg/kg as needed. was prospectively followed required intraoperative Anaesthesiol 9:6, postoperatively. muscle relaxation and 537-43(1988) eng. endotracheal intubation for “respiratory tagging” that limited surgical maneuvers. 4 135 Adesunkanmi AR. Retrospective review of Cardiorespiratory status was 7 deaths occurred, none Dysphoria and patient Where there is no 203 patients undergoing a continuously monitored. attributable to the acceptance not distinguished anaesthetist: a study of variety of surgical No psychiatric adverse event anesthesia. No from emergence reactions. 282 consecutive patients procedures at 2 Nigerian reporting methodology is cardiorespiratory using intravenous, spinal medical centers. presented. adverse events were and local infiltration Anesthesia was conducted reported. Emergence

anaesthetic techniques. by the surgeon. Patients delirium/confusion was Nelson L.S. Strayer, R.J. Trop Doct 27:2, received IV diazepam, reported in 56.7% of 79-82(1997) eng. 10 mg, (adults) or patients, with dreaming 0.15 mg/kg (children) reported in 5.4% of followed by IV ketamine, patients. 2 mg/kg, (adults) or IM ketamine, 5 mg/kg. Incremental smaller doses were given IV intraoperatively as needed. des vnsascae ihktmn o rcdrlsdto nadults in sedation procedural for ketamine with associated events Adverse 5 127 Ashraf Ganatra M, 32 patients undergoing Cardiorespiratory adverse 2 patients died of Results are difficult to Bhatti BT, Durrani KM. surgical event reporting methodology burn-related complications. interpret. Three patients left Ketamine in burn wound procedures in a Pakistani is not presented, though No cardiorespiratory against medical advice management. Specialist hospital burn unit received hemodynamic measurements adverse events are before all planned procedures 11:4, 327-33(1995) eng. IV ketamine, 2 mg/kg, are reported in the results. reported. Hallucinations were performed. with supplementary “Behavior during recovery” were noted in 6/32 cases 1 mg/kg doses as needed. was prospectively measured. and “nightmares and For further procedures, anxiety” occurred in patients received ketamine 2/32 cases. Of 27 patients on postoperative days available for final no. 2, 4, and 6 while no evaluation, all 27 ketamine was used on preferred to receive days no. 1, 3, and 5. ketamine to facilitate painful procedures (the alternative appears to have been no anesthesia). 6 130 Awojobi OA. Ketamine Brief historical account of No adverse event reporting No adverse events are Descriptive review. anaesthesia for caesarean 35 patients undergoing methodology is presented. reported in this account. section. Trop Doct emergency. cesarean 14:4, 165(1984) eng. delivery and 1 patient undergoing cesarean scar revision in a Nigerian district hospital. Patients received IV chlorpromazine, 50 mg, or IV diazepam, 10 mg, 15 min before induction with IM ketamine, 250 mg. No further doses of ketamine were given; generous local anesthesia was used in this technique. 7 108 Ayim EN, Makatia FX. 105 patients undergoing Cardiorespiratory status was No cardiorespiratory Patient acceptance not The effects of diazepam curettage for incomplete continuously monitored. adverse events occurred. assessed. Psychologically on ketamine anaesthesia. abortion received IV Psychiatric adverse events Incidence of “highly traumatic procedure. East Afr Med J 53:7, ketamine, 1-2 mg/kg, were prospectively sought. unpleasant reactions,” 377-82(1976) eng. and were randomized to which included shouting, one of 3 groups. Group 1 restlessness, crying, received ketamine alone; and terrifying dreams, group 2 received IV was 32% in group 1, (continued on next page) 991 992

Table 1 (continued) AB C D E F diazepam, 10 mg, 5 min 11% in group 2, and 8% in preinduction; group 3 group 3. Patients in group 2 received IV diazepam, were noted to have a 10 mg, at the end of the significantly lower incidence procedure, as the patient of poor anesthesia, as well as showed signs of recovering. a significant attenuation of the rise in blood pressure and heart rate seen in groups 1 and 3. 8 85 Azar I, Ozomek E. 50 patients undergoing Blood pressure, heart rate, Average induction dose was No control group. Dysphoria The use of ketamine for postpartum tubal ligation minute ventilation, arterial 1.27 mg/kg. No reported and patient acceptance not abdominal tubal received IV meperidine, blood gas measurements, respiratory or cardiovascular distinguished from ligation. Anesth Analg 50 mg, followed and postoperative side adverse events. 27% of hallucinations and 52:1, 39-42(1973) eng. 15-30 min later by IV effects were prospectively patients had “incoherence or incoherence. ketamine, slowly infused sought. hallucinations;” of these, until adequate anesthesia 3 patients had “vivid was obtained. hallucinations.” Repeat boluses of 20 mg ketamine were given prn (as needed). 9 93 Becsey L, Malamed S, 214 patients undergoing Cardiorespiratory parameters No cardiorespiratory adverse Radnay P, Foldes FF. elective termination of were prospectively measured events occurred. Rates of Reduction of the pregnancy were randomized and recorded. Psychiatric restlessness, crying, and psychotomimetic and in double-blind fashion adverse events were screaming, as well as the circulatory side-effects to receive a preinduction prospectively sought in characterization of “agitated” of ketamine by droperidol. or preemergence regimen standardized fashion. or “frightened” were between Anesthesiology 37:5, or placebo. 10% and 20% in placebo 536-42(1972) eng. All patients received IV patients. These adverse ketamine 2.5 mg/kg given psychiatric events were not for 30 s. Preinduction diminished in the diazepam regimens included or thiopental group, but were

droperidol 75 μg/kg and reduced to less than 5% in the Nelson L.S. Strayer, R.J. droperidol, 75 μg/kg, droperidol and droperidol/ with fentanyl 0.375 μg/kg. fentanyl groups. The addition Preemergence regimens of fentanyl to droperidol did included diazepam, not confer an appreciable 150 μg/kg, and thiopental, benefit. Postoperative vomiting 1.5 mg/kg. All drugs were was common in all groups; this given intravenously. was attributed to the uterotonic medications given as part of the abortive procedure. des vnsascae ihktmn o rcdrlsdto nadults in sedation procedural for ketamine with associated events Adverse 10 111 Bishop RA, Litch JA, 11 patients undergoing minor Cardiorespiratory status was No cardiovascular adverse Altitude. Stanton JM. procedures by general continuously monitored. events occurred. Of Ketamine anesthesia at practitioners in a hospital in No psychiatric adverse event 11 patients, 3 required high altitude. the Mt Everest region of Nepal, reporting methodology is supplemental oxygen for High Alt Med Biol altitude 3900 m, received IV presented. saturation b80% more than 1:2, 111-4(2000) eng. midazolam, 0.05 mg/kg, 60 s unresponsive to basic followed by IV ketamine, airway maneuvers. Of these 1 mg/kg, given for 1-2 min, three, 2 were unacclimatized with smaller supplemental to the altitude. No “emergent dosesasneeded. nightmares” occurred. 11 113 Bonanno FG. Ketamine 62 patients undergoing a variety Heart rate, RR, eye No cardiorespiratory Dysphoria and patient in war/tropical surgery of surgical procedures received movements, the presence adverse events occurred. acceptance not distinguished (a final tribute to the IV ketamine, 2 mg/kg, (n = 60) of laryngospasm, trismus, Postoperative hallucinations from hallucinations. racemic mixture). or IM ketamine, 4-5 mg/kg, lacrimation, and excessive were reported in all patients; Injury 33:4, (n = 2), followed by a titratable salivation were recorded the duration of postoperative h 323-7(2002) eng. ketamine drip for the duration prospectively. Psychiatric allucinations appeared to be of surgery. Most received IV adverse event reporting is shorter with premedicant diazepam, 5-10 mg, not presented, but the diazepam. immediately before induction. incidence of “hallucinations” was measured. 12 98 Brewer CL, Davidson JR, 28 psychiatric inpatients No adverse event reporting No cardiorespiratory adverse Minimal methodology. Effect Hereward S. Ketamine aged 18 to 67 undergoing methodology is presented. events were reported. of patient's usual medications (“Ketalar”): a safer a total of 86 electroconvulsive “In most cases, patients unknown. Emergency anaesthetic for ECT. therapy sessions received IV anesthetized with ketamine physicians unlikely to Br J Psychiatry 120:559, ketamine, 2.2 mg/kg, (n = 38), maintained an adequate perform ECT. 679-80(1972) eng. IM ketamine, 4.4 mg/kg, airway in the supine (n = 24), or IV thiopentone, position.” No “hallucinatory 4.5 mg/kg, (n = 24). All patients or other emergence were taking their usual phenomena” occurred in psychotropic medications. this cohort. 13 24 Campbell G, Magee D, A retrospectively generated Cardiorespiratory status was One ketamine patient Chart review design. Dosing Kovacs J. Procedural (chart review) audit of monitored per local ED comedicated with midazolam and route of administration sedation and analgesia procedural sedation practices protocols. A prior definitions had an SaO2 b90%. No other not reported. in a Canadian Adult in an adult tertiary-care were used to define cardiorespiratory adverse Tertiary Care Emergency center (n = 979) reported cardiorespiratory adverse events are reported. One Department: a case on 26 patients who received events. No psychiatric patient is reported to have had series. Can J Emerg Med ketamine for a variety of ED adverse event reporting a postprocedure emergence 8:2, 85-93(2006) English. procedures. Dosing information methodology is presented. reaction. is not reported. Comedications included an unspecified benzodiazepine (n = 7), propofol (n = 3) and fentanyl (n = 2). (continued on next page) 993 994

Table 1 (continued) AB C D E F 14 68 Caro DB. Trial of ketamine 52 patients undergoing a No adverse event reporting No cardiorespiratory adverse Loosely controlled in an accident and ED. variety of painful methodology is presented. events occurred. noncomparative trial. Anaesthesia 29:2, procedures in the ED No vomiting before 227-9(1974) eng. received the minimum recovery of consciousness dose of IV ketamine that occurred. Sixty-seven percent allowed for acceptable patients had no dreams, 25% procedural conditions had pleasant dreams, 6% had (45 patients received strange dreams, 2% had very between 50 and 100 mg) unpleasant dreams. One as well as 10-20 mg additional patient had IV diazepam, either “considerable restlessness” before ketamine or while recovering, requiring before the conclusion of the administration of the procedure. additional diazepam followed by propanidid. 15 74 Cartwright PD, Pingel SM. 60 patients undergoing Vital signs were measure No cardiorespiratory adverse 1 patient was withdrawn Midazolam and diazepam short gynecologic every few minutes. events occurred. No excitatory from the study because in ketamine anaesthesia. procedures were Psychiatric adverse events phenomena occurred she was switched to Anaesthesia 39:5, randomized to receive were prospectively sought during induction. Emergence halothane anesthesia 439-42(1984) eng. either IV diazepam, and recorded by MDs, RNs, delirium was present in 16.7% the result of inadequate 0.12 mg/kg, or and through a patient of midazolam patients vs 20% analgesia with ketamine. midazolam, 0.07 mg/kg; questionnaire given 12 hours of diazepam patients; pleasant all patients then received postsurgery. dreams, 20% vs 20%; IV ketamine, 2 mg/kg. unpleasant dreams, 6.7% vs 26.7%; nausea/vomiting, 20% vs 33.3%; patient acceptance, 100% vs 93.3%. 16 27 Chudnofsky CR, Weber JE, 70 patients undergoing Cardiorespiratory status was No adverse cardiovascular No control group. Stoyanoff PJ, Colone PD, painful procedures in continuously monitored by events. Three apneic episodes, Wilkerson MD, the ED received IV ED protocol and adverse 2 of which required BVM

