Uncommon ophthalmologic disorders in intensive care unit patients

Journal of Critical Care (2012) 27, 746.e9–746.e22

Uncommon ophthalmologic disorders in intensive care unit patients☆ Andre Grixti MD a,⁎, Maziar Sadri MD, MRCS, DOHNS, FRCA primary b , Amit Vikram Datta MS (ophthalmol), FRCSEd, FRCOphth c a

Department of Ophthalmology, Arrowe Park Hospital, Arrowe Park Rd, Upton, Wirral, CH49 5PE, UK Department of Anaesthesia Cambridge University Hospital, Cambridge, UK c Department of Ophthalmology, Hairmyres Hospital, East Kilbride, Glasgow, UK b

Keywords: Intensive care unit (ICU); Ophthalmologic disorders; Eye disorders; Eye care

Abstract Ophthalmologic complications are frequently encountered in intensive care unit (ICU) patients (Grixti et al. Ocul Surf 2012;10(1):26–42). However, eye care is often overlooked in the critical care setting or just limited to the ocular surface because treatment is focussed on the management of organ failures. Lack of awareness about other less common intraocular sight-threatening conditions may have a devastating effect on the patient's vision. To identify specific, frequently missed uncommon ocular disorders in ICU, a literature review using the keywords “Intensive Care,” “Eye care,” “ITU,” “ICU,” “Ophthalmological disorders,” “Eye disorders” was performed. The databases of CINAHL, PuBMed, EMBASE, and Cochrane library were searched. The higher quality studies are summarized in the table with statements of methodology to clarify the level of evidence. The most prevalent ophthalmologic disorders identified in critically ill subjects include exposure keratopathy, chemosis, and microbial keratitis. In addition, uncommon eye disorders reported in ICU include metastatic endogenous endophthalmitis, acute primary angle closure, ischemic optic neuropathy, pupil abnormalities, vascular occlusions, and rhino-orbital cerebral mucormycosis. Early diagnosis and effective treatment will help to prevent visual loss. © 2012 Elsevier Inc. All rights reserved.

Abbreviations: ICU, intensive care unit; CASP, critical appraisal

skills programme; APAC, acute primary angle closure; IOP, intraocular pressure; NMB, neuromuscular blockers; CNS, central nervous system; CRAO, central retinal artery occlusion; CRVO, central retinal vein occlusion; ION, ischemic optic neuropathy; AION, anterior ischemic optic neuropathy; PION, posterior ischemic optic neuropathy; RAPD, relative afferent pupillary defect; EPD, efferent pupillary defect; ROCM, rhino-orbital cerebral mucormycosis.

☆ The authors declare that they have no competing interests or financial support. ⁎ Corresponding author. Tel.: +44 7783974823. E-mail address: [email protected] (A. Grixti).

0883-9441/$ – see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jcrc.2012.07.013

1. Introduction Patients in the intensive care unit (ICU) have impaired systemic and ocular protective mechanisms as a result of metabolic derangements and multiple-organ dysfunction. Such patients are at an increased risk for ophthalmologic complications, which may result in serious visual impairment. Because sedated ICU patients are unable to convey ophthalmologic complaints, lack of awareness of the risk of injury and failure of regular ocular screening by ICU staff mean that ophthalmologic disorders may go unrecognized.

746.e10 The most common ocular disorders identified in ICU patients include exposure keratopathy (3.6%-60%), chemosis (9%-80%), and microbial keratitis [1]. The variation in the reported incidence for exposure keratopathy resulted from different assessment methods for corneal pathology [1]. Several treatment protocols and algorithms have been proposed to facilitate the management of these disorders in critically ill subjects. However, comparatively little research has been conducted on other less common ocular pathologies in ICU, which may have a devastating effect on the patient's vision. These include metastatic endogenous endophthalmitis, acute primary angle closure (APAC), ischemic optic neuropathy (ION), pupil abnormalities, vascular occlusions, and rhino-orbital cerebral mucormycosis (ROCM). In this article, we discuss these less known ophthalmologic complications encountered in the intensive care setting, to raise awareness on this subject among intensivists and ophthalmologists.

2. Methods of literature search A literature search was performed using the keywords “Intensive Care,” “Eye care,” “ICU,” “ophthalmologic disorders,” and “Eye disorders.” The databases of CINAHL, PuBMed, EMBASE, and COCHRANE library were all used in the initial search. A total of 714 hits were provided through the search engines. The abstracts of these articles were reviewed by the authors separately, and 171 articles were considered relevant to the topic. Of the 171 selected articles, 103 articles focused on common conditions and did not meet the criteria for inclusion. The remaining 68 articles consisted of case reports or studies on uncommon ophthalmologic conditions encountered in the intensive care setting and were therefore included in this review. A manual search was then performed on the reference list of all initially identified articles. The studies included in this review were conducted at different times, so the parameters and methods used changed over time. Therefore, there was a significant heterogeneity and lack of the raw data in the articles, which made it impossible to perform a meta-analysis. However, we identified the better quality studies, that is, those with a higher level of evidence, with acceptable methodology according to the guidance provided by the Critical Appraisal Skills Programme. Most articles (41%) focus on endogenous fungal endophthalmitis. The major studies have been summarized in the table with their main conclusions. On the other hand, only a cluster of studies or case reports have been identified on APAC (19%), ION (23%), pupil disorders (6%), vascular occlusions (7%), and ROCM (4%) and are mentioned in the text.

A. Grixti et al.

3. Uncommon ophthalmologic disorders occurring in the ICU setting 3.1. Metastatic endogenous endophthalmitis Endogenous endophthalmitis is a sight-threatening infection of the intraocular structures secondary to hematogenous spread of bacterial or fungal agents to the choroid and the vitreous cavity from a remote primary septic focus [2-4]. 3.1.1. Endogenous fungal endophthalmitis Candida albicans is the most virulent yeast species responsible for this condition [2,5-7]. Other pathogenic candida species include Candida tropicalis, Candida parapsilosis, and Candida glabrata [8]. In ICU, endogenous candida endophthalmitis has become the most important cause of blood-borne nosocomial infections, which has surpassed bacterial aetiologies, contributing significantly to mortality and prolonged hospital stay [2,5,9-13]. 3.1.1.1. Prevalence. The incidence of ocular candidiasis in patients with candidemia may range from 0 up to 50% [5,6,8-11,14-23]. This variation may be related to differences in the criteria and methods of ophthalmologic examination, the retrospective nature of some reports, and relatively small samples of patients studied. The major studies on endogenous fungal endophthalmitis have been summarised in Table 1. Some of these studies mainly evaluate the prevalence of hematogenous candida endophthalmitis in hospitalized patients. However, because systemic fungemia normally happens in the critically ill population, classification of these studies in the same table seemed logical by the reviewers. 3.1.1.2. Pathogenesis. The most common predisposing factors identified by Edwards et al [13] include the use of multiple antibiotics (84%), surgery (63%), immunosuppression (54%), indwelling intravenous catheters that provide portals of entry for microorganisms (46%), malignancy (21%), diabetes (13%), liver disease (8%), and alcoholism (8%). These findings correlate with those of other studies [5,6,8-10,15-18,23-26] (Table 1). Similar risk factors have been described for hematogenous bacterial endophthalmitis [3,27-29]. The common association between ocular candidiasis and systemic antibiotics was attributed to an overgrowth of candida in the gastrointestinal tract, followed by increased episodes of candidemia, particularly during abdominal surgery [13,26]. A significant correlation was also observed between genitourinary candidiasis and ocular involvement [30]. 3.1.1.3. Clinical features and diagnosis. Hematogenous dissemination of candida to the eye can produce a focal or multifocal chorioretinitis that can spread to the vitreous, resulting in an endophthalmitis [2,5,8]. Candida chorioretinitis is distinguished by the presence of focal, deep, creamy white chorioretinal lesions without evidence of direct vitreous involvement. On the other hand, candida

Uncommon ophthalmologic disorders in ICU patients endophthalmitis is characterized by chorioretinitis with accompanying vitritis and intravitreal floating “cotton-ball” colonies [5,10,29]. Nonspecific fundus lesions include nerve fiber layer infarcts, intraretinal hemorrhages, cotton wool spots, and white-centered hemorrhages (Roth spots). Such lesions have other etiologies other than candidemia, including vascular nonperfusion, hypertension, diabetes mellitus, anemia, collagen vascular disorders, lymphoproliferative states, and hematogenously disseminated infections such as bacterial endocarditis, which are seen frequently among critically ill patients [4,5,12]. Less commonly, anterior uveitis, papillitis, scleritis, or panophthalmitis may be present [7,10,17]. Patients with endophthalmitis may experience floaters, ocular pain, and decreased vision [2]. However, in ICU, ocular lesions may go undetected due to inability of sedated subjects to express symptoms of visual loss [8,9]. Moreover, visual symptoms are uncommon in the presence of peripheral chorioretinal lesions without vitritis [4,8,9]. Candida endophthalmitis is an important marker of disseminated candidiasis [2,6,10,13]. Edwards et al [13] observed systemic candida infection in 78% of autopsy patients with ocular candidiasis. Similar high rates of deep organ involvement have been described in other postmortem studies [17,24]. Microbiological investigations are often time consuming, and blood culture results may be negative, despite the presence of disseminated candida infection [8,10]. Studies documented positive blood culture results in only 18% to 53.8% of cases with hematogenous fungal or candida endophthalmitis [10,13,15,17,26]. Early detection of ocular lesions by dilated indirect ophthalmoscopy in high-risk patients with suspected candidemia may be critical for prompt diagnosis and treatment of this systemic illness in the absence of positive clinical and laboratory parameters [2,5,6,8-12,17,24]. Hence, the presence of these criteria should alert the ICU physician to the possibility of candida endophthalmitis and should seek ophthalmologic advice. 3.1.1.4. Treatment. Although occasional reports [22,31,32] described spontaneous resolution of candida endophthalmitis, untreated, this condition may progress rapidly with resultant retinal necrosis, retinal detachment, and permanent visual loss [4,9,16]. Treatment includes the following: (1) Systemic antifungal therapy with amphotericin B or fluconazole, in the presence of disseminated candidiasis and ocular disease without vitreous involvement. (2) Intravitreal injection of amphotericin B or newer broad-spectrum antifungal agents such as voriconazole, with or without pars plana vitrectomy in the presence of chorioretinitis with accompanying vitritis [4,5,8,33]. Studies reported resolution of fungal endophthalmitis in 53% to100% of subjects treated with systemic amphotericin