Hallinen DL, Jaggi FM, midazolam, 0.07 mg/kg, events prospectively sought. ventilation. One episode of Nelson L.S. Strayer, R.J. Boczar ME, Perry MA. followed 2 min later by Psychiatric adverse events laryngospasm that required A combination of IV ketamine, 2 mg/kg. prospectively sought and responded to BVM midazolam and ketamine according to criteria defined ventilation. Five mild for procedural sedation a priori. psychiatric adverse events and analgesia in adult requiring no treatment; no ED patients. Acad Emerg moderate or severe psychiatric Med 7:3, 228-35(2000) eng. adverse events. Patient acceptance 99%. Emesis occurred in 3% of patients. des vnsascae ihktmn o rcdrlsdto nadults in sedation procedural for ketamine with associated events Adverse 17 64 Coad NR, Mills PJ, 50 women undergoing elective Adverse events, including No cardiorespiratory or High premedicant Verma R, termination of pregnancy were cardiovascular and psychiatric adverse events in midazolam dose. Ramasubramanian R. randomized to IV ketamine, psychiatric adverse events, either group. The incidence of Evaluation of blood loss 2 mg/kg, or methohexitone, were specifically sought postoperative nausea was during suction 1 mg/kg. IV midazolam, and recorded. significantly higher in the termination of pregnancy: 0.15 mg/kg, was administered ketamine group. ketamine compared with 3 min before induction. methohexitone. Acta Anaesthesiol Scand 30:3, 253-5(1986) eng. 18 81 Corssen G, Domino EF. 130 patients aged 6 wk to Cardiorespiratory parameters Slight respiratory depression Uncontrolled study. Dissociative anesthesia: 86 y undergoing a variety were prospectively measured was noted in the first 30-60 s further pharmacologic of procedures (including and recorded. No psychiatric after IV administration, after studies and first clinical many intraoral procedures) adverse event reporting that respiratory status returned experience with the were given IV or IM methodology is presented. to normal. No cardiorespiratory phencyclidine derivative (small children) ketamine i adverse events occurred. CI-581. Anesth Analg n doses ranging from Psychiatric adverse events 45:1, 29-40(1966) eng. 1-2.2 mg/kg (IV) and occurred are described but 5.5-11 mg/kg (IM) for not quantified. 15-60 s. 19 114 D'Angelo VF. Ketamine: Review of 851 cases where Cardiorespiratory status was No cardiorespiratory adverse Review. Reactions to a 5-year study. J Am ketamine was given as the continuously monitored events are reported. Bad ketamine not documented Osteopath Assoc 77:3, primary anesthetic to patients by sphygmomanometer, dreams or crying was in 14% of cases. 213-21(1977) eng. “chosen at random” for a wide precordial stethoscope, and documented in 6.2% of cases. Wide variety of variety of surgeries. Patients electrocardiogram by the Nausea or vomiting was premedicants. were premedicated with an anesthesiologist. No documented in 1.3% of cases. assortment of agents, usually psychiatric adverse event IV meperidine, 50 mg. reporting methodology is Afterward, patients received presented; detailed results IV ketamine 1. 65-2.2 mg/kg appear to have been with smaller supplementary ascertained by chart review. doses as needed. 20 116 Demling RH, Ellerbe S, 45 burn patients No cardiorespiratory or No cardiorespiratory adverse Semiquantitative, Jarrett F. Ketamine undergoing 150 eschar psychiatric adverse event events occurred. No severe retrospective analysis. anesthesia for tangenital excisions received IM reporting methodology is psychiatric adverse events excision of burn eschar: ketamine, 4 mg/kg, with presented. occurred. Approximately a burn unit procedure. repeat dosing as necessary. 10% of patients demonstrated J Trauma 18:4, “A type of music “excitement and hallucinations” 269-70(1978) eng. enjoyed by the patient” that resolved quickly with was played during verbal support. Increasing the procedure. doses were necessary in patients that required frequent procedures.

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Table 1 (continued) AB C D E F 21 71 Dundee JW, Lilburn JK. 185 patients undergoing Blood pressure was No cardiorespiratory adverse Unblinded study. Ketamine-lorazepam. short gynecologic prospectively recorded; events are reported. Of the Attenuation of psychic procedures received no other cardiorespiratory 50 patients who did not receive sequelae of ketamine by either no premedication adverse event reporting any premedication, lorazepam. Anaesthesia or lorazepam 4 mg by methodology is presented. postoperative nausea/vomiting 33:4, 312-4(1978) eng. the oral, intramuscular, Postoperative vomiting, occurred in 42, with a high or intravenous route delirium, unpleasant dreams prevalence of delirium and before administration and patient acceptance were unpleasant dreams. Acceptance of IV ketamine, 2 mg/kg prospectively sought. rate in this group was 24%. or 1 mg/kg; 0.25 mg/kg In all other groups, lorazepam ketamine boluses were by any route dramatically given prn to maintain decreased all postoperative anesthesia. adverse events except nausea and vomiting, and patient acceptance was near 100%. 22 123 Ekele BA. Using ketamine Review of 134 No adverse event reporting No cardiorespiratory adverse Limited methodology for diagnostic laparoscopy. consecutive gynecologic methodology is presented, events were reported. One description in what Nigeria Journal of Clinical laparoscopies performed by though the operations were patient had tonic-clonic appears to be a Practice 3:5-7(2000) the author in a Nigerian carried out in “the main movements. Delirium, retrospective review. English. teaching hospital. Each patient theater equipped with all described as “incoherent received IV ketamine 1 mg/kg resuscitative gadgets.” verbal outbursts and followed by half-dose restlessness” occurred in supplements as needed. 10% of cases. Nausea or vomiting was reported in 5% of cases. 23 62 Ellingson A, Haram K, 26 patients undergoing forceps No cardiorespiratory adverse One patient from each group No additional ketamine Sagen N. Ketamine and delivery were randomized to event reporting methodology required a brief period of was given until the

diazepam as anaesthesia receive IV ketamine, 2 mg/kg, is presented, however the assisted ventilation because procedure was finished, Nelson L.S. Strayer, R.J. for forceps delivery. delivered for 30 s with anesthesia was delivered by of apnea. Of 13 patients, therefore some patients A comparative study. Acta additional smaller doses as an anesthesiologist. The 7 found recovery from were incompletely Anaesthesiol Scand 21:1, needed postprocedure, or IV acceptability of the ketamine to be unpleasant, anesthetized at the end of 37-40(1977) eng. diazepam, 30 mg, in anesthesia to both patient whereas 0/13 patients found the procedure. combination with nitrous oxide. and obstetrician was recovery from diazepam-N20 In some cases the patient was prospectively sought. to be unpleasant. There was premedicated with promethazine no vomiting in either group. or meperidine during the first stage of labor. 24 84 Erbguth PH, Reiman B, 300 patients undergoing Cardiorespiratory status was One patient experienced Psychologically traumatic adults in sedation procedural for ketamine with associated events Adverse Klein RL. The influence therapeutic abortion were continuously monitored. laryngospasm; details were procedure. of chlorpromazine, randomized to IV Adverse psychiatric events not provided. Postoperative diazepam, and droperidol chlorpromazine, 10 mg, were prospectively sought vomiting occurred in no on emergence from or placebo, followed 2 min in the operating room (OR), chlorpromazine-droperidol ketamine. Anesth Analg later by IV ketamine, 1 mg/lb, by trained ecovery room patients, up to 34% of 51:5, 693-700(1972) eng. given for 1 min. At the end of RNs, and by predischarge placebo-placebo patients. the procedure, patients were and 24 hour postoperative Patient characterization of randomized to placebo, interviews. the anesthesia as good or IV diazepam 5 mg, or IV excellent ranged from 58% droperidol, 5 mg. Smaller in the placebo-placebo group to intraoperative ketamine 78% in the placebo-diazepam doses were given as needed. group and the chlorpromazine- diazepam group. 25 124 Ersek RA. Dissociative An account of one outpatient No adverse event reporting The author states that no Descriptive review. anesthesia for safety's surgery center's experience methodology is presented. untoward events occurred in sake: ketamine and with ketamine-diazepam his case series. He reports diazepam-a 35-year anesthesia given to 2 hospital admissions personal experience. approximately 30 000 Patients (all other patients were Plast Reconstr Surg for 35 y by a plastic surgeon discharged postoperatively). 113:7, 1955-9(2004) eng. without anesthesia MD or RN The first patient became assistance. Each patient excessively sedated after received PO diazepam, 20 mg, the second dose of ketamine, on arrival to the surgery center. though Sa02 and BP remained Once in the operating suite, normal throughout; she was IM droperidol, 1.25 mg, admitted to the hospital for IM was administered, followed postoperative monitoring and by an IV diazepam infusion discharged the following day. until the slurring of speech, The second patient became followed by IV ketamine, excessively sedated with 75 mg, slow infusion. Repeat diazepam alone and was doses of ketamine and diazepam admitted postoperatively; were given according to need. she was also discharged without sequelae. (continued on next page) 997 998

Table 1 (continued) AB C D E F 26 78 Ezri T, Szmuk P, Historical review of Aspiration, convulsions, No instances of aspiration, Retrospective study with Stein A, Konichezky 1870 patients undergoing apnea, postoperative convulsions, or apnea during minimal chart review S, Hagai T, Geva D. peripartum operations, dysphoria, postoperative induction were found in the methodology described. Peripartum general including 1496 patients vomiting, transient ketamine group. The incidence anasthesia without who received IV diazepam, hypertension, and of postoperative dysphoria was tracheal intubation: 0.05 mg/kg, and ketamine, transient hypotension 22.1%; 9.7% incidence of incidence of aspiration 1 mg/kg, with additional bolus were specifically sought postoperative vomiting, 5.7% pneumonia. Anaesthesia doses of ketamine, 0.2 mg/kg, in this chart review. incidence of transient 55:5, 421-6(2000) eng. as needed. hypertension, and 2.1% incidence of transient hypotension. 27 128 Feller, I. Anesthesia Brief historical account of more No adverse event reporting The author reports “excellent Descriptive review. requirements for the than 2000 procedures for more methodology is presented. results” with “minimal severely burned patient, than 400 patients undergoing complications.” Supplemental in status of ketamine surgery related to burn injuries. oxygen is recommended in in anesthesiology, These patients received an this report because “some 419-21. Ann Arbor, unspecified titrated dose of IV patients have shallow Michigan: NPP Books, ketamine, which was often respirations” during the 1990. “less than the recommended procedures. An erythematous dose” and repeated throughout rash about the head, neck, the procedure as needed. and chest occurred in b5% IV diazepam was given in an of patients. The necessity of unspecified dose before the increasing the ketamine dose procedure and before the last as tolerance develops in ketamine dose to avoid patients needing multiple “psychologic aberrations after procedures is noted. ketamine.” 28 80 Fine J, Finestone SC. 1400 patients received No cardiorespiratory adverse No cardiorespiratory adverse Minimal methodology

Sensory disturbances IV ketamine, 1-1.5 mg/kg, event reporting methodology events are reported. 20% of presented. Nelson L.S. Strayer, R.J. following ketamine for unidentified surgical is presented. All patients patients had no dreams. anesthesia: recurrent procedures. No standardized were interviewed Of the 80% of patients who hallucinations. cotherapy methodology is postoperatively and dreamed, 50% reported Anesth Analg 52:3, presented. questioned with regard to pleasant dreams and 30% 428-30(1973) eng. thepresenceorabsenceof reported unpleasant dreams. dreams, and, among patients 3 patients reported occasional who had dreams, if these recurrent dreamlike dreams were pleasant or hallucinations for 1 to 3 wk unpleasant. postoperatively. des vnsascae ihktmn o rcdrlsdto nadults in sedation procedural for ketamine with associated events Adverse 29 61 Freuchen I, Ostergaard J, Randomized, double-blind trial Cardiorespiratory parameters No cardiorespiratory adverse Flunitrazepam is no longer Kühl JB, Mikkelsen BO. (n = 136) where 69 patients were continuously recorded. events occurred in either group; available in North America. Reduction of undergoing therapeutic abortion Psychiatric adverse events flunitrazepam attenuated the rise psychotomimetic side received IV ketamine, 2 mg/kg, were prospectively assessed in blood pressure observed in effects of Ketalar and flunitrazepam, 2 mg, mixed by observation and the placebo group. Flunitrazepam (ketamine) by Rohypnol in the same syringe and injected postoperative patient survey. greatly reduced the requirements (flunitrazepam). for 60 s, and 67 patients for further intraoperative A randomized, double-blind received IV ketamine, 2 mg/kg, ketamine doses, as well as the trial. Acta Anaesthesiol and placebo. incidence of postoperative Scand 20:2, 97-103(1976) confusion and motor restlessness. eng. Of 66 patients in the placebo arm where data were available, 30 reported amnesia for dreams; 16 reported pleasant dreams and 20 reported unpleasant dreams, of which 12 were described as nightmares. Of 69 patients in the treatment arm, 68 reported amnesia for dreams and 1 reported pleasant dreams. 30 101 Galloon S. Ketamine 272 women undergoing either No adverse event reporting No cardiovascular adverse for dilatation and diagnostic D and C or methodology is presented events occurred. Systolic blood curettage. Can Anaesth therapeutic abortion received though the study was pressure and diastolic blood Soc J 18:6, IV ketamine, 2.2 mg/kg, carried out in an pressure increased in every 600-13(1971) eng. and supplemental doses of anesthesiologist-controlled patient within 2 minutes of 0.5 mg/kg as needed. Patients OR setting. Furthermore, ketamine injection, reaching were divided into 5 roughly the results are presented to maximum values in 10-15 min. equal premedicant groups-all a degree of detail that HR increased in 95% of patients. premedicants were given IM suggests that both Of 25 patients who received 90 min preprocedure. Groups cardiorespiratory and spirometry as part of the study, included pantopon (an opioid), psychiatric adverse events 11 became apneic for a period 0.286 mg/kg + scopolamine, were prospectively sought. between 30 and 120 s. Four 0.4 mg; pantopon + atropine, percent of patients required either 0.6 mg; atropine only; jaw support for “obstructed scopolamine only; and breathing” or supplemental diazepam, 0.143 mg/kg, + oxygen for “unsatisfactory color.” scopolamine. An additional Unpleasant dreams occurred 50 patients received in 16.3% of patients, including supplemental nitrous oxide 14.5% in the scopolamine-only anesthesia. group, 28% in the atropine-only group, and 5.8% in the diazepam-scopolamine group. The rate of unpleasant dreams did not vary between the 999 abortion and diagnostic D (continued on next page) 1000

Table 1 (continued) AB C D E F and C group. Nausea or vomiting occurred in 41.5% of patients; this incidence was significantly reduced by scopolamine and scopolamine + diazepam, but not by atropine. A rash appeared in 17% of patients, this disappeared within 15-20 min and did not recur with repeat ketamine administrations. 31 92 Garfield JM, Garfield FB, 48 servicemen undergoing skin No cardiorespiratory No cardiorespiratory adverse Stone JG, Hopkins D, grafting or minor orthopedic adverse event reporting event data are presented. Johns LA. A comparison procedures were randomized methodology is The incidence of postoperative of psychologic responses to receive IV ketamine presented. Preoperative anxiety was 9/24 ketamine to ketamine and (mean dose 1.6 mg/kg for “baseline anxiety” patients, who showed no thiopental-nitrous 90 s) with additional doses as levels were assessed by correlation to preoperative oxide-halothane anesthesia. necessary or thiopental-nitrous a standardized scale. anxiety levels. Of 24 ketamine Anesthesiology 36:4, oxide-halothane anesthesia. Psychiatric adverse patients, 4 expressed 329-38(1972) eng. In addition, each group was events were prospectively dissatisfaction with the divided into a “minimal sought and recorded anesthetic technique. In the briefing” or “detailed briefing” in a detailed, thiopental group, postoperative subset, where either a few standardized patient anxiety occurred in details or a complete account survey. 3/24 patients and dissatisfaction of the expected anesthetic occurred in 1/24 patients. side effects were discussed with the patient preoperatively. 32 126 Ginsberg H, Gerber JA. 100 patients undergoing minor Cardiorespiratory and No cardiorespiratory adverse Incompletely controlled CI-581: a clinical report surgical procedures received psychiatric adverse events events occurred. Mean SBP prospective series. on 100 patients. IV ketamine, most often at a were prospectively recorded, elevation was 31 mm Hg, S Afr Med J 42:43, dose of 1.5 mg/kg with smaller including a formal DBP elevation 26.6 mm Hg.

1177-9(1968) eng. supplemental doses as needed. acceptance evaluation on Mean heart rate elevation Nelson L.S. Strayer, R.J. In 11 cases, supplemental the day after the anesthetic was 22 beats per minute. anesthesia (usually with nitrous in 55 patients. Tachynpnea “often occurred,” oxide) was given. and30sofapneawasnotedin one patient. Mild hallucinations werenotedin3patients,and patient acceptance was 96%. Postoperative nausea occurred in 2% of patients. 33 60 Gjessing J. Ketamine 40 elderly patients undergoing Detailed cardiorespiratory 67% of patients were age Methodology is detailed but adults in sedation procedural for ketamine with associated events Adverse (Cl-581) in clinical a variety of surgeries (including and metabolic measurements N75. No cardiorespiratory confusing and incomplete. anaesthesia. Acta abdominal operations, hip were taken prospectively. or psychiatric adverse Anaesthesiol Scand fractures, and amputations) A structured cognitive events were reported in 12:1,15-21(1968) eng. received ketamine, 1 mg/kg, evaluation was undertaken this cohort. Authors conclude with additional half-doses preanesthesia and that anesthetic results improve given as needed. An unspecified postanesthesia, but no with increasing age. proportion of patients received psychiatric adverse event placebo, and some were reporting methodology is premedicated with promethazine. presented. Eleven patients received supplementary anesthesia. 34 4 Green SM, Clem KJ, Survey of 175 missionary Survey specifically assessed 19 serious complications Survey design. Exact clinical Rothrock SG. Ketamine physicians addressing clinical monitoring and adverse reported by 55 respondents circumstances, including safety profile in the experience with ketamine in events. in an estimated 12 844 cases, the use of cotherapies, developing world: the developing world. most that did not result in not necessarily recalled survey of practitioners. adverse sequelae. Basic by respondent. Acad Emerg Med 3:6, mechanical monitoring was 598-604(1996) English. used in a minority of cases, and often the person administering ketamine was also performing the procedure. 35 26 Green SM, As part of a much larger Cardiorespiratory function No cardiovascular adverse Rothrock SG, pediatric study, 17 mentally and the occurrence of events occurred. “Soft stridor” Hestdalen R, Ho M, disabled adults (median age 28) psychiatric adverse events and oxygen desaturation to Lynch EL. Ketamine received IM ketamine, were continuously 88% occurred in 1 patient, sedation in mentally 2.9-4.7 mg/kg (n = 15), monitored per ED which resolved with airway disabled adults. or IV ketamine, 1 mg/kg ketamine protocol. repositioning. Brief “possible Acad Emerg Med 6:1, (n = 2), for a variety of seizures” occurred in 3 patients, 86-7(1999) eng. ED procedures. Five of all known for seizures, 2 of these patients received whom were known for daily concurrent midazolam. seizures; these episodes resolved without treatment. Postemergence emesis occurred in 3 patients. No recovery hallucinations or agitation occurred in this cohort. (continued on next page) 1001 1002

Table 1 (continued) AB C D E F 36 65 Green SM, Sherwin TS. Prospective case series of Airway complications, No airway complications or Small series. Incidence and severity 26 patients aged 16-21 hypersalivation, emesis, hypersalivation occurred. Emesis of recovery agitation undergoing painful procedures and the adequacy of sedation was reported in 2 patients and an after ketamine sedation in the ED. Patients received were prospectively assessed. urticarial rash occurred in one in young adults. Am J opioid analgesia as needed Agitation, crying, and patient. One patient had recovery Emerg Med 23:2, before the painful procedure. npleasant hallucinations agitation and one patient had 142-4(2005) English. IV ketamine was administered or nightmares during recovery crying; in both cases as determined by the treating recovery were each symptoms resolved without physician in doses ranging prospectively recorded on treatment and patients were between 1.0 and 1.9 mg/kg a visual analog scale by calm at the time of discharge. with a mean of 1.3 mg/kg. the provider. No unpleasant hallucinations No benzodiazepines were or nightmares occurred. administered at any time. 37 103 Hejja P, Galloon S. 150 patients undergoing dilation Vital signs were continuously No adverse cardiorespiratory Pantopon is not commonly A consideration of and curettage received pantopon monitored. Psychiatric adverse events are reported. used in modern EM practice. ketamine dreams. (an opioid), 0.28 mg/kg, 90 min adverse events were 11% of patients had unpleasant Can Anaesth Soc J 22:1, before induction with IV prospectively sought by a dreams; this did not vary 100-5(1975) English ketamine, 2.2 mg/kg. Anesthesia study investigator during significantly among the 3 groups. was maintained with repeat the procedure, during 75% of patients who identified ketamine doses, 0.5 mg/kg. recovery by a nurse themselves as home-dreamers Patients were divided into observation protocol, as well dreamed under ketamine; 2% 3 groups: controls, patients as a formal assessment by of patients who identified blindfolded during the one of the study investigators themselves as non–home- procedure, and patients postrecovery. dreamers dreamed under blindfolded during the procedure ketamine. 98% of patients and until return of consciousness. reported that they would have the same anesthetic again or did not care; 2% of patients reported that they would not like to have the same anesthetic again.