746.e11 B alone or in combination with other antimycotic agents [5,12,13,15,18,22,24,25]. However, amphotericin B has particularly toxic adverse effects and achieves poor concentrations in the vitreous compared with fluconazole [33]. Complete resolution of candida endophthalmitis with intravenous fluconazole has been documented [34]. However, clinical trials that evaluate the effectiveness of fluconazole in candida endophthalmitis are limited in the literature. A randomized control trial conducted by Rex et al [20] identified no significant difference in outcome between fluconazole and amphotericin B for the treatment of candidemia or candida endophthalmitis. A number of studies reported continued progression [5,20,26] and development of new lesions despite antifungal therapy [12,17,33]. Monitoring of the lesions during treatment through periodic indirect ophthalmologic examinations is advocated so that more aggressive therapy can be initiated in the event of continued deterioration [6,9,25]. 3.1.1.5. Prognosis. Candida endophthalmitis indicates a poor prognosis and high mortality in patients with candidemia [2,10]. There is a paucity of reports that have specifically evaluated the mortality of patients with candida endophthalmitis, ranging from 0 to 80% [6,9,10,13,25,26,35,36]. These reviewers attribute the higher mortality rates in earlier studies to confounding factors such as lack of newly manufactured drugs and lower standards of ICU care. 3.1.2. Endogenous bacterial endophthalmitis 3.1.2.1. Prevalence. With the continued development of newer, more efficacious antibiotics, endogenous bacterial endophthalmitis has become increasingly rare, accounting for only 2% to 11% of all cases of endophthalmitis [3,12,27,29]. However, it remains a potentially devastating condition leading to visual loss in 50% of all affected subjects [3,27]. 3.1.2.2. Pathogenesis. A wide variety of pathogens have been described to cause intraocular infection [3,4,28,37]. In 1977, Shammas [38] recognized Neisseria meningitides along with Streptoccus pneumoniae as the most prevalent microorganisms responsible for infection before 1976. Subsequently, in 1986, Greenwald et al [27] observed a change in the spectrum of causative organisms, with displacement of meningococcus by Bacillus cereus, especially among intravenous drug abusers. Gram-positive bacteria are the most common causative agents, accounting for 71% up to 92% of cases studied [29,39]. Pseudomonas aeruginosa is becoming increasingly recognized as an important pathogen, particularly within the intensive care population and in neonates [3,28,40,41]. It is an exceptionally virulent organism that may run a fulminant course, progressing to rapid visual loss [3,28]. Recent reports also identified Klebsiella pneumonia as another common pathogenic agent [41]. Immunosuppression and chronic medical conditions are significant predisposing factors to infection [3,27], particularly

A summary of the studies on metastatic endogenous fungal endophthalmitis

Author

Year

Method/Design

Sample description

Results and prevalence rates

Comments/Conclusion

Griffin et al [24]

1973

Part 1: retrospective case series Part 2: prospective cohort

21 cases of hematogenous candida endophthalmitis (HCE) in hospitalized patients with candidemia Part 1: 6 clinical cases Part 2: 15 postmortem cases

Intraocular candida lesions are a strong indication of disseminated candidasis. Chorioretinal lesions without vitreous invasion are highly sensitive to early treatment with amphotericin B.

Henderson et al [15]

1981

Prospective cohort

131 postoperative patients in a surgical ICU receiving total parenteral nutrition (TPN)

Part 1: predisposing factors - Recent surgery (6/6) - IV catheters (6/6) - Systemic antibiotic therapy (6/6) - C albicans infection (6/6) - Positive blood culture result (5/6) Findings: complete resolution of focal chorioretinal lesions with amphotericin B Part 2: risk factors - IV catheterization (15/15) - Intensive antibiotic therapy (15/15) - Gastrointestinal disease (9/15) - Recent bacterial sepsis (11/15) Findings: 13/15 cases with HCE also had deep organ involvement 9.9% (13/131) of subjects developed chorioretinal lesions compatible with HCE (group 1) 118/131 patients had no ocular involvement (Group 2) Risk factors for HCE - Positive blood culture results for candida—group 1: 53.8% (7/13) vs group 2: 1.7% (2/118) (P b .0005) - Gastrointestinal hemorrhage— group 1: 84.6% (11/13) vs group 2: 8.4% (10/118) (P b .0005) - Central venous catheterization— group 1: 100% (13/13) vs group 2: 55.9% (66/118) (P b .0005) - Swan-Ganz catheter—group 1: 53.8% (7/13) vs group 2: 13.6% (16/118) (P b .0005) - Mucocutaneous candida infection— group 1: 69.2% (9/13) vs group 2: 16.1% (19/118) (P b .0005) Mortality was 53.8% (7/13) for group 1 vs 26.3% (31/118) for group 2 (P b .05, χ2 test)

746.e12

Table 1

There is a strong correlation between ocular candidiasis and the presence of positive blood culture results for candida, suggestive of invasive candidiasis.