38 83 Hervey WH, 151 patients undergoing No cardiorespiratory No cardiorespiratory adverse Psychologically traumatic Nelson L.S. Strayer, R.J. Hustead RF. therapeutic abortion were adverse event reporting events are reported. procedure. Ketamine for dilatation randomized to IV ketamine, methodology is presented. Postoperative nausea or and currettage procedures: 100 mg, with subsequent Adverse psychiatric events vomiting was present in 57% patient acceptance. 50 mg doses as needed were prospectively sought of group I (ketamine only), Anesth Analg 51:4, (n = 53); IV thiopental, in the OR, by trained 35% of group II (ketamine- 647-55(1972) eng. 150 mg, followed by IV recovery room RNs, thiopental-NO2), and 23% ketamine, 100 mg, and nitrous and by predischarge of group III (thiopental-NO2). oxide with subsequent thiopental postoperative interviews. Unpleasant dreams were as needed (n = 37); or IV reported in 32% of group I, thiopental, 150 mg, followed 8% of group II, and no patients adults in sedation procedural for ketamine with associated events Adverse by nitrous oxide with subsequent in group III. Patients rejected thiopental as needed (n = 61). the anesthetic technique in 42% Patients in the last group were of group I, 32% of group II, paralyzed and intubated. and 5% of group III. 39 115 Ikechebelu JI, 295 women undergoing Vital signs were continuously There were no reported Dysphoria and patient Udigwe GO, Obi RA, diagnostic laparoscopy were monitored. Postoperative cardiorespiratory adverse acceptance not distinguished Joe-Ikechebelu NN, randomized to receive IV adverse events such as vomiting, events in any group. In the from emergency delirium. Okoye IC. The use of ketamine, 1 mg/kg (n = 117); talkativeness, restlessness, ketamine only group, 15% simple ketamine IV ketamine, 1 mg/kg + dizziness, and idiosyncratic of patients had emergence anaesthesia for days— diazepam, 10 mg (n = 76); or reactions were prospectively delirium, 6% nausea/vomiting. case diagnostic laparoscopy. IV ketamine + promethazine, assessed. 1 patient had breathlessness J Obstet Gynaecol 50 mg (n = 102). and air hunger and one had 23:6, 650-2(2003) tonic-clonic movements; both English. responded to diazepam. In the ketamine-diazepam group, 1% of patients had emergence delirium, 7% had nausea/ vomiting, and the mean recovery time was prolonged from 45-200 min. In the ketamine- promethazine group, 3% had emergence delirium and 1% had nausea/vomiting, with a mean recovery of 70 min. 40 105 Joly LM, Benhamou D. 76 patients undergoing a variety Study specifically assessed Desaturation was more common Both adverse events were Ventilation during total of surgeries were given IV pulse oximetry readings in the room air group than the in obese patients, note intravenous anaesthesia diazepam, 0.1 mg/kg, and over the course of the supplemental oxygen group. medications dosed with ketamine. ketamine, 2.5 mg/kg, and surgery and recovery. Two patients required per kilogram. Can J Anaesth 41:3, randomized to supplemental Psychiatric adverse event endotracheal intubation for 227-31(1994) English. oxygen and room air. reporting is not presented. apnea associated with generalized rigidity. 41 136 Kamm GD. 50 patients undergoing a variety Cardiorespiratory status was No cardiorespiratory Minimal methodology Ketamine anaesthesia by of surgical procedures received continuously monitored. adverse events occurred. presented in this brief report. continuous intravenous PO haloperidol, 0.1 mg/kg, No psychiatric adverse Psychiatric adverse drip. Trop Doct maximum 5 mg 1 h before event reporting methodology events are not 8:2,68-72(1978) eng. induction of anesthesia with is presented. commented upon. an IV ketamine drip (rate not quantified) that was maintained until several minutes before the completion of the procedure. Average ketamine dose was 4-6 mg/kg per hour.

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Table 1 (continued) AB C D E F 42 134 Ketcham DW. Historical account of No adverse event reporting A single anesthetic death was Descriptive review. Where there is no approximately 8000 patients methodology is presented. reported, when a mother was anaesthesiologist: the many who received ketamine for allowed to hold her child uses of ketamine. Trop Doct various surgical and nonsurgical before recovery from anesthesia, 20:4, 163-6(1990) English. procedures for a 15-y period in and the child was held in a a rural mission hospital in neck-flexed position. No other southern Bangladesh. Diazepam adverse events were reported. premedication was given Specifically no laryngospasm 2.2 mg/kg PO 1 h preprocedure occurred, despite ketamine or IV near the time of induction. technique being used many Patients received IV ketamine, times for esophagoscopy 2.2 mg/kg, or IM 4.4 mg/kg. and bronchoscopy. The same provider typically administered the anesthesia and performed the surgical procedure. 43 90 King, Steven. Brief historical account of No adverse event reporting No cardiorespiratory adverse Brief review, minimal A new intravenous or 106 patients undergoing methodology is presented events occurred. “There was methodology. Dysphoria intramuscular anesthetic. unspecified operations who though the study was a noticeable but not disturbing and patient acceptance Anesthesiology received ketamine either carried out in an depression of the respiration not distinguished from 28:258(1967) English. IV (n = 56) or IM (n = 38) anesthesiologist-controlled for 2 to 3 min.” Psychiatric postoperative hallucinations. or IM followed by IV (n=12), OR setting. adverse events were not at a dose of 2.2 mg/kg. Further quantified, but “About 50% half-doses were given as needed. of the adults had definite hallucinations, often of a terrifying nature.” No postoperative vomiting occurred. 44 102 Krestow M. 100 patients undergoing Cardiorespiratory adverse No cardiorespiratory adverse Psychologically traumatic The effect of therapeutic abortion alternated event reporting methodology events are reported in either procedure. postanaesthetic dreaming between 2 groups: One group is not presented though the group. The incidence of on patient acceptance of received IV ketamine, 2 mg/kg, study was carried out in an unpleasant dreams after

ketamine anaesthesia: at induction and 1 mg/kg at the anesthesiologist-controlled ketamine was 36%. Nelson L.S. Strayer, R.J. a comparison with time of cervical dilation; the OR setting. 12 to 24 hours No patient in the thiopentone thiopentone-nitrous oxide other group received postprocedure, patients were group had an unpleasant dream. anaesthesia. Can Anaesth thiopentone, 5 mg/kg, and a specifically questioned by 34% of patients in the ketamine Soc J 21:4, 385-9(1974) nitrous oxide/oxygen mixture an anesthesiologist about group rejected ketamine as an English. at induction with additional their dreams and acceptance agent for future surgery; thiopentone, 1.7 mg/kg, of the anesthetic technique. all patients in the thiopentone at cervical dilation. All patients group accepted their anesthetic received 10 mg droperidol for future surgery. 60 min before surgery. 45 75 Kumar A, Bajaj A, 50 women undergoing short Cardiorespiratory adverse Of controls, 13 found ketamine Presence of silent adults in sedation procedural for ketamine with associated events Adverse Sarkar P, Grover VK. gynecological procedures event reporting is not anesthesia acceptable and 8 not headphones on emergence The effect of music were given IM morphine presented. Adverse acceptable. 20 patients in the might be disconcerting on ketamine induced .15 mg/kg and promethazine, psychiatric events were music group found ketamine to some patients. emergence phenomena. 0.4 mg/kg, 1 h before induction specifically sought by anesthesia acceptable and Anaesthesia 47:5, with IV ketamine, 2 mg/kg. survey on postoperative 1 unacceptable. 438-9(1992) English. Patients were then randomized day 2. to listen to silent headphones or music of their choice for 5 min before induction and 15 min after the completion of the procedure. 46 77 Lederer W. Peripartum Historical account of patients Monitoring was “restricted No cardiorespiratory adverse Descriptive review. general anaesthesia without undergoing 65 operations and to intermittent measurement events occurred. “Frightening tracheal intubation. 347 minor surgical interventions of blood pressure, pulse rate, hallucinations were infrequent, Anaesthesia 55:11, in a Ugandan hospital. Patients and respiratory rate.” and, when present, 1140(2000) English. received IV ketamine, 0.5 mg/kg, not completely controlled by followed by 0.25 mg/kg doses benzodiazepines.” every 10-15 min prn. 47 70 Lilburn JK, Dundee JW, 315 patients undergoing minor Cardiorespiratory monitoring No cardiorespiratory adverse Large number of Nair SG, Fee JP, gynecologic procedures were was in place per operating events were reported. The treatment groups. Johnston HM. Ketamine randomized to receive one of room protocols. Psychiatric incidence of unpleasant sequelae. Evaluation 14 premedicant regimens, adverse events and patient dreams and degree of patient of the ability of various including saline placebo, acceptability were acceptability varied widely premedicants to attenuate 10-40 min before induction. prospectively sought by across the premedicant its psychic actions. The treating anesthesiologist standardized methodology. regimens. Of 5 patients who Anaesthesia 33:4, was blinded to the group received placebo, 2 reported 307-11(1978) eng. allocation. All patients then unpleasant dreams and received IV ketamine, 2 mg/kg, 1 patient accepted the anesthetic for induction, with additional technique. Of the treatment 0.25 mg/kg boluses as needed. groups, IV lorazepam 4 mg Premedicant regimens included provided the most consistent varying combinations of improvement in patient diazepam, flunitrazepam, acceptance, with a complete lorazepam, fentanyl, abolition of unpleasant trifluoperazine, pentobarbital, dreams and 100% patient hydroxyzine, meperidine and acceptance if given 30-40 min promethazine. before induction. A significant prolongation of recovery time was associated with lorazepam premedication. (continued on next page) 1005 1006

Table 1 (continued) AB C D E F 48 97 Lilburn JK, Dundee JW, 255 patients undergoing No cardiorespiratory No cardiorespiratory Minimal methodology Nair SG. Attenuation minor gynecological adverse event reporting adverse event presented in this brief report. of psychic sequelae procedures received methodology is data are presented. from ketamine an intravenous presented. Psychiatric 35% of patients [proceedings]. Br J premedicant 10 min adverse events were who received placebo Clin Pharmacol 4:5, before receiving IV prospectively assessed had unpleasant dreams, 641P-2P(1977) eng. ketamine, 2 mg/kg, and evaluated in a and 64% found the for induction with postoperative survey. anesthetic unacceptable. smaller repeat doses All premedicants as necessary. reduced psychiatric adverse Premedicants included events and increased patient saline placebo; diazepam, acceptability. 15 mg and 0.2 mg/kg; The lorazepam and flunitrazepam, 1.5 mg flunitrazepam and 0.02 mg/kg; premedicants offered lorazepam, 4 mg; the greatest reduction droperidol, 5 mg; in unpleasant dreams droperidol, 5 mg with and improvement in fentanyl, 0.1 mg; anesthesia acceptability. pentobarbital, 100 mg; Based on these results, hydroxyzine, 100 mg; the authors administered IV meperidine, 100 mg; lorazepam 4 mg to and promethazine, 155 additional patients 25 mg. 30 min preinduction and report 100% anesthetic acceptability in this cohort. 49 89 Lorhan PH, Lippman M. 87 patients of average No adverse event There were no ASA Minimal methodology Clinical appraisal of the age 84 (including reporting methodology class I or II operations; presented. Extraordinarily use of ketamine 3 patients aged more is presented though 22 operations were high-risk patients in ..Sryr ..Nelson L.S. Strayer, R.J. hydrochloride in the than 100) undergoing the study was carried ASA class III, 55 class IV, this series. aged. Anesth. Analg. 91 surgical procedures out in an anesthesiologist- and 14 class V. Anesthesia (Cleveland) 50: received a variable dose controlled OR setting. was supplemented with May-Jun, of droperidol before IV other agents intraoperatively 448-51(1971) ketamine, 2.2 mg/kg, in 4 cases. Five perioperative supplemented with deaths occurred, none smaller doses as needed attributed to the anesthetic. intraoperatively. 9 cases of severe hypertension occurred, treated successfully adults in sedation procedural for ketamine with associated events Adverse with reserpine. No other actionable or clinically significant adverse event is reported. 50 88 Maduska AL, 10 patients presenting No adverse event There were no Hajghassemali M. with active labor received reporting methodology cardiorespiratory Arterial blood gases in ketamine, 1 mg/kg, is presented, though adverse events. mothers and infants by slow intravenous all patients received There was no during ketamine injection. routine perinatal difference between anesthesia for vaginal An arterial blood gas hemodynamic controls and the delivery. Anesth Analg sample was obtained at monitoring. ketamine group in 57:1, 121-3(1978) eng. the time of delivery or either mothers or 3 min postinjection, infants with regard whichever came first. to pH, Pco2,Po2, This experimental group and Apgar scores. was compared against Two patients in the 10 control patients who ketamine group received 50 mg “seemed restless” meperidine and spinal after delivery and anesthesia for labor. were successfully Arterial blood gas samples managed with were sent from this group 10 mg IV diazepam. at the time of delivery. 51 79 Mattila MA, Larni HM, 109 patients undergoing Cardiorespiratory No cardiorespiratory The postprocedure use of Nummi SE, Pekkola PO. dilation and curettage adverse event reporting adverse events are methylergotamine is Effect of diazepam on received morphine methodology is not reported. 20% of unlikely in EM practice. emergence from 8-14 mg 1 h before presented though the patients in the placebo Patient's subjective ketamine anaesthesia. receiving IV ketamine study was carried out group had unpleasant acceptance of ketamine A double-blind 1.5 mg/kg at induction. in an anesthesiologist- dreams/experiences, not reported. study. Anaesthesist With the ketamine controlled OR setting. compared to 6% of 28:1, 20-3(1979) eng. bolus, 55 patients were Psychiatric adverse patients in the randomized to receive IV events were prospectively diazepam group. diazepam 10 mg and sought by both physician Nausea or vomiting 54 patients were and nurse in was present 2% of randomized to placebo. postoperative assessment. diazepam-treated Supplemental patients compared ketamine was given to 24% of controls. 0.2-0.4 mg/kg prn. Most patients received methylergotamine 0.2 mg IV at the end of the procedure.

(continued on next page) 1007 1008 Table 1 (continued) AB C D E F 52 96 Moore J, McNabb TG, 75 patients undergoing Cardiorespiratory status No cardiorespiratory Varying, uncontrolled Dundee JW. Preliminary minor obstetric was continuously adverse events premedicants. report on ketamine operations received IV monitored. Psychiatric occurred. Unpleasant in obstetrics. Br J ketamine, 2 mg/kg, adverse events were dreams occurred in Anaesth 43:8, followed by smaller prospectively sought. 8% of patients; 3/75 779-82(1971) eng. doses as needed. patients reported the Premedicants varied and anesthetic unacceptable. included diazepam, meperidine pentazocine, papaveratum, and pentobarbital. 53 67 Morgan M, Loh L, 138 patients aged 2 mo Cardiorespiratory and There were no Uncontrolled study with Singer L, Moore PH. to 89 y undergoing psychiatric adverse cardiovascular widely varying premedicant Ketamine as the sole minor surgical events were adverse events. regimens. anaesthetic agent for procedures received prospectively sought Airway obstruction minor surgical IV ketamine, 2.2 mg/kg, in the OR and recovery occurred in 11.5% procedures. for 45-60 s or IM room. of patients, all of Anaesthesia 26:2, ketamine, 10-12 mg/kg, which responded to 158-9(1971) eng. with incremental IV airway repositioning doses given as needed. maneuvers or the Premedicants were not insertion of an controlled and variously oropharyngeal airway. included papaveratum, 10% of patients droperidol, diazepam, reported frightening and “miscellaneous” dreams; 2 patients agents. required diazepam sedation postoperatively. Postoperative vomiting occurred in 4.2%. 54 106 Nanayakkara B. 65 patients undergoing Cardiorespiratory No cardiovascular Dysphoria and patient Maintenance of minor surgical procedures status was continuously adverse events acceptance not distinguished oxygenation during in Sri Lankan hospital monitored. Patients occurred. 7.6% of from postoperative total intravenous received IV diazepam, were prospectively patients showed a fall hallucinations. Nelson L.S. Strayer, R.J. anaesthesia with 0.1 mg/kg, followed by assessed for in Sao2 to b90% after ketamine while IV ketamine, 2 mg/kg, “hallucinations.” ketamine administration; breathing air. Ceylon given for 1 min. of these 3/5 required a Med J 39:4, Half-dose ketamine jaw-thrust maneuver to 160-2(1994) English. supplements were given maintain a patent airway. as needed. Upper airway obstruction appears to have been diagnosed based on snoring. Postoperative hallucinations occurred adults in sedation procedural for ketamine with associated events Adverse in 7.6%, and vomiting occurred in 12%. 55 131 Odetoyinbo O. 67 patients aged 6-43 y Cardiorespiratory No cardiorespiratory Protective effect of lidocaine Ketamine: Parenteral undergoing tonsillectomy status was continuously adverse events occurred; is unknown, as there was anaesthesia for at a Nigerian hospital monitored by a nurse specifically there were no control group who did tonsillectomy. Trop received IV diazepam, anesthetist. no cases of laryngospasm. not receive lidocaine spray. Doct 17:1, 0.2 mg/kg (max 10 mg) No psychiatric adverse No “emergency delirium” Dysphoria and patient 21-2(1987) eng. 5-10 min preinduction. event reporting occurred, but “patients acceptance not distinguished The pharynx was then methodology is were rather more restless from emergence reactions. anesthetized with presented. than usual.” 3-4 doses of 10% The authors note a lidocaine spray prolonged recovery time (10 mg/dose). Patients ranging from 40 min to then received IM 2 h. Postoperative ketamine 5 mg/kg and vomiting occurred in were positioned in neck 31% of patients. hyperextension with sandbags under the shoulders so that blood would flow anteriorly rather than posteriorly. An additional dose of IV ketamine, 1 mg/kg, was given just before the commencement of the operation. 56 118 O'Dowd MJ, Sil B. 50 patients with retained Cardiorespiratory No cardiorespiratory Ketalar its products of conception status was continuously adverse events use by a single undergoing uterine monitored. occurred. 20% of operator. Med J evacuation in a Zambian No psychiatric adverse patients had Zambia 11:5, hospital received event reporting unpleasant dreams. 151-3(1977) English. IV ketamine, 2 mg/kg. methodology is Postoperative Anesthesia and operative presented. emesis occurred procedure was performed in one patient. by the same provider. 57 100 Oduntan SA, Gool RY. 100 patients undergoing Cardiorespiratory No cardiorespiratory Limited methodology Clinical trial of various surgical procedures status was continuously adverse events are description. ketamine (CI-581): a received 1-1.25 mg/kg IV monitored. No psychiatric reported. Limb preliminary report. ketamine followed by a adverse event reporting movements Can Anaesth Soc J 17:4, ketamine infusion or smaller methodology is presented. occurred in 12% 411-6(1970) eng. boluses as needed. of patients; limb (continued on next page) 1009 1010 Table 1 (continued) AB C D E F rigidity 15%, nausea/ vomiting in 4%. Restlessness was observed postoperatively in 5% of patients with hallucinations in 2%. Of hallucinations in 2 patients, in one patient were they described as frightening. 58 66 Paix BR, Capps R, 117 patients undergoing No adverse event “Oximeter readings Descriptive review. Neumeister G, mostly lower extremity reporting methodology generally dipped to Semple T. Anaesthesia wound-related surgeries is presented. around 90% after in a disaster zone: after a natural disaster induction, then rapidly a report on the in Indonesia received rose to exceed 95%.” experience of an either IV midazolam, “Only 4 of 117 Australian medical team 5 mg, or diazepam, spontaneously in Banda Aceh 2 to 5 mg,a “small ventilating patients following the “Boxing intravenous morphine required temporary jaw Day Tsunami.” dose at the anesthetist's support and a further Anaesth Intensive discretion,” and ketamine, 2 required oral airways.” Care 33:5, 80-100 mg, with “Approximately one 629-34(2005) English. quarter-dose boluses of patient in 10 appeared ketamine as well as to have unpleasant “further benzodiazepines psychic phenomena.” and opioids as necessary” to maintain adequate surgical conditions. 59 76 Pederson L, Benumof J. 23 Kenyan patients Study specifically Mean Sao2 values Elevation 6000 feet, Incidence and undergoing a variety of assessed pulse oximetry reached their nadir Pio2 127 mm Hg. magnitude of minor surgical procedures readings over the course (90.8%) in the first hypoxaemia received ketamine of the surgery and minute after induction. ..Sryr ..Nelson L.S. Strayer, R.J. with ketamine in a rural either IV 2 mg/kg or IM recovery. Psychiatric In 4 patients, Sao2 African hospital. 8 mg/kg with additional adverse event reporting dropped b90%; 2 Anaesthesia IV boluses 0.5 mg/kg as methodology is not patients b85%; 48:1, 67-9(1993) needed. Sao2 was presented. 2 patients b75%. English. continuously monitored. In all cases, saturations Age range was 4 mo to returned to normal 60 y; 12 patients were spontaneously with younger than supplemental oxygen. 10 y of age. 60 104 Pesonen P. Pulse 65 war-wounded patients Study specifically Of 57 analyzable results, No control group. adults in sedation procedural for ketamine with associated events Adverse oximetry during were given IV diazepam, assessed pulse oximetry 6 patients had brief ketamine anaesthesia 0.1 mg/kg, and ketamine, readings over the course periods of saturation in war conditions. 2 mg/kg, followed of the surgery and b90%, including Can J Anaesth 38:5, by a titratable ketamine recovery. Psychiatric 2 patients who 592-4(1991) English. drip for the duration of adverse event reporting had periods of surgery. Pulse oximetry methodology is not saturation b80% measurements were presented. associated with recorded throughout. snoring. All 6 patients responded to airway repositioning measures. 61 109 Porter K. Ketamine in Historical account of Cardiorespiratory status There were no prehospital care. Emerg 32 patients aged 9-87 was continuously cardiovascular adverse Med J 21:3, undergoing various monitored. events, including in 351-4(2004) eng. prehospital management No psychiatric adverse 2 patients who were procedures including event reporting hypotensive on EMS extrication, limb reduction/ methodology is presented. arrival. In these splintage, and in one 2 patients SBP was case an above-knee maintained and not amputation. Patients increased. received IV ketamine, Hypersalivation 20, 25, 50 or 100 mg, occurred in one instance, initially, with additional the 9-y-old child, 20, 25, or 50 mg doses but was “not a clinical given as needed. problem.” No other Patients received IV respiratory adverse midazolam, 0.5-2 mg, events occurred. as needed for psychiatric Midazolam was given distress on emergence. in 12/32 patients who were recovering from ketamine administration and exhibited “aggression or agitation.” 62 117 Roberts JR, Geeting GK. Case report describing Continuous The patient entered Case report design. Intramuscular ketamine an uncontrollably violent cardiorespiratory a tranquil/dissociative for the rapid tranquilization cocaine-intoxicated monitoring was state within 2-3 min of the uncontrollable, HIV-positive 28-y-old instituted as soon as postinjection and was violent, and dangerous man who used a spurting feasible postinjection. then able to be managed adult patient. J Trauma ulnar artery laceration No psychiatric adverse conventionally. 51:5, 1008-10(2001) eng. as a weapon. The patient event methodology is Transient hypertension was temporarily presented. and tachycardia occurred restrained and received without sequelae. 1011 (continued on next page) 1012 Table 1 (continued) AB C D E F IM ketamine, 5 mg/kg; No cardiorespiratory or several minutes later the psychiatric adverse patient received IM events occurred in this lorazepam, 4 mg. case. Follow-up psychiatric and laboratory assessment was unremarkable. 63 69 Roopnarinesingh S, Apparently prospective “Each patient's airway No adverse Dysphoria and patient Kalipersadsingh S. evaluation and vital signs were cardiorespiratory events acceptance not Manual removal of the of 30 patients undergoing supervised by the occurred. “Hallucinations distinguished from placenta under ketamine. surgery for retained house-officer.” in the form of pleasant postoperative Anaesthesia 29:4, placenta in Trinidad. No psychiatric adverse dreams” were present hallucinations. 486-8(1974) eng. Each patient received IV event reporting in 2 patients, and one diazepam 10 mg or methodology is patient became IV chlorpromazine, presented, but “any “arrogant” on emergence. 25 mg, 3-5 min before adverse reactions” induction with IV were prospectively ketamine, 100 mg. recorded. No anesthesiologist was present, but the surgeon had a junior physician assistant. 64 23 Sacchetti A, Senula G, A prospectively generated Cardiorespiratory Ketamine use was Uncontrolled use study. Strickland J, Dubin R. procedural sedation status was monitored associated with a Dosing, route, and nature Procedural Sedation registry (n = 1028) reported per local ED protocols; single undefined of adverse event in the Community on 145 patients who received cardiorespiratory adverse adverse event (0.7%), not reported. Emergency ketamine for a variety of events and the presence which was the lowest Department: Initial ED procedures. of “agitation” were adverse event rate of all Results of the Dosing and comedication prospectively recorded agents included in the ProSCED Registry. information is not reported. on structured forms. study that are typically Acad Emerg Med used for procedural (2007) ENG. sedation. 83% of procedural sedations in this series were carried Nelson L.S. Strayer, R.J. out by a single operator. 66 91 Sears BE. Case report in the form None. “Hypoxic cardiac No further information Complications of of letter to editor. arrest secondary to is provided. ketamine. respiratory depression Anesthesiology has been observed in 35:2, 231(1971) a debilitated adult.” English. 67 73 Sklar GS, Zukin SR, 90 patients undergoing a Cardiorespiratory No cardiorespiratory Uncontrolled study Reilly TA. Adverse variety of minor surgical parameters were adverse events were with widely varying reactions to ketamine procedures received a monitored as per reported. The rate of premedicant regimens. anaesthesia. Abolition focused interview by a operating room protocol. dreaming was between adults in sedation procedural for ketamine with associated events Adverse by a psychological trained provider where Psychiatric adverse 30% and 45%. technique. anesthetic expectations events were prospectively No patients had Anaesthesia 36:2, were discussed and sought and formally unsatisfactory dreams 183-7(1981) eng. patients advised that they assessed by the treating and no patients were may experience vivid anesthesiologist based unwilling to have hallucinations, the on a predetermined ketamine anesthesia again. content of which they instrument. could determine. Approximately half the patients then received “a wide variety” of premedications as determined by the anesthesiologist; all patients received IV ketamine, 1-2 mg/kg, with supplemental doses as needed. 68 72 Spreadbury TH. 30 elderly women This study was primarily No adverse Dysphoria and patient Anaesthetic techniques (10 younger than 80 y designed to assess cardiorespiratory events acceptance not distinguished for surgical correction and 20 women older than short-term outcomes, occurred intraoperatively from postoperative of fractured neck of 80 y) undergoing femoral but cardiorespiratory or in the immediate hallucinations. femur. A comparative neck fracture repair and psychiatric adverse postoperative period. study of ketamine received ketamine IV, events were prospectively One patient in the and relaxant anaesthesia 2 mg/kg, with sought and recorded, ketamine group died in elderly women. supplemental half including a battery of in the first 15 d Anaesthesia 35:2, doses as needed. sophisticated postoperative (attributed to wound 208-14(1980) eng. Patients in pain mental and physical abscess and septicemia), preoperatively were given functioning tests. compared to 7 in the “an analgesic” and oral relaxant group. diazepam, 5-10 mg, More late deaths was given if received occurred in the “relaxant” anesthesia, ketamine group, usually consisting of however, so that the thiopentone with a final survival rate paralytic and volatile was equal. Of the anesthetic. 30 ketamine patients, 5 had hallucinations or dreams, but no unpleasant dreams. Of 30 relaxant patients,