A. Grixti et al.

Prospective cohort

38 hospitalized patients with fungemia

McDonnell et al [17]

1984

Retrospective autopsy report review

133 autopsies in patients with invasive fungal infection

Brooks [9]

1989

Prospective cohort

32 hospitalized patients with candidemia

Schmid et al [25]

1991

Retrospective chart review

23 hospitalized patients with a presumptive diagnosis of HCE receiving antifungal treatment

C albicans sepsis was identified in 72% (27/38) of cases with fungemia. - 10/27 (37%) subjects with candidemia developed HCE (group 1) - 17/27 (63%) subjects with candidemia had no ocular involvement (group 2) A higher incidence of TPN and hemodialysis was observed in group 1 vs group 2 (50% vs 29.4% and 40% vs 11.8%, respectively); (P, NS) Candida antigenemia by latex agglutination was positive in 3 of 4 patients in group 1 who had negative antibody serology results. Ocular involvement was identified in 10% (14/133) of subjects with fungal infection. - 11.7% (11/94) with Candida - 8.3% (2/26) with Aspergillus - 7.7% (1/14) with Cryptococccus Ocular involvement occurred in 22.7% (5/22) of subjects with Candida tropicalis vs 6.3% (3/48) with C albicans infection (P b .01). Patients with ocular lesions had more widely disseminated systemic organ involvement (mean, 7 organs) than did patients without ocular involvement (mean, 2 organs). Candida chorioretinitis compatible with HCE was identified in 28% (9/32) of subjects. Patients with HCE had more positive blood culture results for candida (mean, 4.3) than did patients without ocular involvement (mean, 2.8). However, this trend did not reach statistical significance (P = .1, 2-tailed t test with unequal variance). Risk factors for HCE - IV drug abuse (11/23) - Surgical patients with indwelling catheters (7/23) Response to antifungal treatment

Antigen titers may be more sensitive than antibody titers in detecting disseminated candidiasis. TPN and hemodialysis are associated with a greater risk of HCE.

Ocular lesions consistent with fungal disease are strong indicators of systemic fungal infection.

Periodic ophthalmologic examinations are recommended in all subjects with candidemia. Reviewers' note: The prevalence of HCE quoted in the article is the cumulative prevalence of chorioretinitis with and without vitreous involvement.

A combination of amphotericin B and flucytosine is recommended as the treatment of choice for HCE. Reviewers' note: The authors have not performed a statistical analysis (continued on next page)

746.e13

1981

Uncommon ophthalmologic disorders in ICU patients

Parke et al [16]

Author

Year

Method/Design

Sample description

Menezes et al [10]

1994

Retrospective chart review

13 hospitalized patients with HCE

Donahue et al [5]

1994

Prospective multicentered observational study

118 hospitalized patients with candidemia

Results and prevalence rates

Comments/Conclusion

(IV amphotericin B, average cumulative dose 1580 mg, and IC or oral flucytosine, mean cumulative dose 231 g) - 20/23 had regression of inflammatory lesions and 19/23 showed improvement in visual acuity - 3/23 developed new lesions Candida endophthalmitis was identified in 17% (13/76) of hospitalized patients with suspected systemic candidiasis. Risk factors for HCE - Multiple antibiotics: 92% (12/13) - ICU subjects: 77% (10/13) - Positive blood culture results for candida: 46% (6/13) - Positive candida culture results from any site: 92% (12/13). The mortality rate for subjects with HCE was 77% (10/13) for hospitalized patients and 80% (8/10) for ICU patients. This rate was higher than the overall mortality for all subjects in ICU (17%) and ICU patients with candidemia (61%). 11/118 (9.3%) subjects developed candida chorioretinitis, all of whom received amphotericin B None (0%) of the subjects on antifungal therapy progressed to Candida endophthalmitis. Risk factors for candida chorioretinitis - Fungemia with C albicans species (P b .051) - Immunosuppression (P = .016) - Multiple positive blood culture results (P = .002, Fisher exact test) - Visual symptoms (P b .01, Fisher exact test) Multiple positive blood culture results were present in 100% (11/11)

to prove the efficacy of treatment. However, the rate of clinical and pathological improvement is so high that it would be unlikely that such results are not statistically significant.

746.e14

Table 1 (continued)

Candida endophthalmitis in critically ill patients is an indicator of a poor prognosis and higher mortality.

Ophthalmologic examination is recommended in subjects with candidemia who have positive risk factors for candida chorioretinitis. Reviewers' note: The low prevalence of endophthalmitis (0%) is explained by the use of a classification system that does not account chorioretinitis as a type of endophthalmitis.

A. Grixti et al.

1995

Prospective cohort

41 postoperative subjects with clinical evidence of septicemia

Nolla-Salas et al [6]

1996

Prospective cohort

46 nonneutropenic ICU patients with candidemia

HCE is the only evidence of disseminated candidasis that can be detected without invasive measures. Fundoscopy is important for early detection of postoperative candida-induced septicemia.