(continued on next page) 1013 1014 Table 1 (continued) AB C D E F 4 had hallucinations or dreams, with one patient having a terrifying dream. The operating conditions were noted to be superior with relaxant anesthesia. 69 63 Stefánsson T, 8 patients of average age Numerous No cardiorespiratory Small, uncontrolled study. Wickström I, Haljamäe H. 83 undergoing surgical cardiorespiratory and or psychiatric adverse Hemodynamic and correction of a hip metabolic parameters events occurred. metabolic effects of fracture received IV were prospectively ketamine anesthesia droperidol, 2.5 mg, examined. in the geriatric patient. followed 30 min later by No psychiatric adverse Acta Anaesthesiol slow IV injection of event reporting Scand 26:4, ketamine until the patient methodology is presented. 371-7(1982) eng. was unable to react to verbal command (mean dose 1.75 mg/kg, delivered for 2 min). Anesthesia was supplemented by a continuous infusion of ketamine, titrated to effect. 70 110 Streatfeild KA, 46 patients undergoing No cardiovascular No cardiovascular Altitude 8500 ft, atmospheric Gebremeskel A. minor surgical procedures adverse event adverse events were pressure 570 mm Hg. Arterial oxygen received IV diazepam, reporting methodology reported. The mean saturation in Addis 0.1-0.2 mg/kg, 3-5 min is presented. Respiratory preinduction SaO2 Ababa during before induction with status and Sao2 were was 96%. The SaO2 diazepam-ketamine ketamine IV, 2 mg/kg, prospectively monitored nadir occurred at anaesthesia. Ethiop given for 10 s. and recorded. 3 min and was 55%. Med J 37:4, No psychiatric adverse 30 patients had a 255-61(1999) English. event reporting saturation of 90% or Nelson L.S. Strayer, R.J. methodology is presented. less; of these 8 fell below 80% and received supplemental oxygen. Psychiatric adverse events were not reported. 71 94 Sussman DR. 239 patients undergoing Adverse event reporting In 86 patients 31 y or Dysphoria and patient A comparative 247 assorted operations methodology is not older, incidence of l acceptance not distinguished evaluation of ketamine in a hospital in Guyana presented, however aryngospasm was 4%, from emergence reactions. anesthesia received IV ketamine, cardiorespiratory coughing 2%, in children and adults. 2.2 mg/kg, or IM status seemed to be upper airway adults in sedation procedural for ketamine with associated events Adverse Anesthesiology 40:5, ketamine, 11 mg/kg, continuously monitored obstruction 7%, 459-64(1974) English. followed by supplemental in the anesthesiologist- inadequate analgesia smaller doses as needed controlled operating 1%, excessive motor with or without premedicant IM room setting. activity/hypertonus diazepam, 10-15 mg. The author reports that 16%, “dangerous” he saw all patients hyper-or hypotension postoperatively and 2%, and cardiac reviewed all nursing arrhythmia 1%. notes for complications. In patients 16 y old or older, emergence reactions occurred in 26% of patients who received diazepam and 22% of patients who did not receive diazepam. 72 120 Swelem SE. 118 patients undergoing Cardiorespiratory status No cardiorespiratory Dysphoria and patient Intravenous anaesthetics minor gynecological was continuously adverse events acceptance not for minor gynecological procedures received monitored. Patients occurred. 8% of distinguished from operations. Middle either IV ketamine, were monitored for patients in the postoperative East J Anaesthesiol 100 mg (n = 25), or IV “smoothness of recovery.” ketamine-only group hallucinations. 5:8, 545-51(1980) diazepam, 10 mg, followed had “hallucinations” English. by IV ketamine (n = 93). and 8% had an An additional 352 patients urticarial rash. received a variety of Ketamine-diazepam other anesthetic was judged by the combinations in this study, authors to be the including thiopental, “most satisfactory” althesin, propanidid, of the 10 anesthetic meperidine combinations tested promethazine, hexobarbital, and judged superior and buthalitone. Halothane to ketamine alone. supplementation was provided as needed, though none of the patients in either of the 2 ketamine groups required it. 73 99 Taylor PA, Towey RM. 7 patients received Chest x-rays designed The placement of The clinical significance Depression of laryngeal scopolamine, 0.4 mg, to detect the deposition contrast on the back of the findings is unknown. reflexes during ketamine IM 1 hour before induction of contrast in the lungs of the tongue elicited anaesthesia. Br Med J with ketamine, 2 mg/kg, were taken 1, 2, and a swallowing reflex 2:763, 688-9(1971) English. which was maintained 5 min after contrast in all 7 patients Partial 1015 (continued on next page) 1016 Table 1 (continued) AB C D E F with a continuous ingestion. No other laryngospasm infusion. 10 mL of contrast adverse event reporting developed in one (Dionosil) was then methodology is presented. control after given placed on the back of the 2 mL contrast. tongue. 7 controls There was no clinical received 0.4 mg IM of indication of aspiration scopolamine and 1 h in any case, however, later swallowed 10 mL all 7 patients had contrast. evidence of contrast material present in the lungs on x-ray examination. This study was repeated 1 y later on 17 additional patients, who received either atropine or scopolamine as a premedicant. In the second study, 12 of 17 patients inhaled contrast. 74 122 Tighe SQ, Rudland SV. Retrospective account No adverse event “No patient receiving Semiquantitative review; Anesthesia in northern Iraq: of 71 anesthetic procedures reporting methodology ketamine had adverse events not an audit from a field carried out at a military is presented. unpleasant dreams specifically sought. hospital. Mil Med 159:2, field hospital in Sirsenk, or other sequelae.” 86-90(1994) eng. Iraq. 12 patients were anesthetized using spontaneously breathing technique with IV ketamine, 1-2 mg/kg, and midazolam, 0.07 mg/kg. 75 129 Tolksdorf, W, F Reinhard, 60 patients undergoing Cardiorespiratory Two patients in group High midazolam dose. Nelson L.S. Strayer, R.J. M Hartung and S Bauman. minor gynecological status was continuously 2 received treatment Comparative study operations received monitored of intraoperative of the effects of either thiopental, intraoperatively and hypertension. midazolam-ketamine enflurane, and nitrous postoperatively. Assisted ventilation anesthesia and thiopental oxide (group 1, n = 30), “Psychiatric state” was by BVM was sodium induced IV midazolam 5 mg with prospectively assessed performed for enflurane-nitrous oxide IV ketamine, 0.5-1 mg/kg for 3 h postoperatively. prespecified criteria anesthesia for minor (group 2, n = 30), and was needed in gynecological operations, or IV midazolam, 7.5 mg, 40% of patients in In Status of ketamine with IV ketamine, group 2 and 60% of adults in sedation procedural for ketamine with associated events Adverse in anesthesiology, 481-90. 2-3 mg/kg (group 3, patients in group Ann Arbor, Michigan: n = 30). Smaller 3. 1 patient in group NPP Books, 1990. supplementary doses 2 had unpleasant were given as needed. dreams; no unpleasant dreams occurred in group 3. Vomiting occurred in 8% of ketamine patients. Anesthesia was unacceptable in 2 patients in group 2. The remainder of patients in groups 2 and 3 had “positive” or “moderate” acceptance of the anesthetic. 76 112 Trouwborst A, Retrospective account of No adverse event No adverse events Semiquantitative review; Weber BK, 1033 anesthetic reporting methodology are attributed to adverse events not Dufour D. Medical procedures carried out is presented. ketamine; however, specifically sought. statistics of battlefield at 2 military field no mention of casualties. Injury 18:2, hospitals near the ketamine's safety is 96-9(1987) eng. Thailand/Cambodia found in the article. border. 516 patients were anesthetized using spontaneously breathing technique with IV ketamine, 2 mg/kg, and either diazepam, 0.2 mg/kg, or midazolam, 0.1 mg/kg. 77 133 Veeken H. Ketamine Brief historical account No adverse event r “No complications” Descriptive review. drip anaesthesia for of 40 patient undergoing eporting methodology occurred in this caesarean section. cesarean delivery in a is presented. cohort. No further Trop Doct 19:1, Kenyan hospital. details are given. 47(1989) eng. In all patients the skin was opened under local anesthesia, without any systemic agents or premedicants. Just before uterine incision, IV ketamine, 75 mg, was administered as a 1017 one-time bolus. (continued on next page) 1018 Table 1 (continued) AB C D E F 78 125 Vinnik CA. Historical account of Blood pressure, pulse The author reports The case series is a An intravenous N2000 patients rate, and electrocardiogram the absence of any descriptive review, and the dissociation technique undergoing plastic tracing were continuously cardiorespiratory or survey results are subject to for outpatient plastic surgery procedures monitored. psychiatric adverse all the limitations of surgery: tranquility (breast augmentation, No psychiatric adverse events in this series. this design. in the office surgical facial fracture reductions, event reporting 94% of survey facility. Plast and blepharoplasty, among methodology is presented respondents reported Reconstr Surg 67:6, others) performed in an in the historical account; absence of any 799-805(1981) eng. office setting, without an the structured survey recollection of the anesthesia MD or RN. was designed to surgery. For procedures expected retrospectively assess All respondents denied to be of N2 hour duration, psychological adverse postoperative delirium, patients were premedicated events. hallucinations, with PO lorazepam, or “bad trips,” 4 mg; IM butorphanol, and all respondents 0.4 mg; and IM promazine, would recommend the 25 mg, 1 h before surgery. anesthetic technique. For shorter procedures, Four years later, no premedicants were this author published used. All patients received an additional account IV diazepam, 5 mg, of several thousand followed several minutes more patients, later by 10 mg increments further attesting to the until responsive only to safety and efficacy painful stimuli (usual dose, of the technique. 25 mg). Afterward, all patients received IV ketamine, 75 mg, with additional 25-50 mg doses of ketamine and 10 mg doses of diazepam as needed for the duration of surgery. In addition, a survey of 100 randomly Nelson L.S. Strayer, R.J. selected patients receiving this technique within 6 y was carried out by an affiliated RN. 79 107 Weerasekera DS, Retrospective A theater nurse was No cardiorespiratory Retrospective study. Gunawardene KK. observational study of assigned to monitor complications occurred Dysphoria and Ketamine as an 4851 patients cardiorespiratory status in this cohort. patient acceptance not anaesthetic agent for undergoing tubal throughout the procedure. “Postoperative distinguished adults in sedation procedural for ketamine with associated events Adverse tubal sterilisation. ligation in a Sri Lankan No psychiatric adverse hallucinations within from postoperative Ceylon Med J 41:3, hospital. All patients event reporting the first 6 h after hallucinations. 102-3(1996) English. received IV diazepam, methodology is surgery was observed 0.1 mg/kg, followed by presented. in most patients.” 96% IV ketamine, 2 mg/kg, of patients had no given for 1 min. recollection of the surgery when questioned at 24 h. 80 95 White PF, Ham J, 60 patients undergoing Cardiorespiratory No adverse Way WL, Trevor AJ. dilation and curettage adverse events were cardiorespiratory events Pharmacology of were randomized to receive prospectively sought. occurred in any group. ketamine isomers in racemic ketamine, Psychiatric adverse In the 20 patients in the surgical patients. (+)ketamine, or (−)ketamine. events were racemic group, the Anesthesiology 52:3, Patients received prospectively sought incidence of adverse 231-9(1980) eng. racemic ketamine, postoperatively by a psychiatric events ranged 2 mg/kg, or its isomeric trained psychologist between 10% and 30%, equivalent in according to a depending on the double-blind fashion. standardized protocol. measurement used, and ketamine acceptability was 65%. Of note, the positive enantiomer was superior to the racemic mixture at almost all measured end points, whereas the converse was true for the negative enantiomer. 81 28 Willman EV, 114 patients undergoing a Cardiorespiratory and No cardiovascular No control group. Andolfatto G. variety of ED procedures psychiatric adverse adverse events occurred. A Prospective Evaluation received a 1:1 mixture of events were 3 patients had oxygen of “Ketofol” (ketamine/ ketamine prospectively recorded desaturation, with one propofol Combination) (10 mg/mL) and propofol on a standardized form. patient requiring BVM for Procedural Sedation (10 mg/mL) delivered in ventilation. 3 patients and Analgesia in the 1-3 mL aliquots. Some patients required airway Emergency Department. received opioid analgesics repositioning. Ann Emerg Med preprocedure. 1 patient developed 49:23-30(2007) ENG. an agitation on emergence requiring IV midazolam, 0.025 mg/kg. 2 patients had “mild dysphoria” requiring no intervention. 1019 (continued on next page) 1020 Table 1 (continued) AB C D E F No postprocedure vomiting occurred. Median ketofol dose was 0.75 mg/kg of propofol and ketamine. 96.5% procedures required no additional medication. Median satisfaction scores (rated from 0 to 10) were 10, 10, and 10 for physicians, nurses, and patients. 82 132 Zimmermann H. 200 patients undergoing No adverse event 5 cases required a It is unclear if data were Ketamine drip cesarean delivery at reporting methodology change in anesthesia collected prospectively or anaesthesia rural Zimbabwean is presented. with oxygen, nitrous reviewed retrospectively for caesarean section. hospital received IV oxide, and halothane in this study. Relationship Report on 200 cases ketamine, 100 mg, given for surgical extension between decision to treat from a rural hospital in for 60 s,followed by a of the procedure. and patient dysphoria/ Zimbabwe. Trop Doct maintenance drip. In the 195 remaining acceptance unknown. 18:2, 60-1(1988) Diazepam or flunitrazepam cases, no cardiorespiratory English. were given intravenously adverse events occurred. as needed postoperatively Psychiatric adverse events “to provide a sound were not quantified, sleep and depress but diazepam was given possible psychomimetic postoperatively in reactions.” Most cases 15.5% of patients and were managed by flunitrazepam in 9.5%. nonphysician “auxillaries.” Note patients in this series of cesarean deliveries were unfasted. 83 119 Zohairy AF, 237 patients undergoing Cardiorespiratory status No cardiorespiratory adverse Dysphoria and patient Siddiqi SM. The use minor surgical procedures was continuously events occurred. An acceptance not of ketamine HCl in in a Qatar hospital were monitored. erythematous rash about the distinguished from Nelson L.S. Strayer, R.J. minor surgery. Middle studied. All adults No psychiatric adverse neck and upper chest occurred emergence delirium. East J Anaesthesiol (74% of patients) received event reporting in 8% of patients and resolved 3:121-9(1971) IV meperidine, 50 mg, methodology is presented within 15 min. 2% of and IV phenergan, 25 mg, but “trained nurses” patients had “emergence 45 min before induction observed patients for delirium with excitation” with IV ketamine, 2 mg/kg, postoperative and were “easily managed” followed by smaller doses complications. with meperidine. as needed. Most children Postoperative emesis received IM ketamine, 4 mg/kg. occurred in 4% of patients. 84 87 Zsigmond EK, Matsuki A, 14 patients undergoing In addition to serial The time of greatest Two respiratory depressants adults in sedation procedural for ketamine with associated events Adverse Kothary SP, Jallad M. gynecologic surgery were blood gas measurements, respiratory depression given to all patients. Arterial hypoxemia premedicated with IM electrocardiogram, occurred 2 min caused by intravenous diazepam, 0.15 mg/kg, pulse, and blood pressure postinjection. At that time, ketamine. Anesth Analg and either meperidine, were continuously mean Pao2 values 55:3, 311-4(1976) 1.5 mg/kg, or morphine, monitored throughout decreased from baseline English. 0.15 mg/kg. 7 patients the study. Chest 84-58 Torr, with PaCO2 were then induced with movements were values rising from IV ketamine, 2 mg/kg, monitored by baseline 34- 38 Torr. given for 30 s, and plethysmography. Mean arterial pH at 7 patients were induced No psychiatric adverse 2 min postinjection with IV diazepam, event reporting was 7.37. Respiratory 0.2 mg/kg, given for methodology is presented. rate decreased from 30 s followed 5 min later baseline 19 breaths per by ketamine, 2 mg/kg, minute to 11 at 2 min. given for 30 s. More than half of the Arterial blood gas samples patients had brief periods were obtained at time 0, of apnea. The ketamine/ 2, 5, and 10 min after diazepam group did ketamine administration. not show any The study design significant difference stipulated that no airway- when compared to the opening maneuvers were ketamine group. performed. Blood pressure and heart rate were both elevated after ketamine administration; this effect was significantly attenuated by concurrent diazepam administration. 85 137 Klose R, Peter K. 41 adult patients No adverse event 2 episodes of Unclear methodology. Clinical studies on undergoing burn-related p reporting methodology hypotension are Much larger ketamine single-drug anesthesia rocedures at a German is presented. reported, as well as 1 dose than is currently using ketamine in specialty burn clinic episode of cyanosis. recommended. patients with burns. received IV ketamine, qMotor agitationq Anaesthesist 22:3, 4-5 mg/kg, followed by occurred in 3 patients 121-6(1973) German. 1-2 mg/kg doses as needed. intraoperatively and 6 patients postoperatively. One patient had “dreams” postoperatively. 86 138 Vidal Cerdán J. A historical description No adverse event Blood pressure noted Descriptive review. Comments on 400 of 400 patients undergoing reporting methodology to increase an average anesthesias with unspecified types of is presented. of 10 mm Hg without ketamine operations or painful any elevations requiring 1021 (continued on next page) Table 1 (continued) 1022 AB C D E F chlorhydrate. Rev Esp transport at a Spanish treatment. 2 patients Anestesiol Reanim center. 133 patients required airway 18:2, 244-59(1971) received IV ketamine repositioning. One patient Spanish. alone at a dose of required intubation. 1-3.5 mg/kg; others Psychiatric adverse received barbiturate effects were observed and/or narcotic but not quantified. pretreatment. 87 140 Mauad Filho F, 22 patients in labor Basic maternal and Control group results Results are poorly reported. Meirelles RS. were given IV ketamine, fetal vital signs appear are not reported. 1/22 Dysphoria and patient [Materno-fetal acid-base 1 mg/kg, with to have been experimental patient acceptance not distinguished equilibrium evaluation in supplemental doses of prospectively experienced apnea, from dreams/hallucinations. (author's transl)]. Rev Bras 0.5 mg/kg as needed. measured. Psychiatric 1 nausea, 4 “perineal Pesqui Med Biol 8:5-6, These patients were adverse event rigidity,” 4 “dreams/ 401-13(1975) Portuguese. compared with 20 methodology is not hallucinations.” 11/22 control patients reported. patients demonstrated in labor who received a significant increase no medications. A variety in blood pressure. of maternal and fetal physiologic parameters were prospectively studied. 88 139 Tarnow J, Hess W. Case report of a patient No adverse event After ketamine Case report methodology. Pulmonary hypertension with coronary artery reporting methodology administration, mean and pulmonary disease who developed is presented. Patient pulmonary artery edema caused by acute pulmonary edema was in a setting where pressure rose from intravenous ketamine. after receiving advanced monitoring, 27-65 mm Hg, Anaesthesist 27:10, IV ketamine, 1.5 mg/kg, including pulmonary pulmonary vascular 486-7(1978) German. for induction of artery catheter resistance increased anesthesia. measurements, threefold and left was performed. ventricle filling pressure increased from 18-48 mm Hg. These hemodynamic