Uncommon ophthalmologic disorders in ICU patients

Rantala and VaahtorantaLehtonen [23]

with candida chorioretinitis, 63% (15/24) with nonspecific lesions, and 51% (42/83) with normal fundi (P = .007, χ2 test). Group 1:10/41 subjects with HCE Group 2: 31/41 subjects without HCE Overall, candidemia was present in 1 8/41 subjects and 9/10 patients in group 1. Therefore, 50% (9/18) of subjects with candidemia developed ocular candidiasis. Risk factors for HCE (group 1 vs group 2) - Broad spectrum antibiotics for N1 week (90% vs 45%; P b .05, Fisher exact test) - Central venous catheterization (80% vs 71%) - Parenteral nutrition (70% vs 55%) - Surgery of the pancreas and small intestine (50% vs 39%) A mortality rate of 50% and multiorgan failure was observed in group 1. HCE was present in 13% (6/46) of ICU subjects with candidemia. C albicans was identified in 5/6 subjects with HCE. Risk factors for HCE - Prolonged antibiotic therapy - TPN - Underlying surgical conditions The overall mortality rate was 66.7% in patients with HCE and 55% in subjects without ocular involvement (P, NS, Fisher exact test).

A high mortality is present in ICU subjects with candidemia. Regular ophthalmologic examination is advocated in this population. Reviewers' note (1): The authors tried to assess the efficacy of parenteral fluconazole in the treatment of HCE. However, due to a small sample size, the results were not considered to be conclusive. Reviewers' note (2): No statistical test was conducted to show the significance of the risk factors.

746.e15

(continued on next page)

Author

Year

Method/Design

Sample description

Results and prevalence rates

Comments/Conclusion

Krishna et al [18]

2000

Prospective cohort

31 patients with candidemia

A 2-wk ophthalmology follow-up is recommended in all candidemic subjects with an initial negative ocular examination. Reviewers' note: Only 12/23 patients in Group 2 had a follow-up after 2 weeks. Therefore, the above statement is not accurate and the rest of the group with insufficient follow-up might have developed ocular candidiasis which may have been overlooked. This makes the sample size too small to make a robust decision about the length of follow-up.

Feman et al [19]

2002

Prospective cohort

82 hospitalized patients with a positive systemic fungal culture result

Rodriguez-Adrian et al [12]

2003

Prospective cohort

Part 1: 77 ICU patients over a 12-mo period.

Candida chorioretinitis was present in 26% (8/31) of subjects with candidemia (group 1), and 23/31 subjects had no ocular involvement (group 2). No patient developed endophthalmitis. During follow-up of group 1, ocular candidiasis was diagnosed in the following: - 5/8 subjects on initial examination - 1/8 subjects within 1 wk - 2/8 subjects within 2 wk No evidence of ocular involvement occurred in 12 subjects of group 2 followed up between 4 and 24 wk Kaplan-Meier analysis revealed that 70% of patients with candidemia will remain free of ocular candidiasis after 2 wk of follow-up. Chorioretinitis was diagnosed in 2.4% (2/82) of patients with disseminated fungal disease. Both cases progressed to fungal endophthalmitis. Part 1: 19% (15/77) had nonspecific retinal lesions consistent with disseminated bacterial or candidal infection (DBCI)

Part 2: 180 nonneutropenic patients with candidemia

The low frequency of fungal endophthalmitis was attributed to earlier diagnosis and treatment of fungal sepsis with prophylactic antifungal agents. Nonspecific retinal lesions are seen frequently among ICU patients and are often related to underlying systemic disease. Therefore, ophthalmologic examination should be limited to patients with known fungal sepsis.

A. Grixti et al.

- Only 1/15 had clear-cut sepsis-related retinal lesions. - 87% (13/15) had ≥1 systemic disease that could explain retinal findings With analysis of variance, the following variables correlated with the presence of retinal lesions: - Systemic disease (odds ratio [OR], 8.37; 95% confidence

746.e16

Table 1 (continued)

Kannangara et al [11]

2007

Prospective Cohort

46 hospitalized patients with candidemia

Mehta et al [8]

2007

Retrospective chart review

12 ICU patients with candida-induced sepsis

- 15% (27/180) of candidemic subjects had retinal lesions - 1% (2/180) had vitreous involvement - 2.7% (5/180) developed chorioretinal lesions without vitreal extension - 1% (2/180) developed Roth spots - 10% (18/180) had retinal hemorrhages or cotton wool spots that could have been due to either DBCI or systemic disease Candida chorioretinitis was documented in 2.2% (1/46) of subjects. This single case was due to C albicans infection. Ocular lesions were identified in 50% (6/12) of subjects - Chorioretinitis was present in 7/12 eyes of 6 patients. - Roth spots were seen in 1/12 eyes. - None developed vitritis or endophthalmitis. Predisposing factors for ocular involvement - Diabetes mellitus: 50% (3/6) - Systemic immunosuppression: 50% (3/6)

The low rate of vitreal extension from chorioretinal lesions is due to the high rate of empirical use of antifungal agents in this high-risk population.

Reviewers' note: Sample size includes hospitalized but not exclusively ICU subjects. Therefore, the frequency identified in this study cannot be generalized to ICU. Early ophthalmologic examination is recommended in subjects with suspected invasive candidiasis. Immunosuppression and diabetes mellitus increase the risk of fungemia and ocular involvement.