derangements were Nelson L.S. Strayer, R.J. associated with pulmonary edema and resultant arterial hypoxemia. Fentanyl .01 mg/kg “promptly reversed the systemic and pulmonary vascular effects of ketamine.” Adverse events associated with ketamine for procedural sedation in adults 1023

Because no such agent exists, the emergency practitioner must be mindful that comedications, particularly midazolam, must choose the drug or drug combination best suited to the may cause dose-related hypoventilation, and in all proce- goals of the procedure and the characteristics of the patient dural sedation cases should be prepared to provide airway and practice environment. and respiratory support. Fentanyl and midazolam offer the weight of tradition but Ketamine causes centrally mediated catecholamine reup- are consistently associated with the highest complication rate take inhibition that generally results in a modest increase in among modern procedural sedation regimens [23,147-149]. heart rate and an elevation of blood pressure, which on Although providing analgesia, amnesia, anxiolysis and occasion can be marked. This is not a concern in most ED reversibility, this combination has a comparatively delayed patients and there are no reports of ketamine-induced peak effect and prolonged duration of action with a narrow myocardial ischemia. Furthermore, the literature is replete therapeutic index, which hinders effective titration [150]. with studies of ketamine use in the elderly [60,63,72,89], Propofol features favorable pharmacokinetics but no including its use in coronary artery bypass grafting, where it analgesia; painful procedures therefore require aggressive continues to be favored by some cardiothoracic surgeons dosing to bring about comparatively deeper sedation, which [53]. However, whereas the stimulation of cardiac output is exposes the patient to its potent vasodilatory and respi- an advantage in the hypotensive patient, the resulting ratory depressant properties that may become clinically increase in myocardial oxygen demand can be consequential significant in longer procedures [151-155]. Propofol's [167], and in patients known for or at risk for coronary artery fleeting duration of action does reduce the risk of adverse disease, caution is prudent. Ketamine's cardiostimulatory events [156,157], and propofol produces a high degree of effect is blunted by pharmacologic sympatholysis; drugs muscle relaxation which is advantageous in orthopedic in the benzodiazepine, opioid, and β-adrenergic antagonist reductions [158]. Etomidate is rapidly metabolized and class have been proven effective in this regard. A practical provides unmatched hemodynamic neutrality but also lacks approach is to carefully monitor rate-pressure product in analgesic efficacy and may cause respiratory depression patients with risk factors and, in the event of a concerning [150,159,160]. Its use in procedural sedation is complicated rise, give small doses of midazolam or fentanyl to effect. by a relatively high incidence of vomiting and disruptive The patient with known severe atherosclerotic heart myoclonus [159,161-165]. disease may not be an appropriate candidate for ketamine Ketamine effectively provides anesthesia for procedural or any procedural sedation, depending on the urgency of sedation and protects patient safety. It is alone in its the procedure. predictable effect when administered by the intramuscular The use of ketamine for procedural sedation is most likely route, with peak levels occurring in 4 to 6 minutes and to be complicated by psychological emergence reactions. when given intravenously causes dissociation within 1 to 2 Most unpremedicated patients experience dreams or hallu- minutes. Its duration of action is 20 to 40 minutes cinations that may be perceived as odd or enjoyable; indeed intramuscularly and 10 to 15 minutes intravenously, an ketamine is used recreationally for this purpose. As patients advantage when compared to fentanyl/midazolam [48,166]. reintegrate external stimuli, 10% to 20% of patients, Although recovery time is longer than with propofol or however, go through frightening depersonalization. etomidate, ketamine offers analgesia that outlasts sedation Although not dangerous, such experiences can be associated —a benefit in the patient who is expected to have with considerable distress. They are readily managed with postprocedure pain [126]. Ketamine has a number of benzodiazepines, and their occurrence can be reduced with unique adverse effects, however, that must be anticipated environmental techniques such as the provision of music or a by providers. quiet recovery area. Although this may not be feasible in Airway and breathing are rarely compromised when emergency settings, patients can be coached preinduction to ketamine is used as monotherapy. Every day thousands of great effect. We find explaining the likelihood of dreaming, patients undergo operations facilitated by ketamine in and offering to the patient that they may choose their dream, comparatively spartan settings with minimal monitoring at if desired, requires little time and produces satisfying results. the hands of a single operator who performs the procedure Several pharmacological approaches to ketamine's poten- and the anesthesia [53,134]. That so few adverse events tial to cause psychiatric adverse effects are acceptable. result from this practice attests to ketamine's cardiore- Predissociation strategy. Administration of a sedative spiratory dependability; however, the potential for respira- (most often a benzodiazepine, but propofol shows promise in tory depression and airway malpositioning is well this role [28]) before or with ketamine reliably reduces the documented. As apnea appears to be more likely with incidence of emergence reactions, in some cases to zero large intravenous bolus doses administered rapidly, keta- [61,70,97]. Respiratory depression is increased and recovery mine should be dosed according to ideal body weight and prolonged in a dose-dependent manner. In a study by infused for 1 to 2 minutes. Chudnofsky et al [27], 70 ED patients received intravenous Continuous hemodynamic monitoring including pulse midazolam, 0.07 mg/kg, a relatively high dose, which led to oximetry is the standard of care for procedural sedation 99% patient satisfaction but produced 3 instances of where such equipment is available. The emergency physician respiratory depression, 2 of which required BVM ventilation. 1024 R.J. Strayer, L.S. Nelson

Preemergence strategy. Adverse psychiatric events The strength of a meta-analysis corresponds to both the occur in the recovery period, therefore the administration strength of its component studies and on the ability of a of a sedative shortly before emergence results in their reviewer to combine the results of the component studies, abolition with efficacy equal to a predissociation strategy which in turn is dependent on the similarity of their methods [108]. The advantage of this approach is that the peak effect [176]. In the present review, we sought to collect all studies of the sedative corresponds to the vulnerable period in the pertinent to emergency medicine practice. These articles patient's recovery, so a smaller sedative dose can be used. range from surveys of developing-world physicians to case However, most procedural sedation adverse events occur in reports to sophisticated blinded experiments in tightly first minutes after drug administration [147], and if a sedative controlled operating room settings. Patient populations, is to be given routinely, it may be preferable for its peak provider characteristics, dosing, and comedication regimens effect to occur when multiple providers are at the bedside. were far too varied for quantitative combination. We PRN strategy. This is the approach of choice in the therefore performed a narrative review, which presents a pediatric population, where prophylactic sedation confers complete survey of the literature with results not numerically no benefit [13,168]. It is a sensible option in adults, who pooled but reported as structured abstracts with a holistic are more prone to adverse psychiatric events, as long as it analysis [175]. This type of methodology is subject to a is combined with preinduction counseling and attentive variety of weaknesses [32,177]; however, given ketamine's surveillance for signs of psychiatric discomfort, which low adverse event rate, a prospective trial of sufficient size to should be managed with prompt administration of a potent, assess safety is unlikely to be performed, and we felt a titratable sedative (eg, midazolam). This strategy mini- qualitative review offered the best means to answer our mizes the risk of respiratory depression and will shorten research question. the time to recovery in most patients who will not require In attempting to select studies relevant to procedural sedative cotherapy. sedation in the ED from thousands of articles published Regardless of the strategy chosen, the provider must be primarily in the anesthesia literature, we defined a set of vigilant in recognizing and treating emergence reactions at exclusion criteria that are imperfect both in their efficacy their first appearance, as the transition to conscious and in their application. For example, we excluded studies perception can be terrifying [169]. on intubated patients and studies that used continuous The development of a severe emergence reaction is a cotherapies to supplement ketamine anesthesia. Although traumatic experience for an entire ED. Still, the possibility of the presence of an endotracheal tube precludes airway and such an event should not drive decisions to use ketamine for breathing adverse event reporting, this criterion also procedural sedation on adult patients, as proficient applica- excludes valid data on emergence reactions; furthermore, tion will preclude their occurrence. Furthermore, providers some studies do not indicate whether patients were who dismiss ketamine for procedural sedation may overlook intubated for the procedure. Reviewing articles from it in situations of greater urgency, where its unique decades past presented additional obstacles in applying pharmacology may be of particular benefit and psychiatric exclusion criteria, as many abstracts are not available in adverse effects are of little concern. Such situations include their referring databases and methods sections are of therapy for severe asthma [170], RSI in hemodynamically inconsistent quality. tenuous conditions and management of the uncontrollably Lastly, although we formulated strict adverse event violent patient [117]. definitions a priori, our efforts to systematically account for Finally, studies unambiguously indicate that (S)+ketamine, such events were confounded by the nebulous nature of an or esketamine, offers higher potency, shorter duration of adverse event itself. A clinically significant adverse event action, and fewer adverse effects—including a marked occurs when the patient has obvious harm, or the provider reduction in emergence reactions—compared to the racemic must perform an important therapeutic maneuver but what mixture [50,171-174]. The isomeric preparation is available in counts as important is difficult to define. For example, most Europe and deserves further study in the ED setting. procedural sedation literature considers BVM ventilation an important therapeutic maneuver, but it is unclear how many episodes of respiratory depression treated with BVM ventilation would have resolved uneventfully without 6. Limitations intervention. One study of 8000 patients in a tropical single-provider environment reported minimal adverse Literature reviews are nonexperimental and do not events [134] while in an anesthesiologist-controlled modern produce new data. Their purpose is to group existing data operating room; of 76 patients who were given a similar with the expectation that the weight of the aggregate will medication regimen, 2 required endotracheal intubation for provide more explanatory power than the component studies apnea [105]. This provocative discrepancy may be because provide individually. A quantitative systematic review, also of underreporting of adverse events in the larger study, but known as a meta-analysis, pools data from disparate studies another explanation is that the incidence of reported adverse using statistical methods to generate a larger dataset [175]. events depends not only on patient or drug characteristics Adverse events associated with ketamine for procedural sedation in adults 1025 but on how assiduously such events were sought and how double-blind, placebo-controlled trial. Ann Emerg Med 2000;35: much deviation from normal physiology was tolerated 229-38. [13] Wathen JE, Roback MG, Mackenzie T, Bothner JP. Does midazolam before an intervention performed. Because the therapeutic alter the clinical effects of intravenous ketamine sedation in children? maneuvers themselves are associated with risk, it is possible A double-blind, randomized, controlled, emergency department trial. that when administering a very safe drug, more advanced Ann Emerg Med 2000;36:579-88. monitoring techniques might actually cause more harm than [14] Ng KC, Ang SY. Sedation with ketamine for paediatric procedures in they prevent. the emergency department-a review of 500 cases. Singapore Med J 2002;43:300-4. [15] Ip U, Saincher A. Safety of pediatric procedural sedation in a Canadian emergency department. Can J Emerg Med 2000;2:15-20. [16] McCarty EC, Mencio GA, Walker LA, Green NE. Ketamine sedation 7. Conclusion for the reduction of children's fractures in the emergency department. J Bone Joint Surg Am 2000;82-A:912-8. When ketamine is used for procedural sedation in adults, [17] Petrack EM, Marx CM, Wright MS. 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