Uncommon ophthalmologic disorders in ICU patients

intervals [CI]:3.24-21.56) - Female gender (OR, 6.47; 95% CI, 4.36-9.59) - Hemodialysis (OR, 3.29; 95% CI, 1.51-7.18) DBCI had no significant correlation with retinal lesions. Part 2:

NS indicates not significant; IV, intravenous.

746.e17

746.e18 diabetes mellitus, malignancy, endocarditis, and gastrointestinal tract infection [29,39,41]. 3.1.2.3. Clinical features and diagnosis. Visual symptoms are similar to fungal endophthalmitis. In severe cases, anterior fibrinous uveitis with hypopyon, corneal edema, iris nodules or plaques, distorted pupil, chemosis, and lid swelling may be present in the anterior segment, which should prompt ophthalmology consultation [4]. Greenwald et al [27] devised a classification of the type of metastatic bacterial endophthalmitis by location. A distinction was made between “posterior focal” and “posterior diffuse” endophthalmitis on the basis of vitreal involvement. These terms correlate well with those described earlier for candida chorioretinitis and candida endophthalmitis. Focal endophthalmitis had a good prognosis, whereas posterior diffuse cases nearly always progressed to blindness [27]. The etiologic agent in metastatic bacterial endophthalmitis can be identified reliably by positive blood culture result in 71% [27] to 72% [29] of affected subjects compared with 73.9% of vitreous cultures [29]. Vitreous aspiration may be reserved for cases in which other culture specimens are negative or in the absence of improvement on treatment [27]. 3.1.2.4. Treatment and prognosis. In contrast to exogenous endophthalmitis, systemic antibiotic therapy directed against the primary focus of infection is essential in endogenous endophthalmitis because bacteria must first cross the blood ocular barrier to cause infection [27,29]. Greenwald et al [27] stated that intravitreal antibiotics combined with vitrectomy should be reserved for cases with posterior diffuse endophthalmitis. However, a significant improvement in visual acuity was observed in subjects who received a combination of intravenous and intravitreal antibiotics with conservative use of vitrectomy, initiated early in the course of infection [29,39,42]. Mortality rates of 7% to 14% were reported as a result of complications of sepsis [27,29]. Thus, a thorough ophthalmologic and general physical examination is imperative in sedated intensive care patients who have sepsis along with signs of ocular infection.

3.2. Acute primary angle closure previously known as acute glaucoma Acute primary angle closure is a sight-threatening emergency caused by sudden elevation of the intraocular pressure (IOP) secondary to pupil block [2,43,44]. Systemic anticholinergic agents commonly used in ICU such as ipatropium bromide, chlorpromazine bromide, amitriptyline, thioridazine, and cyclizine increase dilatation of the pupil and may precipitate pupillary block [2,43-47]. Several studies recognized APAC as a complication of parenteral anticholinergic drugs used during general anesthesia [48-50]. In addition, nebulized sulbutamol, a β2-

A. Grixti et al. adrenoreceptor agonist to aid respiratory function, increases aqueous humour production and acts in synergy with ipatropium bromide to elevate the IOP [45-47,51-54]. Direct inoculation of the aerosolized drugs in the conjunctival sac could be responsible for the ocular effect of these agents [53]. Proper fitting of the face mask and use of protective eyewear may minimize ocular deposition of nebulized drugs [45,46,53,54]. Preventing simultaneous administration of nebulized β-adrenergic and anticholinergic agents [45,46,53] and pretreatment with topical miotics in subjects at risk of angle closure have been recommended [45,46,55]. Topiramate, an antiepileptic drug, can also induce APAC [2]. Evidence showed that preanesthetic use of intravenous atropine in healthy or glaucomatous patients does not increase IOP [56,57]. However, APAC precipitated by aerosolized atropine, in the management of chronic bronchitis, was described by Berdy et al [55]. In ICU, the presence of a red eye with corneal haze, shallow anterior chamber and a fixed mid-dilated pupil that does not react to light (directly or consensually) should raise a high index of suspicion for APAC. In conscious patients, this may be accompanied by severe pain, vomiting, and confusion. If suspected, ophthalmology advice should be sought urgently [43,44]. In addition, use of an ICare-type rebound tonometer (Tiolat Oy, Helsinki, Finland) to measure IOP by ICU staff may be a valuable asset in detecting APAC. This instrument is relatively easy to use and provides acceptable measurements of IOP in the hands of nonophthalmologists [58]. However, in ICU, the typical signs and symptoms of APAC such as pain, confusion, and vomiting may be wrongly attributed to other medical conditions, resulting in inappropriate pharmacologic treatment, which may protract the acute episode and delay correct diagnosis [47].

3.3. Pupil abnormalities The pupillary light reflex is primarily mediated by the parasympathetic system and contains several synapses. Retinal ganglion cells convey sensory information via the optic nerve to the pretectal nucleus. Each pretectal nucleus is then connected to both Edinger-Westphal nuclei by internuncial neurons. Subsequently, preganglionic motor neurons pass through the inferior division of the oculomotor nerve and synapse on the ciliary ganglion. Postganglionic motor neurons leave the ciliary ganglion via short ciliary nerves to innervate the sphincter pupillae [59]. Neuromuscular blockers (NMBs) commonly used in ICU have anticholinergic properties that can modulate the pupillary response to light by acting at these synapses [59]. In healthy subjects, an intact blood-brain barrier is impermeable to nondepolarizing NMB agents and prevents penetration of these drugs from the intravascular space to the neuromuscular junctions of the iris [59,60].

Uncommon ophthalmologic disorders in ICU patients This renders the pupillary pathway relatively resistant to metabolic insults [61]. However, in ICU, blood-brain barrier disruption secondary to sepsis, inflammation, oxidative stress, and head trauma, combined with prolonged high-dose administration of NMB agents, may result in central nervous system (CNS) concentrations that produce central effects. This interrupts cholinergic signal transduction resulting in mydriasis [60]. Therefore, CNS actions of NMB drugs should be considered in the differential diagnosis of dilated, nonreactive pupils, especially in ICU. Several other pharmacologic agents with systemic anticholinergic properties including tricyclic antidepressants, antiparkinson agents, and anticonvulsants, along with systemic sympathomimetic drugs such as highdose adrenaline, dopamine, cocaine, and amphetamines, may produce fixed dilated pupils in potentially reversible coma [61]. In contrast, bilateral fixed dilated pupils can be associated with significant CNS pathology [60]. Bilateral oculomotor nerve palsies may result from mechanical compression after uncal herniation through the tentorial notch. This may follow traumatic brain injury or space-occupying lesions due to cerebral edema [61,62]. Other causes include direct trauma to the third nerves, an epileptic seizure, aneurysmal compression, or brainstem ischemia such as infarcts involving the midbrain [2,61,62]. In such cases, imaging of the brain is recommended [2].

3.4. Ischemic optic neuropathy Ischemic optic neuropathy may be subdivided into anterior (AION) or posterior (PION). Anterior ION is caused by infarction of the optic nerve head resulting from occlusion of the short posterior ciliary arteries. Posterior ION is characterized by ischemia to the retrolaminar portion of the optic nerve, which is supplied by the surrounding pial capillary plexus [63,64]. Posterior ION is a rare but potentially serious complication of hypotensive episodes generally described intraoperatively or during critical illness [65,66]. Blood supply to the posterior optic nerve is almost entirely dependent on the pial vasculature, which explains its enhanced vulnerability to ischemia and watershed infarction [65]. Posterior ION is most commonly documented after prone positioning in spinal surgery (0.1%) and after jugular vein ligation in radical neck dissection (0.08%). The consequent elevation in central venous pressure and IOP further aggravate the effects of hypotension [65]. Similarly, systemic hypotension has been implicated in the pathogenesis of AION and progression of preexisting glaucomatous optic neuropathy by reducing optic nerve head perfusion [67,68]. Significant elevation in IOP may also have a deleterious effect on the optic nerve head circulation [69]. Thus, continuation of glaucoma medications during ICU stay should be emphasized.

746.e19 Cullinane et al [63] attributed 9 cases of AION after trauma to a compartment syndrome within the optic nerve canal. This developed secondary to a systemic inflammatory response and massive fluid resuscitation in ICU, with subsequent edema in the optic canal. High levels of ventilatory support required in adult respiratory distress syndrome may also increase the intrathoracic pressure and IOP, leading to optic nerve hypoperfusion [63,66,70]. Anemia combined with hypotension reduces oxygen delivery to the optic nerve, predisposing it to infarction [63,71]. Furthermore, hemodialysis may precipitate both PION and AION [65,72-75]. Protective measures include blood transfusion and supplemental oxygenation in the presence of anemia [63]. Hypovolemia stimulates renal activation of the renin-angiotensin system, resulting in high concentrations of angiotensin II and norepinephrine. The release of these vasoconstrictor agents into the choroid causes ischemia at the optic nerve head [76]. Ischemic optic neuropathy was also described in the ICU secondary to prolonged infusions of multiple vasopressors in the treatment of hypotension. These agents alter the optic nerve blood flow by causing vasoconstriction or vasospasm of the ophthalmic and ciliary arteries [66]. Impaired vasodilatation and increased response to vasoconstrictor substances were noted in atheromatous blood vessels [77-79]. A compromise between maintenance of vital bodily functions and preservation of vision is difficult to achieve in critically ill patients, and further research is recommended on this subject [66,70]. Other causes include hypothermia, which alters the coagulation cascade mechanisms, enhancing serum viscosity, leading to ischemia in the watershed regions of the optic nerve vascular supply [63]. Moreover, ION may occur in the presence of preexisting atheromatous vascular disease or giant cell arteritis when it is typically unilateral [65]. A relative afferent pupillary defect with (AION) or without (PION) optic disk edema and pallor should alert the ICU physician, and ophthalmologic advice should be obtained. In the conscious subject, this is accompanied by sudden painless loss of vision, visual field defects, and dyschromatopsia. Four to 8 weeks after onset, atrophy of the optic nerve head may be observed upon ophthalmoscopy [64]. Prognosis is relatively poor, with a final visual acuity of hand movements or worse in 55% of affected patients [65].

3.5. Retinal vascular occlusions Occlusions of the retinal arterial and venous circulations are commonly associated with systemic disorders such as cerebrovascular and cardiovascular disease, which predispose to significant morbidity and mortality [80-84]. Atherosclerosis, secondary to hypertension, diabetes mellitus, hypercholesterolemia, and smoking, is a major risk factor for thromboembolism and vascular obstruction, accounting for 80% of central retinal artery occlusions (CRAOs) [85]. Occlusion of the central retinal vein and its branches

746.e20 commonly occurs secondary to thrombus formation, as a result of compression by an adjacent thickened atherosclerotic retinal artery. Thrombophilic disorders such as hyperhomocysteinemia, antiphospholipid antibody syndrome, and inherited defects of natural anticoagulants also increase the risk for hypercoagulability, thrombosis, and retinal vascular occlusion [80,85]. Such conditions are common in the ICU. Presentation is often with sudden unilateral reduced vision or visual field loss. An afferent pupillary defect may be observed in CRAO or ischemic occlusion of the central retinal vein. However, diagnosis is difficult in unconscious subjects, and a high index of suspicion is required in the presence of a positive medical history [85]. If suspected, dilated fundoscopy may show flame-shaped and dot-blot hemorrhages, venous tortuosity, retinal edema, and, sometimes, cotton wool spots in venous occlusions. A cloudy white edematous retina corresponding to the area of ischemia (with a cherry red spot at the macula in CRAO), narrowing of the arteries, and emboli may be observed in arterial occlusion. An ophthalmology consultation should be requested, followed by appropriate systemic evaluation.

3.6. Rhino-orbital cerebral mucormycosis Rhino-orbital cerebral mucormycosis is a rare, lifethreatening opportunistic fungal infection caused by Mucor species or Rhizopus. It occurs in several immunocompromised states that are particularly common in critically ill patients [2,43,86]. It is most prevalent in diabetic patients who are also acidotic (diabetic ketoacidosis), which offers favorable conditions for fungal multiplication [2,86]. Studies reported diabetes in 50% to 81% of subjects with mucormycosis [86-88]. It also occurs in renal failure, malignancy, and therapeutic immunosuppression. It represents extensive fungal septic necrosis involving the nasal/ paranasal sinuses, orbit, and cerebral tissues as a result of the angioinvasive properties of mucorales, causing vascular occlusion and infarction [2,86]. The most commonly reported ophthalmologic features include ophthalmoplegia (67%-89%), proptosis (64%-83%), periorbital swelling (43%-66%), and ocular pain (11%-43%) [86,87]. Direct infiltration of the orbital tissues by the fungus may result in ischemic necrosis of the intraorbital cranial nerves or orbital cellulitis [2,86]. Visual loss most commonly due to CRAO was observed in 25% to 80% of the affected subjects [86-88]. Other causes for vision loss comprise cavernous sinus thrombosis, endophthalmitis, or orbital vascular involvement [2,86]. Diagnosis is made based on the clinical picture and histopathologic findings by direct microscopy or culture on Sabroud agar medium [2,86]. Imaging may be necessary to assess the extent of the disease [86]. Treatment with amphotericin B alone has a limited role because of impaired delivery to the site of infection as a result of vascular thrombosis [2,86]. Orbital involvement may require aggres-

A. Grixti et al. sive surgical debridement, including orbital exenteration, which can be lifesaving [2,43,86]. Bhansali et al [86] reported a higher survival rate of 68% in patients who received a combination of medical and surgical treatment. Late diagnosis and associated complications are the most important determinants influencing survival [2,43,86].

4. Conclusion A review of the current literature has shown that critically ill subjects are susceptible to a wide range of ophthalmologic complications. However, in the ICU setting, clinical prioritization with emphasis on the life rather than sightthreatening conditions may result in eye care being overlooked. Targeted training to ICU staff, in addition to further research studies, is necessary to raise awareness on this subject and develop a uniform evidence-based eye care protocol for ICU patients. Postrecovery visual loss can have a devastating effect on the quality of life of any patient who has recovered from prolonged intensive care therapy and may well be the greatest consequence of their period of illness. Therefore, eye care has to be one of the priorities even when the survival of the patient is at risk. In the following text box, we highlight useful learning points in the assessment of ocular disorders in ICU, which may provide practical help to the busy clinician in their decision to treat or to refer.

Key points • History ■ Acute visual loss? ■ Ocular pain? • Ophthalmologic examination ■ Reduced visual acuity? ■ Abnormal pupil reactions (relative afferent pupillary defect/efferent pupillary defect)? ■ Cornea stains with fluorescein? ■ Direct ophthalmoscopy ➢ Absent red reflex? ➢ Retinal hemorrhages/edema? ➢ Swollen optic disk? - Unilateral → AION - Bilateral → papilledema (urgent neuroimaging) Refer early to ophthalmology if any of the above clinical features are present. A red eye with normal pupils and no fluorescein staining may be treated with broad-spectrum topical antibiotic eye drops.

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Acknowledgments [21]

We would like to thank the medical librarians Ms Karen Watson and Ms Amanda Minns for the compilation of this research.

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